Safety and health risk assessment methodology of dermal and inhalation exposure to formulated products ingredients.
Abstract Consumers are commonly exposed to numerous chemical ingredients found in various formulated products especially household and personal care products. Therefore, identification of hazardous ingredients contained in those products should be performed at the early stages of product design to reduce the high cost of redesigning the products at the final stage. Thus, a systematic safety and health risk assessment methodology is required for the product formulation design. In this work, a two-step index-based methodology is presented to estimate the severity of the hazards and the magnitude of risks. In Tier 1 ...
Source: Regulatory Toxicology and Pharmacology : RTP - July 31, 2020 Category: Toxicology Authors: Raslan R, Hassim MH, Chemmangattuvalappil NG, Ng DKS, Ten JY Tags: Regul Toxicol Pharmacol Source Type: research

Evaluation of chronic toxicity of cyclocreatine, a creatine analog, in Sprague Dawley rat after oral gavage administration for up to 26 weeks.
In conclusion, chronic administration of cyclocreatine by oral gavage in Sprague Dawley rats induced the seizures and microscopic lesions in the brain, testes and thyroid. Based on the results of this study the highest tested dose of 600 mg/kg/day (mean Cmax of 151.5 μg/mL; AUC0-24 of 1970 h*μg/mL) was considered the maximum tolerated dose (MTD) in SD rats. PMID: 32745584 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - July 31, 2020 Category: Toxicology Authors: Kale VP, Wallery J, Novak J, Gibbs S, Bourdi M, Do MT, McKew JC, Terse PS Tags: Regul Toxicol Pharmacol Source Type: research

Metabolic fate in adult and pediatric population of steviol glycosides produced from stevia leaf extract by different production technologies.
Abstract More than 60 naturally occurring steviol glycosides in the Stevia rebaudiana Bertoni plant share a similar molecular structure with an aglycone steviol backbone conjugated with β- and α-glycosidic bonds to different sugar moieties. These glycosides are naturally produced in different quantities within the stevia leaf. Certain minor glycosides with superior sensory attributes, such as Reb D and Reb M, are found less than 0.1% in traditional stevia leaves. New technologies can now produce better tasting steviol glycosides by using enzymatic conversion of stevioside and Reb A, which are abundant i...
Source: Regulatory Toxicology and Pharmacology : RTP - July 31, 2020 Category: Toxicology Authors: Purkayastha S, Kwok D Tags: Regul Toxicol Pharmacol Source Type: research

Determination of the stereoisomeric distribution of R-(-)- and S-(+)-methamphetamine in Thai pills in the legal context of "not inconsiderable quantities".
In conclusion, the analyses revealed that the single value for a "not inconsiderable quantity" in Switzerland seems outdated. Most of the sized pills showed a much higher concentration of the more potent S-(+)-methamphetamine. The risks related to taking such a pill are much higher and therefore the limit quantity should be adapted to the potency of the respective enantiomers. PMID: 32730795 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - July 27, 2020 Category: Toxicology Authors: Gelmi TJ, Verrijken M, Weinmann W Tags: Regul Toxicol Pharmacol Source Type: research

Association of dietary intake and urinary excretion of inorganic arsenic in the Japanese subjects.
Abstract Quantitative relationship between intake of inorganic arsenic (iAs) and urinary excretion of iAs and its metabolite, methylarsonic acid (MMA), was investigated for 150 adult Japanese subjects. Duplicate diet was used for the determination of intake and first void of urine on the next day of duplicate diet sampling was used for urinary iAs + MMA determination. Speciation analysis of arsenic in diet and urine was carried out with liquid chromatography-inductively coupled plasma mass spectrometry. Geometric mean iAs intake of the subjects was 0.349 μg/kg/day and that of urinary iAs +&n...
Source: Regulatory Toxicology and Pharmacology : RTP - July 23, 2020 Category: Toxicology Authors: Yoshinaga J, Narukawa T Tags: Regul Toxicol Pharmacol Source Type: research

Use of the kinetically-derived maximum tolerated dose: Opportunities for delivering 3Rs benefits.
PMID: 32679052 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - July 14, 2020 Category: Toxicology Authors: Sewell F, Kimber I, Boobis AR Tags: Regul Toxicol Pharmacol Source Type: research

The genotoxicity of an organic solvent mixture: A human biomonitoring study and translation of a real-scenario exposure to in vitro.
This study aimed to evaluate occupational exposure to a styrene and xylene mixture through environmental exposure assessment and identify the potential genotoxic effects through biological monitoring. Secondly, we also exposed human peripheral blood cells in vitro to both xylene and styrene either alone or in mixture at concentrations found in occupational settings in order to understand their mechanism of action. The results obtained by air monitoring were below the occupational exposure limits for both substances. All biomarkers of effect, except for nucleoplasmic bridges, had higher mean values in workers (N = 17) c...
Source: Regulatory Toxicology and Pharmacology : RTP - July 10, 2020 Category: Toxicology Authors: Ladeira C, Gajski G, Meneses M, Gerić M, Viegas S Tags: Regul Toxicol Pharmacol Source Type: research

