A cross-sector call to improve carcinogenicity risk assessment through use of genomic methodologies.
We present our shared vision for change from leading scientists from academic, government, nonprofit, and industrial sectors and chemical and pharmaceutical safety applications. This call to action builds upon a 2017 workshop on "Advances and Roadblocks for Use of Genomics in Cancer Risk Assessment." The authors propose a path for implementation of innovative cancer risk assessment including incorporating genomic signatures to assess mechanistic relevance of carcinogenicity and enhanced use of genomics in benchmark dose and point of departure evaluations. Novel opportunities for the chemical and pharmaceutical se...
Source: Regulatory Toxicology and Pharmacology : RTP - November 11, 2019 Category: Toxicology Authors: Yauk CL, Harrill AH, Ellinger-Ziegelbauer H, van der Laan JW, Moggs J, Froetschl R, Sistare F, Pettit S Tags: Regul Toxicol Pharmacol Source Type: research

A 26-week 20(S)-ginsenoside Rg3 oral toxicity study in Beagle dogs.
Abstract 20(s)-ginsenoside Rg3 is a red ginseng-derived compound with the formula C42H72O13 that has been increasingly used by humans, leading to safety concerns regarding this use. In the current study, we conducted a 26-week study during which 20(S)-ginsenoside Rg3 (0, 7, 20, or 60 mg/kg) was continuously administered orally to Beagle dogs in order to explore its toxicity in these animals, with control dogs receiving a vehicle capsule. In total, 10 dogs received each dose of this compound (n = 5 male, n = 5 female per dose). Animals were continuously monitored for a 26-week administration period and a ...
Source: Regulatory Toxicology and Pharmacology : RTP - November 11, 2019 Category: Toxicology Authors: Gao Y, Wang G, Wang T, Li G, Lin J, Sun L, Wu X, Sun X, Wang H, Li C, Tian J, Zhu J, Wang K, Cho S Tags: Regul Toxicol Pharmacol Source Type: research

Preclinical safety evaluation of triacylglycerol lipase QLM from Burkholderia ubonensis.
Abstract Triacylglycerol lipases are well characterized enzymes that catalyze the hydrolysis of fats. They are biotechnologically relevant enzymes and are used in a wide range of practical applications in industry. Lipase produced from Burkholderia ubonensis (strain PL266-643-301) (Lipase QLM) is being investigated for use as a processing aid in multiple food applications and may therefore be present at trace level in finished food products. A battery of toxicological studies was therefore conducted on Lipase QLM to support its safe use in food. Lipase QLM was not genotoxic or mutagenic in an in vitro bacterial re...
Source: Regulatory Toxicology and Pharmacology : RTP - November 11, 2019 Category: Toxicology Authors: Mak A, Simon RR Tags: Regul Toxicol Pharmacol Source Type: research

Toxicity of orange peel-originated hesperidin in Sprague Dawley rats.
PMID: 31715200 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - November 9, 2019 Category: Toxicology Authors: Wei L, Wang Y, Li H, Chang Y, Hong M Tags: Regul Toxicol Pharmacol Source Type: research

Acute and subacute (28 days) toxicity of green coffee oil enriched with diterpenes cafestol and kahweol in rats.
Abstract Green coffee oil enriched with cafestol and kahweol was obtained by supercritical fluid extraction using carbon dioxide while its safety and possible effects from acute and subacute treatment were evaluated in rats. For acute toxicity study, single dose of green coffee oil (2000 mg/kg) was administered by gavage in female rats. For subacute study (28 days), 32 male rats received different doses of green coffee oil extract (25, 50, and 75 mg/kg/day). In the acute toxicity study, main findings of this treatment indicated no mortality, body weight decrease, no changes in hematological and biochemical par...
Source: Regulatory Toxicology and Pharmacology : RTP - November 7, 2019 Category: Toxicology Authors: Oliveira NA, Sandini TM, Cornelio-Santiago HP, Martinelli ECL, Raspantini LER, Raspantini PC, Momo C, Oliveira AL, Fukumasu H Tags: Regul Toxicol Pharmacol Source Type: research

U.S. food & Drug Administration's interim reference levels for dietary lead exposure in children and women of childbearing age.
U.S. food & Drug Administration's interim reference levels for dietary lead exposure in children and women of childbearing age. Regul Toxicol Pharmacol. 2019 Nov 07;:104516 Authors: Flannery BM, Dolan LC, Hoffman-Pennesi D, Gavelek A, Jones OE, Kanwal R, Wolpert B, Gensheimer K, Dennis S, Fitzpatrick S Abstract Reducing lead exposure is a public health priority for the US Food and Drug Administration as well as other federal agencies. The goals of this research were to 1) update the maximum daily dietary intake of lead from food, termed an interim reference level (IRL), for children and for women ...
Source: Regulatory Toxicology and Pharmacology : RTP - November 7, 2019 Category: Toxicology Authors: Flannery BM, Dolan LC, Hoffman-Pennesi D, Gavelek A, Jones OE, Kanwal R, Wolpert B, Gensheimer K, Dennis S, Fitzpatrick S Tags: Regul Toxicol Pharmacol Source Type: research

