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Regulatory Toxicology and Pharmacology: RTP

Nigel S B Rawson
The Canadian federal government has proposed significant revisions to the way its patented medicines price regulator assesses the excessiveness of medication prices that are to take effect in 2019. The changes have the potential to decrease Canada's attractiveness as a market for innovative medicines. The objective of this analysis was to compare the number of new drugs given regulatory approval in Canada between 2002 and 2017 with the number in New Zealand and, of those approved in both countries, to compare approval dates...
November 1, 2018: Regulatory Toxicology and Pharmacology: RTP
Saima Amjad, A K Sharma, M Serajuddin
A comparative toxicity assessment was performed to evaluate the effect of cypermethrin nanoparticles (CypNPs) and cypermethrin (Cyp) on murrel, Channa punctatus. Size variation and shape morphology of nanoparticles were confirmed by scanning electron microscopy, UV-Vis absorption spectroscopy and transmission electron microscopy. CypNPs presented shoulder band at a wavelength of 277 nm and size range between 29.23 nm and 49.28 nm. The individuals of C. punctatus were exposed to two sublethal doses of LC50 viz 1/20th (S1 ) of LC50 and 1/10th (S2 ) of LC50 of CypNPs (20...
October 27, 2018: Regulatory Toxicology and Pharmacology: RTP
J Nicolette, E Dakoulas, K Pant, M Crosby, A Kondratiuk, J Murray, P Sonders, R Kulkarni, G Jayakumar, M Mathur, A Patel, R Vicente, K Datta, K Kolaja
The bacterial reverse mutation assay (Ames) is a fundamental genetic toxicology test, and efforts to miniaturize the regulatory GLP version are essential in assessing genotoxic liabilities earlier in the drug development pipeline. Two versions of the Ames were compared: the six-well (miniaturized) plate and the standard 100-mm plate test at two different laboratories. Of twenty-four chemicals tested, a subset of six chemicals was tested in the six-well test only and the remaining eighteen were evaluated in both versions of the test...
October 26, 2018: Regulatory Toxicology and Pharmacology: RTP
Diwas Pradhan, Rajbir Singh, Ashish Tyagi, Rashmi H M, V K Batish, Sunita Grover
Lactobacilli have a long history of safe use in human nutrition, however, inclusion of any new strain, despite its safe usage evidence, warrants proper analysis of its safety and toxicity under the purview of existing regulations. In the present investigation, Lactobacillus plantarum MTCC 5690 and Lactobacillus fermentum MTCC 5689 were evaluated for their safety and toxicity using both in vitro and in vivo approaches. The in vitro assays included mucin degradation, hemolytic activity, biogenic amine production and platelet aggregation assay...
October 24, 2018: Regulatory Toxicology and Pharmacology: RTP
Peter N Lee, Smilja Djurdjevic, Rolf Weitkunat, Gizelle Baker
We estimated, using previously described methodology, the population health impact of introducing a reduced-risk tobacco product (RRP) into Japan. Various simulations were carried out to understand the impact on the population in different situations over a 20-year period from 1990. The overall reduction in tobacco-attributable deaths from lung cancer (LC), ischemic heart disease (IHD), stroke, and chronic obstructive pulmonary disease (COPD) for men and women combined was estimated to be 269,916 over the period if tobacco use disappeared completely at baseline...
October 24, 2018: Regulatory Toxicology and Pharmacology: RTP
Ester Lovsin Barle, Thomas Pfister, Cornelia Fux, Dieter Röthlisberger, Dhananjay Jere, Hanns-Christian Mahler
A toxicological evaluation to determine the product specific permitted daily exposure (PDE) value is an accepted method to determine a safe limit for the carry-over of product residues in multipurpose manufacturing facilities. The PDE calculation for intravitreal (IVT) injection of small and large molecular weight (MW) drugs follows the guiding principles set for systemic administration. However, there are specific differences with respect to the volume administered with IVT administration, pharmacokinetic and pharmacodynamics (PK-PD) parameters and potential for toxicity...
October 24, 2018: Regulatory Toxicology and Pharmacology: RTP
Ruth J Bevan, Reinhard Kreiling, Leonard S Levy, David B Warheit
In 2013, an ECETOC Task Force evaluated scientific understanding of the 'lung overload' hypothesis. As there is no evidence that humans develop lung tumours following exposure to poorly soluble particles (PSPs), emphasis was given to the observed higher sensitivity and specificity of rat lung responses and potential impacts of this on human risk assessment. Key arguments and outcomes are summarised here, together with discussion of additional findings published since 2013. Inhalation exposure to PSPs in all species is associated with localised pulmonary toxicity initiated by a persistent pro-inflammatory response to particle deposition...