Exposure to environmentally-relevant concentrations of hexavalent chromium does not induce ovarian toxicity in mice.
Abstract Exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water (≥250 ppm) is reported to decrease ovarian follicle counts and increase follicular atresia in mice. To assess effects at lower concentrations, herein we exposed B6C3F1 mice to 0.1-150 ppm Cr(VI) in drinking water for 90 days in a GLP-compliant study. Ovarian follicular counts, differentiation, and degeneration were assessed from every 10th serial section (up to 14 sections per ovary). Ovarian follicular counts, differentiation, and rate of atresia were not altered in any exposure group. Gross and microscopic changes w...
Source: Regulatory Toxicology and Pharmacology : RTP - July 8, 2020 Category: Toxicology Authors: Thompson CM, Donahue DA, Hobbs C, Costecalde Y, Franzen A, Suh M, Proctor DM, Harris MA Tags: Regul Toxicol Pharmacol Source Type: research

An analysis of skin lightening products' violations reported in four U.S. databases in 2002-2020: In hunt of surveillance quality enhancement, not just an assessment of the magnitude of the problem.
PMID: 32649956 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - July 7, 2020 Category: Toxicology Authors: Michalek IM, Pintro K, Benn EKT, Liu B, Dos Santos FLC Tags: Regul Toxicol Pharmacol Source Type: research

Read-across: Principle, case study and its potential regulatory application in China.
Abstract Read-across, has generated much attention and has been used in many regulatory schemes as an alternative approach to testing globally. The regulatory application of read-across in the chemical management in China is progressing but still limited. A workshop on the "Read-Across: Principle, Case Study and its Potential Regulatory Application in China", organized by the Chemical Risk Assessment Specialty Group under the Committee of Industrial Toxicology of Chinese Society of Toxicology, was held on May 28, 2019 to discuss the potential broader application and acceptance of read-across to support c...
Source: Regulatory Toxicology and Pharmacology : RTP - July 7, 2020 Category: Toxicology Authors: Gao R, Guan N, Huang M, Foreman J, Kung M, Rong Z, Su Y, Sweet L, Zhu B, Zhu H, Zou H, Li B, Wang Y, Yin H, Yin Z, Zhang X Tags: Regul Toxicol Pharmacol Source Type: research

Heavy metal contamination in recorded and unrecorded spirits. Should we worry?
In this study we ask whether there is any difference between heavy metal concentrations in recorded and unrecorded spirits and, thus, the related health risk. The levels of heavy metals were determined in recorded (n = 97) and unrecorded (n = 100) spirits using inductively coupled plasma optical emission spectrometric analysis and applied to population-based risk assessments, considering average, regular and chronic heavy drinkers. Concentrations of Cu, Zn, and Sn were significantly higher in unrecorded spirits than those in their recorded counterparts and recorded spirits contained significantly higher levels of F...
Source: Regulatory Toxicology and Pharmacology : RTP - July 6, 2020 Category: Toxicology Authors: Pál L, Muhollari T, Bujdosó O, Baranyai E, Nagy A, Árnyas E, Ádány R, Sándor J, McKee M, Szűcs S Tags: Regul Toxicol Pharmacol Source Type: research

Letter to the editors regarding Heringa et al. (2020).
PMID: 32645428 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - July 6, 2020 Category: Toxicology Authors: Smith CJ, Perfetti TA Tags: Regul Toxicol Pharmacol Source Type: research

Development of a next generation risk assessment framework for the evaluation of skin sensitisation of cosmetic ingredients.
van Vliet E, Klaric M Abstract All cosmetic products placed onto the market must undergo a risk assessment for human health to ensure they are safe for consumers, including an assessment of skin sensitisation risk. Historically, in vivo animal test methods were used to identify and characterise skin sensitisation hazard, however non-animal and other new approach methodologies (NAMs) are now the preferred and mandated choice for use in risk assessment for cosmetic ingredients. The experience gained over the last three decades on how to conduct risk assessments based upon NAMs has allowed us to develop a non-animal,...
Source: Regulatory Toxicology and Pharmacology : RTP - July 6, 2020 Category: Toxicology Authors: Gilmour N, Kern PS, Alépée N, Boislève F, Bury D, Clouet E, Hirota M, Hoffmann S, Kühnl J, Lalko JF, Mewes K, Miyazawa M, Nishida H, Osmani A, Petersohn D, Sekine S, van Vliet E, Klaric M Tags: Regul Toxicol Pharmacol Source Type: research

Use compatibility intervals in regulatory toxicology.
Abstract Recently it was recommended to avoid significance tests, in particular dichotomization into significant/non-significant on the basis of a p-value and a fixed 5% significance level (i.e. false positive rate). As an alternative, the interpretation of a suitable effect size and its compatibility interval is recommended, i.e. confidence intervals whose compatibility with the data, the assumptions, and the models is shown. This concept is used for the evaluation of assays in regulatory toxicology with special emphasis on the proof of hazard and proof of safety. Three case studies for multiple endpoints, multip...
Source: Regulatory Toxicology and Pharmacology : RTP - July 6, 2020 Category: Toxicology Authors: Hothorn LA, Ralph Pirow Tags: Regul Toxicol Pharmacol Source Type: research