Residue analysis of gibberellic acid isomer (iso-GA3) in brewing process and its toxicity evaluation in mice.
In this study, the concentration of iso-GA3 and the conversion rate of GA3 to iso-GA3 during the brewing process was studied by high performance liquid chromatography and the potential toxicity of iso-GA3 was evaluated in ICR mice. The concentration of iso-GA3 increased in the saccharification and wort boiling processes while its concentration was stable during fermentation. The maximum conversion rates of GA3 to iso-GA3 in Canadian malt, Australian malt SCO and Australian malt FAQ were 88%, 87% and 87%, respectively. In the acute oral toxicity study, the median lethal dose (LD50) of iso-GA3 was 2.82 g/kg body weight (BW...
Source: Regulatory Toxicology and Pharmacology : RTP - November 6, 2019 Category: Toxicology Authors: Sun W, Liu C, Luo J, Niu C, Wang J, Zheng F, Li Q Tags: Regul Toxicol Pharmacol Source Type: research

State of the science on alternatives to animal testing and integration of testing strategies for food safety assessments: Workshop proceedings.
Abstract Rapidly evolving technological methods and mechanistic toxicological understanding have paved the way for new science-based approaches for the determination of chemical safety in support of advancing public health. Approaches including read-across, high-throughput screening, in silico models, and organ-on-a-chip technologies were addressed in a 2017 workshop focusing on how scientists can move effectively toward a vision for 21st century food safety assessments. The application of these alternative methods, the need for further development of standardized practices, and the interpretation and communicatio...
Source: Regulatory Toxicology and Pharmacology : RTP - November 6, 2019 Category: Toxicology Authors: Karmaus AL, Bialk H, Fitzpatrick S, Krishan M Tags: Regul Toxicol Pharmacol Source Type: research

Letter.
PMID: 31704257 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - November 5, 2019 Category: Toxicology Authors: Cooper KR, Gleason JA, Post GB Tags: Regul Toxicol Pharmacol Source Type: research

Subchronic (91-day) oral toxicity study of cellobiose in rats.
r A PMID: 31704258 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - November 5, 2019 Category: Toxicology Authors: Winkler A, Messinger H, Bär A Tags: Regul Toxicol Pharmacol Source Type: research

The urinary metabolic profile of diethylene glycol methyl ether and triethylene glycol methyl ether in Sprague-Dawley rats and the role of the metabolite methoxyacetic acid in their toxicity.
This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives
Source: Regulatory Toxicology and Pharmacology : RTP - November 5, 2019 Category: Toxicology Authors: Kelsey JR, Cnubben NHP, Bogaards JJP, Braakman RBH, van Stee LLP, Smet K Tags: Regul Toxicol Pharmacol Source Type: research

Characteristics of exposure factors and inhalation exposure to selected spray consumer products in Korean population.
This study evaluated exposure factors for consumer spray products and assessed the particle inhalation exposure. Six consumer spray products were evaluated: an automobile interior cleaner, car deodorizing spray, anti-static spray, waterproofing spray, microorganism deodorizer, and disinfectant spray. The exposure factors were based on 10,000 respondents over 15 years old. Inhalation dose was calculated from the concentration released into the room air and time used. The use rates of the spray products ranged from 0.4 to 11% and differed significantly by gender (p 
Source: Regulatory Toxicology and Pharmacology : RTP - November 4, 2019 Category: Toxicology Authors: Shin H, Jang Y, Lim M, Park JY, Yang W, Lee K Tags: Regul Toxicol Pharmacol Source Type: research

An FDA analysis of clinical hold deficiencies affecting investigational new drug applications for oncology products.
Abstract A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of devel...
Source: Regulatory Toxicology and Pharmacology : RTP - October 31, 2019 Category: Toxicology Authors: Manning ML, Thompson MD, Saber H, Maher VE, Crich JZ, Leighton JK Tags: Regul Toxicol Pharmacol Source Type: research

Development of a prioritization method for chemical-mediated effects on steroidogenesis using an integrated statistical analysis of high-throughput H295R data.
Abstract Synthesis of 11 steroid hormones in human adrenocortical carcinoma cells (H295R) was measured in a high-throughput steroidogenesis assay (HT-H295R) for 656 chemicals in concentration-response as part of the US Environmental Protection Agency's ToxCast program. This work extends previous analysis of the HT-H295R dataset and model by examining the utility of a novel prioritization metric based on the Mahalanobis distance that reduced these 11-dimensional data to 1-dimension via calculation of a mean Mahalanobis distance (mMd) at each chemical concentration screened for all hormone measures available. Herein...
Source: Regulatory Toxicology and Pharmacology : RTP - October 29, 2019 Category: Toxicology Authors: Haggard DE, Setzer W, Judson R, Paul Friedman K Tags: Regul Toxicol Pharmacol Source Type: research