October 23, 2018: Regulatory Toxicology and Pharmacology: RTP
Wei Guo, Yonglin Gao, Wanglin Jiang, Chunmei Li, Fei Lin, Haibo Zhu, Hongbo Wang, Liang Ye, Jia Grace Qi, Xiaobo Cen, Jingwei Tian
Selective serotonin reuptake inhibitors (SSRIs) have developed as novel antidepressants and have been determined to possess higher efficacy and less adverse effects compared to other antidepressants. Our previous studies have showed that LPM570065, a new potent TRI, is relatively nontoxic in acute, subchronic toxicity and genotoxicity evaluations. In the current study, toxicity of LPM570065 was further evaluated on the fertility and early embryonic development in Sprague-Dawley rats. A total of 264 rats were treated with various concentrations of LPM570065 (30 mg/kg, 100 mg/kg, and 300 mg/kg) or used as control...
October 23, 2018: Regulatory Toxicology and Pharmacology: RTP
John C Fuller, Lisa M Pitchford, Naji N Abumrad, John A Rathmacher
2-hydroxybenzylamine (2-HOBA), a naturally occurring compound found in buckwheat, has potential for use as a nutrition supplement due to its ability to protect against the damaging effects of oxidative stress. In a series of rodent toxicity studies, 2-HOBA acetate was well-tolerated and did not produce any toxic effects over 28 or 90 days of repeated oral administration. However, it remained necessary to test the potential toxicity of 2-HOBA acetate in a non-rodent species. In this investigation, 2-HOBA acetate was orally administered to male and female New Zealand White Rabbits for 90 days at doses of 100, 500, and 1000 mg·kg BW-1 ·day-1 (n = 5 per sex/group)...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Kohei Matsushita, Takeshi Toyoda, Tomomi Morikawa, Miwa Takahashi, Kaoru Inoue, Kumiko Ogawa
2-Ethylbutanal (2-EB) has been used as a flavoring agent. Here, we performed a 13-week subchronic toxicity study of 2-EB in F344 rats. 2-EB was given orally by gavage, using doses of 0, 50, 200 or 800 mg/kg BW/day. Reduced body weight gain was noted in both sexes at 800 mg/kg BW. Hematologic assessment showed a decrease in platelet counts in males at 200 mg/kg BW and both sexes at 800 mg/kg BW. Serum biochemistry demonstrated increases in inorganic phosphorus in both sexes at 200 and 800 mg/kg BW, increases in glucose in females at 200 and 800 mg/kg BW and increases in urea nitrogen in both sexes at 800 mg/kg BW...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Shouyi Wang, Qingtao Zhang, Yurong Yu, Ya Chen, Song Zeng, Ping Lu, Deyu Hu
The residue behavior and dietary intake risk of two fungicides (dimethomorph and pyraclostrobin) in grape (Vitis vinifera L.) were investigated from field trials. A modified quick, easy, cheap, effective, rugged, and safe method for simultaneously determining dimethomorph and pyraclostrobin residues in grape and soil was established using high performance liquid chromatography-tandem mass spectrometry. The average recoveries of dimethomorph and pyraclostrobin in the grape and soil matrices varied from 76.88% to 97...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Toshime Igarashi, Hiromasa Takashima, Michihito Takabe, Hiroshi Suzuki, Kazuo Ushida, Tomoko Kawamura, Mariko Matsumoto, Takako Iso, Shihori Tanabe, Kaoru Inoue, Atsushi Ono, Takashi Yamada, Akihiko Hirose
Benzyl salicylate is used as a fragrance ingredient and an ultraviolet light absorber, but its toxicity is unknown. Therefore, toxicity tests and hazard classification were conducted for screening assessment under the Japanese Chemical Substances Control Law. Benzyl salicylate was found to be non-genotoxic in vitro based on the chromosomal aberration test using Chinese hamster lung cells. However, the combined repeated-dose and reproductive/developmental screening toxicity test, in which male and female rats were administered benzyl salicylate by gavage at 0, 30, 100, or 300 mg/kg/day for 42 and 41-46 days, respectively, from 14 days before mating until postnatal Day 4, showed that repeated doses had major effects on the thymus, liver, epididymis, and femur at 100 and/or 300 mg/kg/day...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Lisa M Pitchford, John C Fuller, John A Rathmacher
β-Hydroxy-β-methylbutyrate (HMB) is a leucine metabolite available in calcium salt (CaHMB) and free acid forms as a sports nutrition ergogenic aid. HMB has also been used to support muscle health in the elderly and other populations needing to maintain muscle mass. Several human studies have reported safety data for CaHMB, and rodent sub-chronic toxicity studies have been conducted; however, there are no published genotoxicity studies for HMB. Therefore, three studies (a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and an in vivo mammalian cell micronucleus test) were performed...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Prachi Pradeep, Laura M Carlson, Richard Judson, Geniece M Lehmann, Grace Patlewicz
The application of toxic equivalency factors (TEFs) or toxic units to estimate toxic potencies for mixtures of chemicals which contribute to a biological effect through a common mechanism is one approach for filling data gaps. Toxic Equivalents (TEQ) have been used to express the toxicity of dioxin-like compounds (i.e., dioxins, furans, and dioxin-like polychlorinated biphenyls (PCBs)) in terms of the most toxic form of dioxin: 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). This study sought to integrate two data gap filling techniques, quantitative structure-activity relationships (QSARs) and TEFs, to predict neurotoxicity TEQs for PCBs...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Mohammed Bourdi, Marcelo Amar, Alan T Remaley, Pramod S Terse
Fx-5A peptide complex (Fx-5A), a High Density Lipoproteins (HDL) mimetic, has been shown to reduce atherosclerosis. The safety and toxicokinetics of Fx-5A administered IV by 30 min infusion at 8, 25 or 75 mg/kg body weight or vehicle, once every other day for 27 days, were assessed in cynomolgus monkeys. The Fx-5A was well tolerated at all doses. At the highest dose, there were statistically significant effects on hematology and clinical chemistry parameters that were considered non-adverse. Dose-dependent recoverable non-adverse erythrocytes morphological changes (acanthocytes, echinocytes, spherocytes, microcytes, and/or schistocytes) were observed...