Use of computational toxicology (CompTox) tools to predict in vivo toxicity for risk assessment.
Abstract Computational Toxicology tools were used to predict toxicity for three pesticides: propyzamide (PZ), carbaryl (CB) and chlorpyrifos (CPF). The tools used included: a) ToxCast/Tox21 assays (AC50 s μM: concentration 50% maximum activity); b) in vitro-to-in vivo extrapolation (IVIVE) using ToxCast/Tox21 AC50s to predict administered equivalent doses (AED: mg/kg/d) to compare to known in vivo Lowest-Observed-Effect-Level (LOEL)/Benchmark Dose (BMD); c) high throughput toxicokinetics population based (HTTK-Pop) using AC50s for endpoints associated with the mode of action (MOA) to predict age-adjusted AE...
Source: Regulatory Toxicology and Pharmacology : RTP - July 5, 2020 Category: Toxicology Authors: Silva MH Tags: Regul Toxicol Pharmacol Source Type: research

Human health hazard assessment of quaternary ammonium compounds: Didecyl dimethyl ammonium chloride and alkyl (C12-C16) dimethyl benzyl ammonium chloride.
Abstract Quaternary ammonium compounds (Quats) are a large class of permanently charged cationic chemicals that are used in a variety of consumer and industrial products for their antimicrobial properties. Didecyl dimethyl ammonium chloride (DDAC) and alkyl (C12, C14, C16) dimethyl benzyl ammonium chloride (C12-C16 ADBAC) are frequently used as active ingredients in antimicrobials and are the focus of the current hazard assessment. Robust toxicology databases exist for both DDAC and C12-C16 ADBAC; however, the majority of available studies for DDAC and C12-C16 ADBAC are unpublished, but have been submitted to and ...
Source: Regulatory Toxicology and Pharmacology : RTP - July 5, 2020 Category: Toxicology Authors: Luz A, DeLeo P, Pechacek N, Freemantle M Tags: Regul Toxicol Pharmacol Source Type: research

Rebuttal to the Letter to the Editors Regarding Heringa et al. (2020).
PMID: 32640298 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - July 5, 2020 Category: Toxicology Authors: Heringa MB, Cnubben NHP, Slob W, Pronk MEJ, Muller A, Woutersen M, Hakkert BC Tags: Regul Toxicol Pharmacol Source Type: research

Review of the pharmacokinetics and metabolism of triclopyr herbicide in mammals: Impact on safety assessments.
Abstract A review of pharmacokinetic and metabolism studies show that triclopyr is well absorbed from the oral route in numerous species (≥80%), primarily as parent compound. Absorption is quite rapid in rats, dogs and human volunteers. Plasma or blood clearance is also rapid (t1/2 3-9 h), except for dog (12-96 h). Systemic exposure is not dose-proportional: in the rat above 20 mg/kg (dietary) or between 3 and 60 mg/kg (gavage), or in dogs above 5 mg/kg, with systemic exposure in human more comparable to rat than dog. Triclopyr is highly bound to protein in rat, dog and human plasma (≥97% at or bel...
Source: Regulatory Toxicology and Pharmacology : RTP - July 5, 2020 Category: Toxicology Authors: Bartels M, Brown C, Chung G, Chan M, Terry C, Gehen S, Corvaro M Tags: Regul Toxicol Pharmacol Source Type: research

Skin sensitization in silico protocol.
legass J, Jolly R, Krupp E, Lomnitski L, Magby J, Mestres J, Milchak L, Miller S, Muster W, Neilson L, Parakhia R, Parenty A, Parris P, Paulino A, Paulino AT, Roberts DW, Schlecker H, Stidl R, Suarez-Rodrigez D, Szabo DT, Tice RR, Urbisch D, Vuorinen A, Wall B, Weiler T, White AT, Whritenour J, Wichard J, Woolley D, Zwickl C, Myatt GJ Abstract The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without ...
Source: Regulatory Toxicology and Pharmacology : RTP - July 1, 2020 Category: Toxicology Authors: Johnson C, Ahlberg E, Anger LT, Beilke L, Benigni R, Bercu J, Bobst S, Bower D, Brigo A, Campbell S, Cronin MTD, Crooks I, Cross KP, Doktorova T, Exner T, Faulkner D, Fearon IM, Fehr M, Gad SC, Gervais V, Giddings A, Glowienke S, Hardy B, Hasselgren C, Hi Tags: Regul Toxicol Pharmacol Source Type: research

A flow scheme for cumulative assessment of pesticides for adverse liver effects.
nt W Abstract The European Food Safety Authority (EFSA) is developing approaches to cumulative risk assessment by assigning pesticides to cumulative assessment groups (CAGs). For assignment to CAGs, EFSA relies on common toxic effects (CTEs) on the target system. The developed flow scheme for assignment to liver CAGs sequentially assesses the consistency of the CTE, its adversity, its potential to be secondary to other toxicities, its human relevance, and the relation of the NOAEL for the CTE to the overall NOAEL. If the responses to all questions are "yes", allocation to a CAG is supported; "no&quo...
Source: Regulatory Toxicology and Pharmacology : RTP - July 1, 2020 Category: Toxicology Authors: Colnot T, Melching-Kollmuß S, Semino G, Dekant W Tags: Regul Toxicol Pharmacol Source Type: research