In vitro and in vivo toxicity evaluation of non-neuroleptic phenothiazines, antitubercular drug candidates.
This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safety use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment w...
Source: Regulatory Toxicology and Pharmacology : RTP - October 28, 2019 Category: Toxicology Authors: Salie S, Labuschagné A, Walters A, Geyer S, Jardine A, Jacobs M, Hsu NJ Tags: Regul Toxicol Pharmacol Source Type: research

Data derived extrapolation factors for developmental toxicity: A preliminary research case study with perfluorooctanoate (PFOA).
PMID: 31669196 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - October 26, 2019 Category: Toxicology Authors: Dourson ML, Gadagbui B, Onyema C, McGinnis PM, York RG Tags: Regul Toxicol Pharmacol Source Type: research

Cataracts and statins. A disproportionality analysis using data from VigiBase.
arés-Seisdedos R Abstract The basis of the association between statin use and cataract has been explored using the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase) through January 2019. The reporting odds ratios (RORs) as a measure of disproportionality for reported cataracts and individual statins have been calculated. Subgroup analyses according statin lipophilicity, sex, and age groups have been performed. Moreover, RORs have been calculated for non-statin lipid lowering drugs. An increased disproportionality have been found for most...
Source: Regulatory Toxicology and Pharmacology : RTP - October 26, 2019 Category: Toxicology Authors: Macías Saint-Gerons D, Bosco Cortez F, Jiménez López G, Castro JL, Tabarés-Seisdedos R Tags: Regul Toxicol Pharmacol Source Type: research

Linking internal dosimetries of the propyl metabolic series in rats and humans using physiologically based pharmacokinetic (PBPK) modeling.
Abstract The metabolic series approach has successfully linked internal dosimetries of metabolically related compounds reducing cost and time for chemical risk assessments. Here, we developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the propyl metabolic series including propyl acetate, 1-propanol, propionaldehyde, and propionic acid. Manufacturers use these compounds as organic solvents and intermediates during chemical synthesis. Public exposures can occur through using consumer products containing propyl compounds like cosmetics, aerosol sprays, or foods, and occupational expos...
Source: Regulatory Toxicology and Pharmacology : RTP - October 24, 2019 Category: Toxicology Authors: Smith JN, Tyrrell KJ, Smith JP, Weitz KK, Faber W Tags: Regul Toxicol Pharmacol Source Type: research

Use of benchmark dose models in risk assessment for occupational handlers of eight pesticides used in pome fruit production.
This study used data from studies in support of pesticide registration for eight different compounds to build dose-response models and calculate benchmark doses and confidence limits. The results were compared to the NOAEL of the same study. A probabilistic estimate of dose was compared with all points of departure to demonstrate differences in the protective ability of each different selected limit. While neither the BMD/BMDL nor the NOAEL was consistently more protective, the advantage of using the BMD in quantifying the uncertainty of the point of departure is highlighted, and the feasibility of using current OECD-guide...
Source: Regulatory Toxicology and Pharmacology : RTP - October 23, 2019 Category: Toxicology Authors: Pouzou JG, Kissel J, Yost MG, Fenske RA, Cullen AC Tags: Regul Toxicol Pharmacol Source Type: research

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults.
Abstract Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-β-hydroxybutyrate (βHB) to similar concentrations within minutes, with βHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18-70 years, who drank 25 ml (26.8 g) of the ketone monoester...
Source: Regulatory Toxicology and Pharmacology : RTP - October 23, 2019 Category: Toxicology Authors: Soto-Mota A, Vansant H, Evans RD, Clarke K Tags: Regul Toxicol Pharmacol Source Type: research

Evaluating potential refinements to existing Threshold of Toxicological Concern (TTC) values for environmentally-relevant compounds.
Abstract The Toxic Substances Control Act (TSCA) mandates the US EPA perform risk-based prioritisation of chemicals in commerce and then, for high-priority substances, develop risk evaluations that integrate toxicity data with exposure information. One approach being considered for data poor chemicals is the Threshold of Toxicological Concern (TTC). Here, TTC values derived using oral (sub)chronic No Observable (Adverse) Effect Level (NO(A)EL) data from the EPA's Toxicity Values database (ToxValDB) were compared with published TTC values from Munro et al. (1996). A total of 4554 chemicals with structures present i...
Source: Regulatory Toxicology and Pharmacology : RTP - October 19, 2019 Category: Toxicology Authors: Nelms MD, Pradeep P, Patlewicz G Tags: Regul Toxicol Pharmacol Source Type: research

Impact of electronic cigarette heating coil resistance on the production of reactive carbonyls, reactive oxygen species and induction of cytotoxicity in human lung cancer cells in vitro.
Abstract Electronic cigarette (e-cigarette; e-cig) use has grown exponentially in recent years despite their unknown health effects. E-cig aerosols are now known to contain hazardous chemical compounds, including carbonyls and reactive oxygen species (ROS), and these compounds are directly inhaled by consumers during e-cig use. Both carbonyls and ROS are formed when the liquid comes into contact with a heating element that is housed within an e-cig's atomizer. In the present study, the effect of coil resistance (1.5 Ω and 0.25 Ω coils, to obtain a total wattage of 8 ± 2 W and 40 &plu...
Source: Regulatory Toxicology and Pharmacology : RTP - October 17, 2019 Category: Toxicology Authors: Cirillo S, Urena JF, Lambert JD, Vivarelli F, Canistro D, Paolini M, Cardenia V, Rodriguez-Estrada MT, Richie JP, Elias RJ Tags: Regul Toxicol Pharmacol Source Type: research