October 22, 2018: Regulatory Toxicology and Pharmacology: RTP
Hye-Jung Kim, Albert W Lee, Chongjin Park
Microbacterium foliorum is a naturally occurring bacteria in cruciferous vegetables and ripened cheese. The safety of M. foliorum SYG27B-MF has been assessed in both acute and subchronic studies and a battery of mutagenicity and clastogenicity tests. In a single dose acute study, the LD50 of M. foliorum SYG27B-MF was greater than 3 g/kg bw or 5.1 × 1016 colony forming unit (CFU)/kg bw, the highest dose tested. In a 90-day subchronic toxicity study in 80 Sprague-Dawley rats, no animals died and there were no treatment-related abnormalities at doses of 0, 500, 1000, or 2000 mg/kg bw...
October 9, 2018: Regulatory Toxicology and Pharmacology: RTP
Silvia Valero García, Nieves Vila Clérigues, Victoria Fornés Ferrer, Eduardo López Briz, Jose Luis Poveda Andrés
We wanted to evaluate the impact of Mini-Spike 2® Chemo + Puresite (MSCP) use on contamination surface levels, professionals' satisfaction and compounding time at pharmacy compared with Phaseal™. Presence of cyclophosphamide (CYP) and 5-fluorouracil (5FU) was evaluated at three sampling times: baseline; after a decontamination procedure and six months after MSCP use for CYP and 5FU compounding. Testing was carried out using an independent laboratory and wipe testing kit. To test compounding time, four different nurses followed the same compounding protocol with each device...
October 6, 2018: Regulatory Toxicology and Pharmacology: RTP
Janet C Gould, Irvith Carvajal, Todd Davidson, Jessica Graham, Jedd Hillegass, Susan Julien, Alex Kozhich, Bonnie Wang, Hui Wei, Aaron P Yamniuk, Neil Mathias, Helen G Haggerty, Michael Graziano
Protein therapeutics represent a rapidly growing proportion of new medicines being developed by the pharmaceutical industry. As with any new drug, an Occupational Exposure Limit (OEL) should be developed to ensure worker safety. Part of the OEL determination addresses bioavailability (BA) after inhalation, which is poorly understood for protein therapeutics. To explore this, male Sprague-Dawley rats were exposed intravenously or by nose-only inhalation to one of five test proteins of varying molecular size (10-150 kDa), including a polyethylene glycol-conjugated protein...
October 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Ellen M Mihaich, Christopher J Borgert
Exposure to benzene has many sources, from gasoline refueling to tobacco combustion. Although the toxicology of benzene is well studied, the potential for environmental exposure and a heightened interest in identifying substances that may cause toxicity by interacting with the endocrine systems of humans and wildlife resulted in benzene being placed on the second list of chemicals for possible screening under the USEPA's Endocrine Disruptor Screening Program. Therefore, we conducted a thorough, systematic literature search and used a weight-of-evidence methodology to test hypotheses regarding the potential for benzene to act via estrogen, androgen, thyroid, and steroidogenic pathways...
September 29, 2018: Regulatory Toxicology and Pharmacology: RTP
Ian M Fearon, Alison C Eldridge, Nathan Gale, Mike McEwan, Mitchell F Stiles, Elaine K Round
E-cigarettes are battery-powered electronic devices from which users can inhale nicotine following its aerosolisation from a liquid solution. Some regulators and public health bodies consider e-cigarettes as potentially playing a major role in tobacco harm reduction. Their ability to provide nicotine to smokers in both amount and in a manner and form generally similar to cigarette smoking have been proposed as key components to help smokers reduce or cease the use of combustible cigarettes. Nicotine pharmacokinetic studies of e-cigarettes have been performed for a number of years and are beginning to show how nicotine delivery is evolving as the products themselves evolve...
September 8, 2018: Regulatory Toxicology and Pharmacology: RTP
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