Safety assessment of metarrestin in dogs: A clinical candidate targeting a subnuclear structure unique to metastatic cancer cells.
Abstract Pancreatic cancer is a leading cause of cancer-related deaths in the U.S. Ninety percent of patients with stage IV pancreatic cancer die within one year of diagnosis due to complications of metastasis. A metastatic potential of cancer cells has been shown to be closely associated with formation of perinucleolar compartment (PNC). Metarrestin, a first-in-class PNC inhibitor, was evaluated for its toxicity, toxicokinetics, and safety pharmacology in beagle dogs following every other day oral (capsule) administration for 28 days to support its introduction into clinical trials. The study consisted of four do...
Source: Regulatory Toxicology and Pharmacology : RTP - June 30, 2020 Category: Toxicology Authors: Bourdi M, Rudloff U, Patnaik S, Marugan J, Terse PS Tags: Regul Toxicol Pharmacol Source Type: research

Template-based peptide modeling for celiac risk assessment of newly expressed proteins in GM crops.
Abstract Newly expressed proteins in genetically modified (GM) crops are subject to celiac disease risk assessment according to EFSA guidelines. Amino acid identity matches between short peptides (9aa) and known celiac restricted epitopes are required to be further evaluated through peptide modeling; however, validated methods and criteria are not yet available. In this investigation, several structures of HLA-DQ2.5/peptide/TCR (T-cell receptor) complexes were analyzed and two template-based peptide molding software packages were evaluated using various peptides including ones not associated with celiac disease. S...
Source: Regulatory Toxicology and Pharmacology : RTP - June 30, 2020 Category: Toxicology Authors: Song P, Hou Z, Sukumar S, Herman R Tags: Regul Toxicol Pharmacol Source Type: research

Bolstering the existing database supporting the non-cancer Threshold of Toxicological Concern values with toxicity data on fragrance-related materials.
Abstract The use of threshold of toxicological concern (TTC) supports the safety assessment of exposure to low levels of chemicals when toxicity data are limited. The Research Institute for Fragrance Materials (RIFM) delivers safety assessments for fragrance materials that result in safe products for consumer use. A major goal for the RIFM safety assessment program is to invest in alternative methods to animal testing for use in assessment of fragrance materials. This includes use of TTC, which provides a pragmatic approach for safety evaluation of fragrance materials in the absence of chemical-specific toxicity d...
Source: Regulatory Toxicology and Pharmacology : RTP - June 27, 2020 Category: Toxicology Authors: Patel A, Joshi K, Rose J, Laufersweiler M, Felter SP, Api AM Tags: Regul Toxicol Pharmacol Source Type: research

Clinical epidemiology studies on potential effects of endocrine disrupting chemicals (EDCs) should exclude subjects with obesity as determined by BMI.
Abstract Obesity as determined by BMI is a confounder in clinical evaluations of the effects of endocrine disrupting chemicals (EDCs). Validated regulatory tests are used to determine whether a chemical acts via a mode of action (MOA) that affects estrogen, androgen, thyroid or steroidogenic pathways. Test batteries for evaluating EDCs include QSAR, in vitro assays, and animal testing. Studies suggest that EDCs pose the greatest risk during prenatal and early infant development when organ systems are developing. Health effects include lowered fertility, endometriosis, and cancers associated with estrogenic activit...
Source: Regulatory Toxicology and Pharmacology : RTP - June 26, 2020 Category: Toxicology Authors: Smith CJ, Perfetti TA, Hayes AW, Berry SC Tags: Regul Toxicol Pharmacol Source Type: research

Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture.
Abstract Romosozumab (EVENITY™ [romosozumab-aqqg in the US]) is a humanized monoclonal antibody that inhibits sclerostin and has been approved in several countries for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Sclerostin is expressed in bone and aortic vascular smooth muscle (AVSM). Its function in AVSM is unclear but it has been proposed to inhibit vascular calcification, atheroprogression, and inflammation. An increased incidence of positively adjudicated serious cardiovascular adverse events driven by an increase in myocardial infarction and stroke was observed in rom...
Source: Regulatory Toxicology and Pharmacology : RTP - June 23, 2020 Category: Toxicology Authors: Turk JR, Deaton AM, Yin J, Stolina M, Felx M, Boyd G, Bienvenu JG, Varela A, Guillot M, Holdsworth G, Wolfreys A, Dwyer D, Kumar SV, de Koning EM, Qu Y, Engwall M, Locher K, Ward LD, Glaus C, He YD, Boyce RW Tags: Regul Toxicol Pharmacol Source Type: research

Corrigendum to "Assessment of the skin sensitisation hazard of functional polysiloxanes and silanes in the SENS-IS assay" [Regul. Toxicol. Pharmacol. 98 (2018) 209-214].
Corrigendum to "Assessment of the skin sensitisation hazard of functional polysiloxanes and silanes in the SENS-IS assay" [Regul. Toxicol. Pharmacol. 98 (2018) 209-214]. Regul Toxicol Pharmacol. 2020 Jun 18;:104710 Authors: Petry T, Bosch A, Koraïchi-Emeriau F, Eigler D, Germain P, Seidel S PMID: 32564919 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - June 18, 2020 Category: Toxicology Authors: Petry T, Bosch A, Koraïchi-Emeriau F, Eigler D, Germain P, Seidel S Tags: Regul Toxicol Pharmacol Source Type: research