The grouping and assessment strategy for organic pigments (GRAPE): Scientific evidence to facilitate regulatory decision-making.
This article presents the Grouping and Assessment Strategy for Organic Pigments (GRAPE). GRAPE is driven by the hypotheses that low (bio)dissolution and low permeability indicate absence of systemic bioavailability and hence no systemic toxicity potential upon oral exposure, and, for inhalation exposure, that low (bio)dissolution (and absence of surface reactivity, dispersibility and in vitro effects) indicate that the organic pigment is a 'poorly soluble particle without intrinsic toxicity potential'. In GRAPE Tier 1, (bio)solubility and (bio)dissolution are assessed, and in Tier 2, in vitro Caco-2 permeability and in vit...
Source: Regulatory Toxicology and Pharmacology : RTP - October 17, 2019 Category: Toxicology Authors: Sauer UG, Kreiling R Tags: Regul Toxicol Pharmacol Source Type: research

Tetrahydrofuran-induced tumors in rodents are not relevant to humans: Quantitative weight of evidence analysis of mode of action information does not support classification of tetrahydrofuran as a possible human carcinogen.
Abstract Inhalation of tetrahydrofuran (THF) causes a marginal increase in the incidence of renal tumors in male rats and an increase in the incidence of liver tumors in female mice. Quantitative weight of evidence (QWoE) was applied to assess experimental support for biologically plausible modes of action (MoA) of tumor formation by THF and their human relevance. QWoE did not obtain support for a MoA to induce kidney tumors in male rats from THF exposure via α2u -globulin nephropathy, exacerbation of chronic progressive nephropathy (CPN), DNA-damage, or recurrent cytotoxicity but obtained moderate to good s...
Source: Regulatory Toxicology and Pharmacology : RTP - October 15, 2019 Category: Toxicology Authors: Dekant W Tags: Regul Toxicol Pharmacol Source Type: research

Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog ®.
Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog®. Regul Toxicol Pharmacol. 2019 Oct 11;:104497 Authors: Korn M, Wohlfart P, Gossas T, Kullman-Magnusson M, Niederhaus B, Dedio J, Tennagels N Abstract SAR342434 is a biosimilar of insulin lispro (Humalog® U-100). Batches of SAR342434 were compared with Humalog® batches of either EU or US origin in a panel of in vitro biological assays that included insulin binding to insulin receptor (IR) isoforms A (IR-A) and B (IR-B) and IR-A/IR-B autophosphorylati...
Source: Regulatory Toxicology and Pharmacology : RTP - October 11, 2019 Category: Toxicology Authors: Korn M, Wohlfart P, Gossas T, Kullman-Magnusson M, Niederhaus B, Dedio J, Tennagels N Tags: Regul Toxicol Pharmacol Source Type: research

Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis.
Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80...
Source: Regulatory Toxicology and Pharmacology : RTP - October 9, 2019 Category: Toxicology Authors: Kumar P, Agarwal A, Singh AK, Gautam AK, Chakraborti S, Kumar U, Kumar D, Bhattacharya B, Panda P, Saha B, Qidwai T, Maity B, Saha S Tags: Regul Toxicol Pharmacol Source Type: research

Pulmonary toxicity in rats following inhalation exposure to poorly soluble particles: The issue of impaired clearance and the relevance for human health hazard and risk assessment.
Abstract Intensive discussions are ongoing about the interpretation of pulmonary effects observed in rats exposed to poorly soluble particles. Alveolar clearance differs between rats and humans and becomes impaired in rats at higher exposure concentrations. Some have doubted the human relevance of toxic effects observed in rats under impaired clearance conditions and have suggested that experimental exposures should stay below concentrations inducing impaired clearance. However, for regulatory purposes, insight in potential health effects at relatively high concentrations is needed to fully understand the hazard. ...
Source: Regulatory Toxicology and Pharmacology : RTP - October 8, 2019 Category: Toxicology Authors: Bos PMJ, Gosens I, Geraets L, Delmaar C, Cassee FR Tags: Regul Toxicol Pharmacol Source Type: research

Applying non-animal strategies for assessing skin sensitisation report from an EPAA/cefic-LRI/IFRA Europe cross sector workshop, ECHA helsinki, February 7th and 8th 2019.
Abstract Four years on since the last cross sector workshop, experience of the practical application and interpretation of several non-animal assays that contribute to the predictive identification of skin sensitisers has begun to accumulate. Non-animal methods used for hazard assessments increasingly are contributing to the potency sub-categorisation for regulatory purposes. However, workshop participants generally supported the view that there remained a pressing need to build confidence in how information from multiple methods can be combined for classification, sub-categorisation and potency assessment. Furthe...
Source: Regulatory Toxicology and Pharmacology : RTP - October 3, 2019 Category: Toxicology Authors: Basketter D, Azam P, Casati S, Corvaro M, Ezendam J, Griem P, Hubesch B, Irizar A, Kern P, Manou I, Mehling A, Rossi LH Tags: Regul Toxicol Pharmacol Source Type: research

