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Regulatory Toxicology and Pharmacology: RTP

Richard J Albertini
All of the lower alkyl methacrylates are high production chemicals with potential for human exposure. The genotoxicity of seven mono-functional alkyl esters of methacrylic acid, i.e. methyl methacrylate, ethyl methacrylate, hydroxyethyl methacrylate, n-, i- and t-butyl methacrylate and 2 ethyl hexyl methacrylate, as well as methacrylic acid itself, the acyl component common to all, is reviewed and compared with the lack of carcinogenicity of methyl methacrylate, the representative member of the series so evaluated...
January 10, 2017: Regulatory Toxicology and Pharmacology: RTP
Chris Barber, Thierry Hanser, Philip Judson, Richard Williams
The ICH M7 guideline for the identification of DNA reactive (genotoxic) impurities draws a distinction between expert and statistical systems. This paper describes factors that can help discriminate between the two systems and how to avoid co-developing them in a way that undermines either their independence or the orthogonality expected by the guidelines.
January 2, 2017: Regulatory Toxicology and Pharmacology: RTP
James Harvey, Andrew Fleetwood, Ron Ogilvie, Andrew Teasdale, Phil Wilcox, Steven Spanhaak
Management of organic non-mutagenic impurities (NMIs) in medicinal products is regulated by the ICH Q3A, B and C guidelines that are applicable at late stages of clinical development (Phase III onwards) and as a consequence there is no guidance for the assessment and control of NMIs in early clinical trials. An analysis of several key in vivo toxicology databases supports the ICH Q3A defined concept that a lifetime dose to 1 mg/day of a NMI would not represent a safety concern to patients. In conjunction with routine (Q)SAR approaches, this 1 mg/day value could be used as a universal qualification threshold for a NMI during any stage of clinical development...
December 27, 2016: Regulatory Toxicology and Pharmacology: RTP
Harris R Lieberman, Mark D Kellogg, Victor L Fulgoni, Sanjiv Agarwal
: It is difficult to determine if certain dietary supplements are safe for human consumption. Extracts of leaves of Ginkgo biloba trees are dietary supplements used for various purported therapeutic benefits. However, recent studies reported they increased risk of liver cancer in rodents. Therefore, this study assessed the association between ginkgo consumption and liver function using NHANES 2001-2012 data (N = 29,684). Since alcohol is known to adversely affect liver function, association of its consumption with liver function was also assessed...
December 24, 2016: Regulatory Toxicology and Pharmacology: RTP
Thomas Petry, Axel Bosch, Xavier Coste, Dorothea Eigler, Pierre Germain, Shawn Seidel, Paul A Jean
The skin sensitization potential of chemicals has traditionally been evaluated in vivo according to OECD testing guidelines in guinea pigs or the mouse local lymph node assay. There has lately been a great emphasis on establishing in vitro test methods reflecting the key biological events in the adverse outcome pathway (AOP) for skin sensitization as published by the OECD. Against this background, a group of 8 polysiloxanes and silanes, seven of them aminofunctionalised, for which in vivo data were already available, has been tested in vitro in the direct peptide reactivity assay (DPRA), the KeratinoSens™ and the human cell line activation test (h-CLAT) and in the modified myeloid U937 skin sensitization test (mMUSST) as far as technically feasible...
December 22, 2016: Regulatory Toxicology and Pharmacology: RTP
Angela L Perez, Melanie Nembhard, Andrew Monnot, Daniel Bator, Elizabeth Madonick, Shannon H Gaffney
Costume cosmetics (lipstick, body paints, eyeshadow) were analyzed for metals using inductively coupled plasma mass spectrometry (ICP-MS). Sb was detected in all samples (range: 0.12-6.3 mg/kg; d.f. 100%), followed by Pb (<0.15-9.3 mg/kg), Ni (<0.20-6.3 mg/kg), Co (<0.5-2.0 mg/kg); with d.f. 80% each, Hg (<0.00015-0.0020 mg/kg; d.f. 50%) and As (0.53 mg/kg, d.f. 10%). Ingestion and dermal exposures were estimated for child- and adult-intermittent and adult-occupational users. Adult-occupational users exceeded the U...