Indicators for lack of systemic availability of organic pigments.
Abstract Experimental data of all 143 organic pigments registered with the European Chemicals Agency, of which 88 were listed in a nanomaterial inventory, was retrieved from the registered substance fact sheets. Availability of the data was 93% for solubility, 82% for bacterial mutagenicity, 79% for acute oral toxicity, 75% for irritation, 59% for skin sensitisation, 36% for repeated dose toxicity and 34% for each clastogenicity and mutagenicity in mammalian cells and 23% for toxicity to reproduction. Pigments mostly had a water and octanol solubility of significantly below 0.1 mg/L, but fourteen were found to b...
Source: Regulatory Toxicology and Pharmacology : RTP - June 18, 2020 Category: Toxicology Authors: Stratmann H, Hellmund M, Veith U, End N, Teubner W Tags: Regul Toxicol Pharmacol Source Type: research

Replacing the refinement for skin sensitization testing: Considerations to the implementation of adverse outcome pathway (AOP)-based defined approaches (DA) in OECD guidelines.
Abstract While single non-animal methods have been adopted in OECD test guidelines, combinations of methods (so called defined approaches, DA) are not. Hardly any animal study can be replaced by a single non-animal method, rather DA are needed. The OECD published the Adverse Outcome Pathway (AOP) on skin sensitization in 2012 and is currently discussing the implementation of DA into a guideline. Obviously, it takes thorough considerations and evaluations to validate such DA. Currently we see four preconditions for a proper and expedient implementation of DA in a guideline: (i) The reference data should be selected...
Source: Regulatory Toxicology and Pharmacology : RTP - June 17, 2020 Category: Toxicology Authors: Kolle SN, Landsiedel R, Natsch A Tags: Regul Toxicol Pharmacol Source Type: research

Yellow-colored extract from cashew byproduct - Nonclinical safety assessment.
This study aimed to evaluate the safety of oral consumption of one carotenoids and anacardic acids-enriched extract (CAE), obtained by green extraction from cashew apple residue fibers, a byproduct of the cashew juice industry. Presenting intense yellow color, CAE could be proposed as a new natural dye. Single and repeated-dose oral toxicity (30 days) were evaluated in female Swiss mice at doses ranging from 50 to 1000 mg/kg, while (anti)mutagenic effects were evaluated in CHO-K1 cells (in vitro Cytokinesis-Block Micronucleus assay - CBMN) and in erythrocytes collected from murine bone marrow (in vivo). CAE did not induc...
Source: Regulatory Toxicology and Pharmacology : RTP - June 17, 2020 Category: Toxicology Authors: Goulart da Silva G, Della Torre A, Elaine de Oliveira Braga L, Bachiega P, Tinti SV, Ernesto de Carvalho J, Dionísio AP, Ruiz ALTG Tags: Regul Toxicol Pharmacol Source Type: research

Calculating safety margins using total plasma concentration versus unbound plasma concentration - Does it make a difference?
Abstract Safety margin, a key aspect of any non-clinical toxicity studies, is calculated by dividing the systemic exposure (AUC) at NOAEL (No Adverse Effect Level) in toxicity studies by the clinical exposure. The validity of using total plasma concentration (Cp) to calculate AUC is often discussed, as it is the unbound plasma concentration (Cup) that elicits the pharmacological and toxicological effects. Data regarding plasma protein binding across species was collected for 114 MSD small molecule compounds which had been discontinued from development either due to non-clinical toxicity or due to clinical Adverse ...
Source: Regulatory Toxicology and Pharmacology : RTP - June 15, 2020 Category: Toxicology Authors: Mukherjee SK, Ferry JB Tags: Regul Toxicol Pharmacol Source Type: research

Establishing health-based biological exposure limits for pesticides: A proof of principle study using mancozeb.
This study aims at establishing equivalent biological exposure limits (EBEL) for pesticides using real-life field data and the Acceptable Operator Exposure Level (AOEL) of mancozeb as the reference. This study included a group of 16 vineyard pesticide applicators from Northern Italy, a subgroup of a more extensive study of 28 applicators. Their exposure was estimated using "patch" and "hand-wash" methodologies, together with biological monitoring of free ethylene-bis-thiourea (ETU) excretion in 24-h pre- and post-exposure urine samples. Modeling was done using univariate linear regression with ETU excre...
Source: Regulatory Toxicology and Pharmacology : RTP - June 13, 2020 Category: Toxicology Authors: Mandić-Rajčević S, Rubino FM, Colosio C Tags: Regul Toxicol Pharmacol Source Type: research

Safety evaluation of E12, W8, X17, and Y9 potatoes: Nutritional evaluation and 90-day subchronic feeding study in rats.
Abstract The nutritional and health effects of four biotech potato events, E12, W8, X17, and Y9, were evaluated in a subchronic rodent feeding study. E12 contains pSIM1278 insert DNA derived from potato and designed to down regulate potato genes through RNAi. These changes result in reduced black spot and reduced acrylamide. W8, X17, and Y9 contain the DNA inserts from pSIM1278 and pSIM1678 to further reduce acrylamide and express a gene from wild potato that protects against late blight. Rats were fed diets containing 20% cooked, dried potatoes from these four events and three conventional potato varieties. Compo...
Source: Regulatory Toxicology and Pharmacology : RTP - June 12, 2020 Category: Toxicology Authors: Mukerji P, Rudgers GW, Gibson C, Roper JM Tags: Regul Toxicol Pharmacol Source Type: research