Transitioning to composite bacterial mutagenicity models in ICH M7 (Q)SAR analyses.
Abstract The International Council on Harmonisation (ICH) M7(R1) guideline describes the use of complementary (quantitative) structure-activity relationship ((Q)SAR) models to assess the mutagenic potential of drug impurities in new and generic drugs. Historically, the CASE Ultra and Leadscope software platforms used two different statistical-based models to predict mutations at G-C (guanine-cytosine) and A-T (adenine-thymine) sites, to comprehensively assess bacterial mutagenesis. In the present study, composite bacterial mutagenicity models covering multiple mutation types were developed. These new models contai...
Source: Regulatory Toxicology and Pharmacology : RTP - October 3, 2019 Category: Toxicology Authors: Landry C, Kim MT, Kruhlak NL, Cross KP, Saiakhov R, Chakravarti S, Stavitskaya L Tags: Regul Toxicol Pharmacol Source Type: research

Subchronic toxicity evaluation of ethanol extract of Cassia tora L. seeds in rats.
Abstract Cassia tora Linn. is an annual or perennial plant of the Fabaceae/Leguminosae family. It is used in traditional medicine for various biological activities including anti-constipation, anti-inflammatory, visual acuity, and hepato-protective activities. The present study was carried out to investigate the potential toxicity of C. tora L. seed ethanol extract (CTSEE) following a 13-week repeated oral administration to Sprague-Dawley rats. CTSEE was administered orally to male and female rats for 13 weeks at 0 (control), 500, 1000, and 2000 mg/kg/day (n = 10, for male and female rats for each dose)....
Source: Regulatory Toxicology and Pharmacology : RTP - October 1, 2019 Category: Toxicology Authors: Lee MJ, Nho JH, Yang BD, Park H, Lee HJ, Lee KH, Jang JH, Jung HK, Kim SR, Cho HW, Park HS, Lim JO, Kim JC Tags: Regul Toxicol Pharmacol Source Type: research

Evaluation of preclinical safety profile of SPH3127, a direct renin inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and cynomolgus monkeys.
Abstract SPH3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable ADME (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase Ι clinical trial. In this work, the subchronic toxicity of SPH3127 in Sprague-Dawley rats and cynomolgus monkeys has been characterized. Rats and monkeys received SPH3127 orally (30, 300, 900 and 20, 100, 450 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days followed by a 28-days recovery period for one third of the animals. The adverse effects of SPH3127 on...
Source: Regulatory Toxicology and Pharmacology : RTP - October 1, 2019 Category: Toxicology Authors: Mao Y, Zhang L, Li H, Li X, Liu Y, Xia G Tags: Regul Toxicol Pharmacol Source Type: research

Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis.
Abstract JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose levels for 34-days to Sprague Dawley rats, and at 5, 20, and 75 mg/kg/day dose levels for 28-days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10 mg/kg females and 40 mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 a...
Source: Regulatory Toxicology and Pharmacology : RTP - September 30, 2019 Category: Toxicology Authors: Kale VP, Gibbs S, Taylor JA, Zmarowski A, Novak J, Patton K, Sparrow B, Gorospe J, Anand S, Cinar R, Kunos G, Chorvat RJ, Terse PS Tags: Regul Toxicol Pharmacol Source Type: research

Sub-acute toxicological study of artemisinin-piperaquine tablets in rhesus monkeys.
Abstract Artemisinin-piperaquine tablet (trade name Artequick, ATQ), is a novel combination therapy for the treatment of malaria and especially for resistant P.falciparum malaria. The aim of our study was to assess the potential sub-acute toxicity profile of ATQ by oral administration route in rhesus monkeys. Monkeys were administrated once daily with doses of ATQ (39.1、78.2、156.4 mg/kg) for 21 days and then followed-up a 56-day recovery period. The administration of ATQ at high dose produced significant changes in the clinical signs primarily involved in gastrointestinal and nervous systems. Body weight los...
Source: Regulatory Toxicology and Pharmacology : RTP - September 30, 2019 Category: Toxicology Authors: Li X, Xu Z, Yuan Y, Deng G, Ru L, Yuan Z, Zhang S, Wang Q, Song J, Xu Q Tags: Regul Toxicol Pharmacol Source Type: research