December 19, 2016: Regulatory Toxicology and Pharmacology: RTP
Mats-Olof Mattsson, Myrtill Simkó
Risk assessment (RA) of manufactured nanomaterials (MNM) is essential for regulatory purposes and risk management activities. Similar to RA of "classical" chemicals, MNM RA requires knowledge about exposure as well as of hazard potential and dose response relationships. What makes MNM RA especially challenging is the multitude of materials (which is expected to increase substantially in the future), the complexity of MNM value chains and life cycles, the accompanying possible changes in material properties over time and in contact with various environmental and organismal milieus, and the difficulties to obtain proper exposure data and to consider the proper dose metric...
December 18, 2016: Regulatory Toxicology and Pharmacology: RTP
Gopinath C Nallani, Shaaban F ElNaggar, Li Shen, Appavu Chandrasekaran
The in vitro comparative animal metabolism study is now a data requirement under EU Directive 1107/2009 for registration of plant protection products. This type of study helps determine the extent of metabolism of a chemical in each surrogate species and whether any unique human metabolite(s) are formed. In the present study, metabolism of racemic [(14)C]-benalaxyl, a fungicide was investigated in cryopreserved rat, dog and human hepatocytes. The metabolites generated were identified/characterized by LC/MS/MS with radiometric detection and comparison with reference standards...
December 18, 2016: Regulatory Toxicology and Pharmacology: RTP
Pitchai Balakumar, Wei Ern WitnessKoe, Yi Syen Gan, Soo Mei JemayPuah, Subramaniam Kuganesswari, Sunil Kumar Prajapati, Rajavel Varatharajan, Sam Annie Jayachristy, Karupiah Sundram, Mohd Baidi Bahari
This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats...
December 18, 2016: Regulatory Toxicology and Pharmacology: RTP
Erina Hanaki, Mikayo Hayashi, Makoto Matsumoto
Nitro-containing compounds such as nitrofuran and nitroimidazole are drugs used for the treatment of infectious diseases. However, many of these nitro-containing drugs are positive in the bacterial reverse mutation assay (Ames test). The recently approved anti-multidrug-resistant tuberculosis (MDR-TB) drug, delamanid (Deltyba™; OPC-67683), a derivative of 4-nitroimidazole, was negative for mutagenicity in the Ames assay. In Salmonella typhimurium, mutagenicity of nitro compounds has been closely associated with the ability of nitroreductase to metabolize (degradation)these compounds...
December 14, 2016: Regulatory Toxicology and Pharmacology: RTP
H R Pohl, M Citra, H A Abadin, I Szadkowska-Stańczyk, A Kozajda, L Ingerman, A Nguyen, H E Murray
The world-wide use of concentrated animal feeding operations (CAFOs) for livestock production demands the need to evaluate the potential impact to public health. We estimated the exposure of various airborne pollutants for populations residing in close proximity to 10 poultry CAFOs located in Central Poland. Ammonia (NH3), carbon dioxide (CO2), carbon monoxide (CO), hydrogen sulfide (H2S), methane (CH4), nitrogen dioxide (NO2), nitrous oxide (N2O), sulfur dioxide (SO2), and organic dust were the pollutants of interest for this study...
December 13, 2016: Regulatory Toxicology and Pharmacology: RTP
Zina Kobbi, Hazar Kraiem, Zakaria Benlasfar, Ammar Marouani, Taieb Massoud, Samir Boubaker, Balkiss Bouhaouala-Zahar, Nadia Fenina
Enoxaparin is a low-molecular-weight heparin widely used for the prevention and treatment of thromboembolism. With the development of several enoxaparin biosimilars, real medical concerns about their safety and efficacy have been raised. This repeated dose toxicity study consists of preclinical toxicological evaluation of a biosimilar biological version of enoxaparin, the drug product "Enoxa", compared to the enoxaparin reference drug product, "Lovenox". Eighty white Wistar rats were treated with "Enoxa" versus the reference product, using subcutaneous therapeutic and toxic doses, varying from 3...
December 10, 2016: Regulatory Toxicology and Pharmacology: RTP
Christophe Rousselle
No abstract text is available yet for this article.