Assessment of lead exposure controls on bridge painting projects using worker blood lead levels.
The objective of the study was to evaluate the effectiveness of exposure controls in preventing elevated blood lead levels (>25 μg/dl) during bridge painting projects. The contractors selected for the study submitted BLL data for 289 workers representing ten work tasks and 11 bridge painting projects. In total, 713 blood lead levels results were evaluated. The mean blood lead level for all work classifications combined was 10.9 μg/dl at baseline compared with 14.9 μg/dl after two months of exposure and 15.0 μg/dl after four months of exposure. Two months after initial exposure, 29% of the painters an...
Source: Regulatory Toxicology and Pharmacology : RTP - June 10, 2020 Category: Toxicology Authors: Guth K, Bourgeois M, Johnson G, Harbison R Tags: Regul Toxicol Pharmacol Source Type: research

Safety evaluation of Ochratoxin A and citrinin after 28 days repeated dose oral exposure to Wistar rats.
Abstract Mycotoxins, ochratoxin A (OTA), and citrinin (CTN) are toxic metabolites of filamentous fungi. The most common fungal species that produce OTA and CTN belong to genera Aspergillus, Penicillium, Fusarium, and Monascus, and these fungal species are found to be contaminant a wide range of grains, food, and food product. The aim of our study was to evaluate the sub-acute repeated dose oral toxicity of OTA and CTN in experimental rodents by following OECD test guidelines for testing chemicals no. 407 with minor modifications. Twenty-five rats of each sex were divided equally into five groups; vehicle control, ...
Source: Regulatory Toxicology and Pharmacology : RTP - June 7, 2020 Category: Toxicology Authors: Jagdale PR, Indradev, Ayanur A, Singh D, Arshad M, Ansari KM Tags: Regul Toxicol Pharmacol Source Type: research

Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2.
Abstract In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intrave...
Source: Regulatory Toxicology and Pharmacology : RTP - June 6, 2020 Category: Toxicology Authors: Gromek K, Hawkins W, Bernier T, Sehner C, Zeller E, Schwind M, Pfister T, Kohan M, Osalodor O, Glogovac M, Tuschl G, Dolan D, Barle EL Tags: Regul Toxicol Pharmacol Source Type: research

How the 62-year old Delaney Clause continues to thwart science: Case study of the flavor substance β-myrcene.
How the 62-year old Delaney Clause continues to thwart science: Case study of the flavor substance β-myrcene. Regul Toxicol Pharmacol. 2020 Jun 06;:104708 Authors: Felter SP, Llewelyn C, Navarro L, Zhang X Abstract The Delaney Clause is a provision of the 1958 Food Additive Amendment to the Food, Drug and Cosmetic Act of 1938 which stipulates that if a substance is found by the Food and Drug Administration to be carcinogenic in any species of animal or in humans, then it cannot be used as a food additive. This paper presents a case study of β-myrcene, one of seven synthetic substances that w...
Source: Regulatory Toxicology and Pharmacology : RTP - June 6, 2020 Category: Toxicology Authors: Felter SP, Llewelyn C, Navarro L, Zhang X Tags: Regul Toxicol Pharmacol Source Type: research

Response to "OECD 428 in vitro dermal absorption mass balance performance based on our in-house database of pesticide studies".
Response to "OECD 428 in vitro dermal absorption mass balance performance based on our in-house database of pesticide studies". Regul Toxicol Pharmacol. 2020 Jun 05;:104707 Authors: Kluxen FM, Grégoire S, Schepky A, Hewitt NJ, Klaric M, Domoradzki JY, Felkers E, Fisher P, McEuen SF, Parr-Dobrzanski R, Fabian E, Wiemann C PMID: 32512117 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - June 5, 2020 Category: Toxicology Authors: Kluxen FM, Grégoire S, Schepky A, Hewitt NJ, Klaric M, Domoradzki JY, Felkers E, Fisher P, McEuen SF, Parr-Dobrzanski R, Fabian E, Wiemann C Tags: Regul Toxicol Pharmacol Source Type: research

Safety assessment of astaxanthin from Haematococcus pluvialis: Acute toxicity, genotoxicity, distribution and repeat-dose toxicity studies in gestation mice.
Abstract Natural astaxanthin is the strongest antioxidant ever discovered, with many biological functions, and it is widely used in the fields of health food and biomedical research. In the present study, we aimed to investigate the plasma concentration, distribution and safety of astaxanthin from Haematococcus pluvialis in pregnant mice. In the acute studies, the oral LD50 of astaxanthin was greater than 20 g/kg·bw. In mouse bone marrow micronucleus test, 10 g/kg·bw astaxanthin did not cause damage to chromosomes and mitotic apparatus of pregnant mice. After treatment with a single dose of 500...
Source: Regulatory Toxicology and Pharmacology : RTP - June 5, 2020 Category: Toxicology Authors: Niu T, Zhou J, Wang F, Xuan R, Chen J, Wu W, Chen H Tags: Regul Toxicol Pharmacol Source Type: research