Toxicological significance of increased serum alkaline phosphatase activity in dog studies of pesticides: Analysis of toxicological data evaluated in Japan.
Abstract Increased serum alkaline phosphatase (ALP) activity is an indicator of hepatobiliary damage in humans and experimental animals. Practically, increased ALP accompanied by no other hepatotoxic changes is often encountered in toxicity studies of pesticides in dogs. Here, we analyzed the toxicological significance of increased ALP in response to 206 pesticides evaluated by the Food Safety Commission of Japan as toxicological evaluation reports in their risk assessment process. Our analysis indicated that increased ALP was more frequent in dogs (108/206) than in rats (36/206). In 87 of 108 pesticides, increase...
Source: Regulatory Toxicology and Pharmacology : RTP - September 27, 2019 Category: Toxicology Authors: Yokoyama Y, Ono A, Yoshida M, Matsumoto K, Saito M Tags: Regul Toxicol Pharmacol Source Type: research

90-Day repeated oral toxicity test of D-allulose produced from Microbacterium foliorum.
This study's finding of a NOAEL of 5,000 mg/kg/day should ensure that D-allulose produced from Microbacterium foliorum is classified as a safe and ordinary substance. PMID: 31568817 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - September 27, 2019 Category: Toxicology Authors: An M, Lee J, Park YC, Park C, Kim HJ Tags: Regul Toxicol Pharmacol Source Type: research

Quantitative prediction of repeat dose toxicity values using GenRA.
Abstract Computational approaches have recently gained popularity in the field of read-across to automatically fill data-gaps for untested chemicals. Previously, we developed the generalized read-across (GenRA) tool, which utilizes in vitro bioactivity data in conjunction with chemical descriptor information to derive local validity domains to predict hazards observed in in vivo toxicity studies. Here, we modified GenRA to quantitatively predict point of departure (POD) values obtained from US EPA's Toxicity Reference Database (ToxRefDB) version 2.0. To evaluate GenRA predictions, we first aggregated oral Lowest O...
Source: Regulatory Toxicology and Pharmacology : RTP - September 21, 2019 Category: Toxicology Authors: Helman G, Patlewicz G, Shah I Tags: Regul Toxicol Pharmacol Source Type: research

Reducing the need for animal testing while increasing efficiency in a pesticide regulatory setting: Lessons from the EPA Office of Pesticide Programs' Hazard and Science Policy Council.
Abstract As part of EPA's commitment to reducing animal testing, the Office of Pesticide Programs (OPP) created the Hazard and Science Policy Council (HASPOC). This group considers requests for waiving animal study requirements for human health risk assessments and makes recommendations based on a weight-of-the-evidence approach. Since its inception in 2012, the HASPOC has evaluated over one thousand requests to waive animal studies required by default for pesticide evaluation. Here, the number of studies waived, and the types of studies represented were analyzed to determine the impact of the HASPOC decisions in ...
Source: Regulatory Toxicology and Pharmacology : RTP - September 20, 2019 Category: Toxicology Authors: Craig E, Lowe K, Akerman G, Dawson J, May B, Reaves E, Lowit A Tags: Regul Toxicol Pharmacol Source Type: research

Assessment of FD & C Yellow No. 6 (Sunset Yellow FCF) effects on sperm count, motility and viability in the rat in a 28-day toxicity study.
Assessment of FD&C Yellow No. 6 (Sunset Yellow FCF) effects on sperm count, motility and viability in the rat in a 28-day toxicity study. Regul Toxicol Pharmacol. 2019 Sep 17;:104479 Authors: Bastaki M, Mendes OR, Bauter MR, Taylor SV Abstract Sunset Yellow FCF was tested for 28-days in male Hsd:SD® rats for its potential effect on sperm quality parameters at dietary concentrations of 6,000, 12,000 and 18,000 ppm, corresponding to target doses of 500, 1000, and 1500 mg/kg bw/day. The measured average daily intake was 490, 944, and 1,475 mg/kg bw/day, based on feed consumption and sta...
Source: Regulatory Toxicology and Pharmacology : RTP - September 17, 2019 Category: Toxicology Authors: Bastaki M, Mendes OR, Bauter MR, Taylor SV Tags: Regul Toxicol Pharmacol Source Type: research

Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database.
ann C Abstract The European Food Safety Authority (EFSA) guidance (EFSA, 2017) for dermal absorption (DA1) studies recommends stringent mass balance (MB2) limits of 95-105%. EFSA suggested that test material can be lost after penetration and requires that for chemicals with
Source: Regulatory Toxicology and Pharmacology : RTP - September 17, 2019 Category: Toxicology Authors: Kluxen FM, Grégoire S, Schepky A, Hewitt NJ, Klaric M, Domoradzki JY, Felkers E, Fernandes J, Fisher P, McEuen SF, Parr-Dobrzanski R, Wiemann C Tags: Regul Toxicol Pharmacol Source Type: research