November 14, 2016: Regulatory Toxicology and Pharmacology: RTP
Thomas Colnot, Wolfgang Dekant
The European Food Safety Authority (EFSA) is developing approaches to cumulative risk assessment of pesticides by assigning individual pesticides to cumulative assessment groups (CAGs). For assignment to CAGs, EFSA recommended to rely on adverse effects on the specific target system. Contractors to EFSA have proposed to allocate individual pesticides into CAGs relying on NOAELs for effects on target organs. This manuscript evaluates the assignments by applying EFSAs criteria to the CAGs "Toxicity to the nervous system" and "Toxicity to the thyroid hormone system (gland or hormones)"...
February 2017: Regulatory Toxicology and Pharmacology: RTP
Xiaoyan Xing, Xuehong Deng, Jinjin Shi, Meishuang Zhang, Guibo Sun, Shimin Tang, Qiuling Huang, Xiaobo Sun
Zishen Yutai pill (ZYP) is an oriental herbal formula, while hepatotoxicity assessment of ZYP was rarely evaluated. Therefore, our aim is to re-evaluate its hepatotoxicity in both normal and carbon tetrachloride (CCl4) induced chronic liver injury rats. In the normal model, two doses of ZYP (1.575 and 9.450 g kg(-1) d(-1); i.e. 1 × , 6 × clinical doses) were given orally to rats for 24 weeks. In the chronic liver injury model, 10% CCl4 was administered to rats abdominally twice a week at a dose of 5 mL kg(-1) for 12 consecutive weeks...
February 2017: Regulatory Toxicology and Pharmacology: RTP
Ricardo Arrieta-Cortes, Paulina Farias, Carlos Hoyo-Vadillo, Mina Kleiche-Dray
: Perfluoroalkyls are stable synthetic chemicals, able to repel oils, fats and water. These compounds have been used in the manufacturing of products such as Teflon(®), lubricants, paints, fire-fighting foams, coatings for pans, carpets, clothes, and paperboard for packaging, among others. It is believed that populations are exposed constantly to them. Its regulation in the world is under development and several controversies are in the course of litigation. One occupational study shows bladder cancer risk...
February 2017: Regulatory Toxicology and Pharmacology: RTP
Laurence H Hand, Kevan Richardson, Stephen T Hadfield, Sarah Whalley, Paul Rawlinson, Ewan D Booth
This paper describes the further development of a read-across approach applicable to the toxicological assessment of structurally-related xenobiotic metabolites. The approach, which can be applied in the absence of definitive identification of all the individual metabolites, draws on the use of chemical descriptors and multi-variate statistical analysis to define a composite "chemical space" and to classify and characterize closely-related subgroups within this. In this example, consideration of the descriptors driving grouping, combined with empirical evidence for lack of significant further biotransformation of metabolites, leads to the conclusion that, in the absence of any specific structural alerts, the relative toxicity of metabolites within a single grouping will be determined by their relative systemic exposure as described by their ADME characteristics...
February 2017: Regulatory Toxicology and Pharmacology: RTP
Ian Kimber, G Frank Gerberick, David A Basketter
Skin sensitization is unique in the world of toxicology. There is a combination of reliable, validated predictive test methods for identification of skin sensitizing chemicals, a clearly documented and transparent approach to risk assessment, and effective feedback from dermatology clinics around the world delivering evidence of the success or failure of the hazard identification/risk assessment/management process. Recent epidemics of contact allergy, particularly to preservatives, have raised questions of whether the safety/risk assessment process is working in an optimal manner (or indeed is working at all!)...
February 2017: Regulatory Toxicology and Pharmacology: RTP
Nor Aijratul Asikin Mohamad Shalan, Noordin M Mustapha, Suhaila Mohamed
Noni (Morinda citrifolia) leaf and fruit are used as food and medicine. This report compares the chronic toxicity of Noni fruit and edible leaf water extracts (two doses each) in female mice. The 6 months study showed the fruit extract produced chronic toxicity effects at the high dose of 2 mg/ml drinking water, evidenced through deteriorated liver histology (hepatocyte necrosis), reduced liver length, increased liver injury marker AST (aspartate aminotransferase) and albumin reduction, injury symptoms (hypoactivity, excessive grooming, sunken eyes and hunched posture) and 40% mortality within 3 months...
February 2017: Regulatory Toxicology and Pharmacology: RTP
Dr Christophe Rousselle
No abstract text is available yet for this article.
February 2017: Regulatory Toxicology and Pharmacology: RTP
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