A novel approach to monitor skin permeation of metals in vitro.
This study provides proof-of-concept for a method that reliably detects concentration changes in physiologically relevant medium. It may shed light on skin absorption and permeation kinetics of metals and risks associated with metal exposure. PMID: 32505642 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - June 4, 2020 Category: Toxicology Authors: Midander K, Schenk L, Julander A Tags: Regul Toxicol Pharmacol Source Type: research

Meta-analysis of animal studies applied to short-term inhalation exposure levels of hazardous chemicals.
Abstract For short-term chemical inhalation exposures to hazardous chemicals, the incidence of a health effect in biological testing usually conforms to a general linear model with a probit link function dependent on inhalant concentration C and the duration of exposure t. The National Academy's Acute Exposure Guideline Levels (AEGLs) Committee relies on these models when establishing AEGLs. Threshold concentrations at AEGL durations are established by the toxic load equation Cn x t = constant, which toxic load exponent n (TLE or n-value) directly follows from the bivariate probit model. When multiple probit d...
Source: Regulatory Toxicology and Pharmacology : RTP - June 3, 2020 Category: Toxicology Authors: Prussia AJ, Hill J, Cornwell CR, Siwakoti RC, Demchuk E Tags: Regul Toxicol Pharmacol Source Type: research

PBPK model reporting template for chemical risk assessment applications.
Abstract Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting t...
Source: Regulatory Toxicology and Pharmacology : RTP - June 2, 2020 Category: Toxicology Authors: Tan YM, Chan M, Chukwudebe A, Domoradzki J, Fisher J, Hack CE, Hinderliter P, Hirasawa K, Leonard J, Lumen A, Paini A, Qian H, Ruiz P, Wambaugh J, Zhang F, Embry M Tags: Regul Toxicol Pharmacol Source Type: research

Confidence interval function analysis to evaluate the risk of mesothelioma among an expanded international cohort of cosmetic talc miners and millers.
Abstract We used pooled data from international cosmetic talc miner/miller cohorts to determine whether hypothesized increased mesothelioma risks are consistent with the observed data. We evaluated the confidence interval function for the observed pooled mesothelioma SMRs (observed = 1; expected = 3.17, 3.34, or 3.60), and calculated the value of α for the upper 100(1 - 2α)% confidence limit that equals various SMRs of interest (1.5, 2.0, 2.5, 3.0). Using the mid-value estimate of expected number of cases (3.34) the probability (α) that the true mesothelioma SMR is at or above 2.0, or at ...
Source: Regulatory Toxicology and Pharmacology : RTP - May 31, 2020 Category: Toxicology Authors: Marsh GM, Ierardi AM Tags: Regul Toxicol Pharmacol Source Type: research

Pulmonary toxicity of silver vapours, nanoparticles and fine dusts: A review.
Abstract Silver is used in a wide range of products, and during their production and use, humans may be exposed through inhalation. Therefore, it is critical to know the concentration levels at which adverse effects may occur. In rodents, inhalation of silver nanoparticles has resulted in increased silver in the lungs, lymph nodes, liver, kidney, spleen, ovaries, and testes. Reported excretion pathways of pulmonary silver are urinary and faecal excretion. Acute effects in humans of the inhalation of silver include lung failure that involved increased heart rate and decreased arterial blood oxygen pressure. Argyria...
Source: Regulatory Toxicology and Pharmacology : RTP - May 28, 2020 Category: Toxicology Authors: Hadrup N, Sharma AK, Loeschner K, Jacobsen NR Tags: Regul Toxicol Pharmacol Source Type: research

Risk assessment of unintentional phthalates contaminants in cosmetics.
Abstract A risk assessment was performed for three types of phthalates, benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), and di(2-ethylhexyl)phthalate (DEHP) unintentionally contaminated in cosmetics. A total of 100 products of 8 types of cosmetics were analyzed employing gas chromatography-mass spectrometry (GC-MS). By applying the maximum detected values of phthalates based on the worst exposure cases, their systemic exposure dosage (SED) was calculated. Accordingly, DEHP was identified as the main unintentional phthalates contaminants (0.10-600.00 ppm) in the cosmetics, with an SED of 3.37 × 1...
Source: Regulatory Toxicology and Pharmacology : RTP - May 28, 2020 Category: Toxicology Authors: Kim MK, Kim KB, Yoon S, Kim HS, Lee BM Tags: Regul Toxicol Pharmacol Source Type: research

Effect of low- and high-level groundwater arsenic on peripheral blood and lung function of exposed rural women.
Abstract The World Health Organization (WHO) recommended maximum contaminant level (MCL) of arsenic (As) in drinking water at 10 μg/L. Many Asian countries still have their MCL for As at 50 μg/L. The current cross sectional study was conducted on asymptomatic females (without As related skin lesions) selected from rural areas of West Bengal, Baruipur and Dhamakhali [low As 11-50 μg/L; N,93]; Kamardanga & Sibhati [high As>200 μg/L; N,70] and Boria [Control; As
Source: Regulatory Toxicology and Pharmacology : RTP - May 23, 2020 Category: Toxicology Authors: Prasad P, Sarkar N, Sinha D Tags: Regul Toxicol Pharmacol Source Type: research