MRI-based preclinical discovery of DILI: A lesson from paracetamol-induced hepatotoxicity.
Abstract Worldwide, drug-induced liver injury (DILI) is a major cause of hepatic failure. It is also the leading cause of withdrawal, cautionary labeling, and restricted usage of licensed drugs; therefore, European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) warn that the existing methods of assessing DILI are insufficient and that some of the translational biomarkers of hepatotoxicity must be relooked. Magnetic resonance imaging (MRI) seems to be a proper tool in elucidating the effects of DILI in both preclinical and clinical studies, providing excellent visualization of the morph...
Source: Regulatory Toxicology and Pharmacology : RTP - September 17, 2019 Category: Toxicology Authors: Grudzinski IP, Ruzycka M, Cieszanowski A, Szeszkowski W, Badurek I, Malkowska A, Bamburowicz-Klimkowska M Tags: Regul Toxicol Pharmacol Source Type: research

Nonclinical safety of tildrakizumab, a humanized anti-IL-23p19 monoclonal antibody, in nonhuman primates.
Abstract Tildrakizumab (also known as MK-3222), is a high-affinity, humanized, immunoglobin G1κ monoclonal antibody targeting the p19 subunit of interleukin-23 recently approved for the treatment of moderate to severe plaque psoriasis in the US, Europe, and Australia. The safety profile of tildrakizumab was characterized in nonclinical studies using a pharmacologically relevant cynomolgus monkey model. In repeat-dose toxicity studies, cynomolgus monkeys were chronically treated with subcutaneous (SC) injections of 100 mg/kg of tildrakizumab every 2 weeks up to 9 months. Tildrakizumab was well tolerated, wi...
Source: Regulatory Toxicology and Pharmacology : RTP - September 16, 2019 Category: Toxicology Authors: Santostefano M, Herzyk D, Montgomery D, Wolf J Tags: Regul Toxicol Pharmacol Source Type: research

In vitro RHE skin sensitisation assays: Applicability to challenging substances.
r D Abstract In the last 20 years, alternative approaches to the identification of skin sensitisation hazards have been at the forefront of the 3Rs and have helped refine the validation and acceptance processes. However, experience with the local lymph node assay showed that, post-validation, challenges still occurred, particularly when a wider diversity of chemical substances was addressed, a situation which will arise with validated in vitro alternatives. In the present work, a range of substances potentially challenging to assess in current nonanimal OECD test guidelines were evaluated in several of the emergin...
Source: Regulatory Toxicology and Pharmacology : RTP - September 5, 2019 Category: Toxicology Authors: Mehling A, Adriaens E, Casati S, Hubesch B, Irizar A, Klaric M, Letasiova S, Manou I, Müller BP, Roggen E, van Vliet E, Basketter D Tags: Regul Toxicol Pharmacol Source Type: research

Variance of body and organ weights in 28-day studies in mice.
zwaay B Abstract The OECD guideline 407 outlines the conduct of 28-day studies in rodents to detect systemic toxicity with focus on endocrine and immunotoxic effects. It was validated with the rat as preferred model species. Justification is required for other rodent species, as an increased variability is expected compared to the rat. We investigated the variability of organ weights in the mouse and compared this to data published for the rat in the validation report of test guideline 407. Furthermore, the influence of the immunotoxic model substance cyclophosphamide on spleen and thymus weights in the mouse in i...
Source: Regulatory Toxicology and Pharmacology : RTP - September 5, 2019 Category: Toxicology Authors: Marxfeld HA, Küttler K, Dammann M, Gröters S, van Ravenzwaay B Tags: Regul Toxicol Pharmacol Source Type: research

Subchronic toxicity of cerium nitrate by 90-day oral exposure in wistar rats.
This study evaluated the subchronic toxicity of cerium nitrate and determined the no observed adverse effect level (NOAEL) in Wistar rats. In accordance with the Organization for Economic Co-operation and Development guidelines, cerium nitrate was orally administered to Wistar rats by gavage at 0, 0.2, 75, 150, and 300 mg/kg bw/day for 90 days, followed by 28 days of recovery period in the 300 mg/kg bw/day and the control groups. The following parameters were evaluated: mortality, abnormalities, body weight, food consumption, hematology, serum biochemistry, urinanalysis, gross necropsy and histopathology. At the en...
Source: Regulatory Toxicology and Pharmacology : RTP - September 5, 2019 Category: Toxicology Authors: Wu Y, Tang X, Yang W, Fan J, Tang L, Wang C, Yu Z, Jia XD, Fan B Tags: Regul Toxicol Pharmacol Source Type: research

Persistence, dissipation, and risk assessment of a combination formulation of trifloxystrobin and tebuconazole fungicides in/on tomato.
Abstract Multi-locational supervised field trials were conducted in different agro-climatic regions in India to study dissipation of trifloxystrobin and tebuconazole in tomato after spraying a combination formulation (trifloxystrobin 25% + tebuconazole 50%, 75WG) at recommended doses: (i) single (trifloxystrobin 87.5 g a.i. ha-1 + tebuconazole 175 g a.i. ha-1) and (ii) double (trifloxystrobin 175 g a.i. ha-1 + tebuconazole 350 g a.i. ha-1). Fruit samples were extracted with ethyl acetate using a modified QuEChERS method. The residues (parent fungicides + met...
Source: Regulatory Toxicology and Pharmacology : RTP - September 4, 2019 Category: Toxicology Authors: Sharma KK, Tripathy V, Rao CS, Bhushan VS, Reddy KN, Jyot G, Sahoo SK, Singh B, Mandal K, Banerjee H, Banerjee T, Bhattacharya S, George T, Beevi N, Sharma K, Tayade A, Gopal M, Walia S Tags: Regul Toxicol Pharmacol Source Type: research