Toxicological testing of a photoactive phthalocyanine-based antimicrobial substance.
ki M, Heinonen T, Jírová D, Letašiová S, Kandarova H, Kolářová H Abstract The aim of the study was toxicological testing of an innovative and efficient antimicrobial agent based on photoactive phthalocyanine (Pc) derivative. A promising Aluminium phthalocyanine (AlPc) with efficient and stable antimicrobial effects was subjected to a battery of toxicological tests to avoid local and systemic toxicity hazard. In compliance with the current European legislation restricting the use of experimental animals, the methods comprised exclusively in vitro procedures based on cellul...
Source: Regulatory Toxicology and Pharmacology : RTP - May 23, 2020 Category: Toxicology Authors: Kejlová K, Bendová H, Chrz J, Dvořáková M, Svobodová L, Vlková A, Kubáč L, Kořínková R, Černý J, Očadlíková D, Rucki M, Heinonen T, Jírová D, Letašiová S, Kandarova H, Kolářová H Tags: Regul Toxicol Pharmacol Source Type: research

Toxicological evaluation of exosomes derived from human adipose tissue-derived mesenchymal stem/stromal cells.
Abstract Several studies report that the therapeutic mechanism of action of mesenchymal stem/stromal cells (MSCs) is mainly mediated by paracrine factors that are released from MSCs such as exosomes. Exosomes are nano-sized extracellular vesicles that are transferred to target cells for cell-to-cell communication. Although MSC-derived exosomes (MSC-exosomes) are suggested as novel cell-free therapeutics for various human diseases, evaluation studies for the safety and toxicity of MSC-exosomes are limited. The purpose of our study was to evaluate the toxicological profile, including skin sensitization, photosensiti...
Source: Regulatory Toxicology and Pharmacology : RTP - May 22, 2020 Category: Toxicology Authors: Ha DH, Kim SD, Lee J, Kwon HH, Park GH, Yang SH, Jung JY, Lee JH, Park SR, Youn J, Lee SH, Kim JE, Lim J, Lee HK, Cho BS, Yi YW Tags: Regul Toxicol Pharmacol Source Type: research

Hydroalcoholic extract of leaf of Arachis hypogaea L. (Fabaceae) did not induce toxic effects in the repeated-dose toxicity study in rats.
cute;ffel RC, Sagrillo MR, Machado AK, Santos ARS, Trevisan G Abstract Arachis hypogaea L. (peanut) leaf is traditionally used for the treatment of insomnia in Asia. However, studies describing the safety and toxicity profile for this plant preparation are limited. Thus, the goal of this study was to investigate the toxicity of peanut leaf hydroalcoholic extract (PLHE) repeated treatment. The extract was administered orally (100, 300 or 1000 mg/kg) in male and female Wistar rats for 28 days (OECD guideline 407). PLHE treatment did not cause mortality or weight variation in the animals. Also, there was no alterat...
Source: Regulatory Toxicology and Pharmacology : RTP - May 13, 2020 Category: Toxicology Authors: Cossetin JF, de Almeida AS, de David Antoniazzi CT, Kudsi SQ, Engelmann AM, Guex CG, de Oliveira JS, Theisen MC, Ritter CS, Doleski PH, da Silva Brum E, Dalenogare DP, Peres DS, Pintos FG, de Andrade CM, Leal DBR, Oliveira SM, de Freitas Bauermann L, Rié Tags: Regul Toxicol Pharmacol Source Type: research

Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation.
Abstract This work provides case studies for the pharmacokinetic (PK) analog approach, where a physiologically based pharmacokinetic (PBPK) model for a target chemical (has no PK data) is evaluated using PK data from a source chemical (has existing PK data). A bottom up PBPK modeling approach (using in vitro and in silico inputs) is used to develop human oral PBPK models for caffeine and diphenhydramine. Models are evaluated using in vivo data from structural and functional PK analogs. At the end of the case studies, in vivo PK data for caffeine and diphenhydramine is introduced and both models were able to simula...
Source: Regulatory Toxicology and Pharmacology : RTP - May 5, 2020 Category: Toxicology Authors: Ellison CA, Wu S Tags: Regul Toxicol Pharmacol Source Type: research

An evaluation of the genotoxicity and subchronic toxicity of the peel extract of Ponkan cultivar 'Ohta ponkan' (Citrus reticulata Blanco) that is rich in nobiletin and tangeretin with anti-dementia activity.
In this study, a series of toxicological studies on the peel extract of Ponkan cultivar 'Ohta ponkan' (Citrus reticulata Blanco), was conducted. No mutagenic activity was observed in a bacterial reverse mutation test, whereas chromosomal aberrations were induced in an in vitro mammalian chromosomal aberration test. No genotoxicity was observed in an in vivo mammalian micronucleus test. In a 90-day study at daily doses of 54, 180, or 540 mg/kg body weight (bw)/day, hyaline droplet nephropathy, which specifically occurs in adult male rats, was observed in males of 540 mg/kg bw/day group. No other adverse effects were o...
Source: Regulatory Toxicology and Pharmacology : RTP - May 1, 2020 Category: Toxicology Authors: Nakajima A, Nemoto K, Ohizumi Y Tags: Regul Toxicol Pharmacol Source Type: research