Derivation of a chronic reference dose for perfluorohexane sulfonate (PFHxS) for reproductive toxicity in mice.
Abstract Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid that was used as an industrial surfactant, but is now found as an environmental contaminant worldwide. In addition to its use as an industrial surfactant, it is a legacy contaminant from the use of aqueous film-forming foams. Despite its widespread occurrence in the environment and evidence of biological activity associated with PFHxS and similar perfluoroalkyl sulfonic acids in rodents, there is no oral toxicity value currently available from the IRIS Database. To derive an oral reference dose (RfD) for PFHxS, available toxici...
Source: Regulatory Toxicology and Pharmacology : RTP - September 2, 2019 Category: Toxicology Authors: Ali JM, Roberts SM, Gordon DS, Stuchal LD Tags: Regul Toxicol Pharmacol Source Type: research

Finding synergies for the 3Rs - Repeated dose toxicity testing: Report from an EPAA partners' forum.
to P, Rasenberg M, Roggeband R, Rowan TG, Schutte K, van de Water B, Westmoreland C, Whelan M, Wilschut A, Zvonimir Z, Cronin MTD Abstract The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum on repeated dose toxicity (RDT) testing to identify synergies between industrial sectors and stakeholders along with opportunities to progress these in existing research frameworks. Although RTD testing is not performed across all industrial sectors, the OECD accepted tests can provide a rich source of information and play a pivotal role for safety decisions relating to the u...
Source: Regulatory Toxicology and Pharmacology : RTP - August 31, 2019 Category: Toxicology Authors: Laroche C, Annys E, Bender H, Botelho D, Botham P, Brendler-Schwaab S, Clayton R, Corvaro M, Dal Negro G, Delannois F, Dent M, Desaintes C, Desprez B, Dhalluin S, Hartmann A, Hoffmann-Doerr S, Hubesch B, Irizar A, Manou I, Müller BP, Nadzialek S, Prieto Tags: Regul Toxicol Pharmacol Source Type: research

Comparative levels of carbonyl delivery between mass-market cigars and cigarettes.
This study sought to analyze carbonyl delivery in marketed cigars and cigarillos and compare them against levels found in cigarettes. To accomplish this the standard cigarette method, CORESTA recommended method 74 (CRM-74), was optimized for cigar smoking including an evaluation of the trapping efficiency and the stability of the carbonyl-hydrazone adducts due to the increased smoke time required for cigar collection. On a per product basis, carbonyl delivery from cigars smoked under CRM-64 conditions was found to yield similar levels of formaldehyde and greater levels of acetaldehyde, acrolein and crotonaldehyde than meas...
Source: Regulatory Toxicology and Pharmacology : RTP - August 29, 2019 Category: Toxicology Authors: Jablonski JJ, Maines JH, Cheetham AG, Gilman IG Tags: Regul Toxicol Pharmacol Source Type: research

Time to first cigarette of the day and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in adult regular and non-daily smokers: (NHANES) 2007-10.
Abstract As the number of regular smokers has decreased over the last decade, the prevalence of light (10 cigarettes per day), light smoking and non-daily smoking and the time to the first cigarette of the day (TTFC), a robust predictor of nicotine addiction, cessation failure, sleep disruption and other health indicators. Findings from a sample of 352 smokers suggest that among intermittent, non-daily and light daily smokers, TTFC of the day was associated with higher levels of NNK metabolite, an effect which was mediated by urinary cotinine levels, but not by the number of cigarettes smoked per day. This suggest...
Source: Regulatory Toxicology and Pharmacology : RTP - August 27, 2019 Category: Toxicology Authors: Branstetter SA, Nye RT, Muscat JE Tags: Regul Toxicol Pharmacol Source Type: research

The food contaminant acetamide is not an in vivo clastogen, aneugen, or mutagen in rodent hematopoietic tissue.
Abstract Acetamide (CAS 60-35-5) is classified by IARC as a Group 2B, possible human carcinogen, based on the induction of hepatocellular carcinomas in rats following chronic exposure to high doses. Recently, acetamide was found to be present in a variety of human foods, warranting further investigation. The regulatory body JECFA has previously noted conflicting reports on acetamide's ability to induce micronuclei (MN) in mice in vivo. To better understand the potential in vivo genotoxicity of acetamide, we performed acute MN studies in rats and mice, and a subchronic study in rats, the target species for liver ca...
Source: Regulatory Toxicology and Pharmacology : RTP - August 27, 2019 Category: Toxicology Authors: Moore MM, Gollapudi B, Nagane R, Khan N, Patel M, Khanvilkar T, Roy AM, Ramesh E, Bals B, Teymouri F, Nault R, Bringi V Tags: Regul Toxicol Pharmacol Source Type: research