Factorial approach for the optimization and development of stability indicating study of the contraceptive suspension for injection(Depo-Provera®).

The study involves use of factorial design for optimization of forced degradation conditions and development of stability indicating method for medroxyprogestrone acetate (MPA) or depo-provera as known in the market. MPA is an important contraceptive and anticancer drug especially for treatment of breast cancer and it is the first time to study the different conditions affecting its stability. MPA was subjected to different variables such as solvent type, pH and the time subjected to UV light. Factorial design has been used during forced degradation to determine significant factors responsible for degradation and to optimize degradation conditions reaching maximum degradation. Factors responsible for forced degradation were statistically evaluated using Bubble and Surface plots. Variables proved to be significant (p < 0.05) and the suggested model represented a perfect example for indicating the efficiency of factorial designs in optimizing the degradation conditions that give maximum percent of degradation. We investigated also the solubility and stability profiles of MPA in aqueous solutions. Stability study results showed a very low stability profile of MPA in all the aqueous solutions with rapid degradation rate more than other solvents. The current research may contribute to enrich the knowledge of the physicochemical properties of this drug for exploring its full anticancer potential in the future.

Congenital anomalies in the offspring of occupationally exposed mothers: a systematic review and meta-analysis of studies using expert assessment for occupational exposures.

STUDY QUESTION: Is there an association between maternal occupational exposure to solvents, pesticides and metals as assessed by expert-based assessment and congenital anomalies in the offspring? SUMMARY ANSWER: There is an association between maternal occupational exposure to solvents and congenital anomalies in the offspring, including neural tube defects, congenital heart defects and orofacial clefts. WHAT IS KNOWN ALREADY: One important environmental risk factor for development of congenital anomalies is maternal occupational exposure to chemicals in the workplace prior to and during pregnancy. A number of studies have assessed the association with often conflicting results, possibly due to different occupational exposure assessing methods. STUDY DESIGN, SIZE, DURATION: For this systematic review with meta-analysis, the search terms included maternal occupation, exposure, congenital anomalies and offspring. Electronic databases MEDLINE and EMBASE were searched for English studies up to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two reviewers independently screened all citations identified by the search. Case-control studies and cohort studies were included if (I) they reported on the association between maternal occupational exposure to solvents, pesticides or metals and congenital anomalies, and (II) assessment of occupational exposure was performed by experts. Data on study characteristics, confounders and odds ratios (ORs) were extracted from the included studies for four subgroups of congenital anomalies. Methodological quality was assessed using the Newcastle-Ottawa Scale. In the meta-analysis, random effects models were used to pool estimates. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 2806 titles and abstracts and 176 full text papers were screened. Finally, 28 studies met the selection criteria, and 27 studies could be included in the meta-analysis. Our meta-analysis showed that maternal occupational exposure to solvents was associated with neural tube defects (OR: 1.51, 95%CI: 1.09-2.09) and congenital heart defects (OR: 1.31, 95%CI:1.06-1.63) in the offspring. Also maternal occupational exposure to glycol ethers, a subgroup of solvents, was associated with neural tube defects (OR: 1.93, 95%CI: 1.17-3.18) and orofacial clefts (OR: 1.95, 95%CI: 1.38-2.75) in the offspring. Only one study investigated the association between maternal occupational exposure to solvents and hypospadias and found an association (OR: 3.63, 95%CI: 1.94-7.17). Results of the included studies were consistent. In our meta-analysis, we found no associations between occupational exposure to pesticides or metals and congenital anomalies in the offspring. LIMITATIONS, REASONS FOR CAUTION: A limited number of studies was included, which made it impossible to calculate pooled estimates for all congenital anomalies, analyse individual chemicals or calculate exposure-response relations. Bias could have been introduced because not all included studies corrected for potentially confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Employers and female employees should be aware of the possible teratogenic effects of solvent exposure at the workplace. Therefore, is it important that clinicians and occupational health specialist provide women with preconception advice on occupational solvent exposure, to reduce the congenital anomaly risk. STUDY FUNDING/COMPETING INTEREST(S): NSp was paid by the Graduate School of Medical Sciences (MD/PhD program), UMCG, Groningen, the Netherlands. EUROCAT Northern Netherlands is funded by the Dutch Ministry of Health, Welfare and Sports. There are no competing interests. REGISTRATION NUMBER: CRD42017053943.

Impact of injection solvent composition on protein identification in column-switching chip-liquid chromatography/mass spectrometry.

In shotgun proteomics, the gold standard technique is reversed-phase liquid chromatography coupled to mass spectrometry. Many researches have been carried out to study the effects on identification performances of chromatographic parameters such as the stationary phase and column dimensions, mobile phase composition and flow rate, as well as the gradient slope and length. However, little attention is usually paid to the injection solvent composition. In this study, we investigated the effect of the injection solvent on protein identification parameters (number of distinct peptides, amino acid coverage and MS/MS search score) as well as sensitivity. Tryptic peptides from six different proteins, covering a wide range of physicochemical properties, were employed as training set. Design of experiments was employed as a tool to highlight the factors related to the composition of the injection solvent that significantly influenced the obtained results. Optimal results for the training set were applied to analysis of more complex samples. The experiments pointed out optimising the composition of the injection solvent had a strong beneficial effect on all the considered responses. On the basis of these results, an approach to determine optimal conditions was proposed to maximise the protein identification performances and detection sensitivity.

From cutting edge to guideline: A first step in harmonization of the zebrafish embryotoxicity test (ZET) by describing the most optimal test conditions and morphology scoring system.

In the last couple of years, the interest in the zebrafish embryotoxicity test (ZET) for use in developmental toxicity assessment has been growing exponentially. This is also evident from the recent proposal for updating the ICHS5 guideline. The methodology of the ZET used by the different groups varies greatly. To further evaluate its successfulness and to take the ZET to the next level, harmonization of procedures is crucial. In the present study, based on literature and empirical data, the most optimal study design regarding temperature, test chamber, exposure period, presence of chorion, solvent use, exposure method, choice of concentrations, and teratogenic classification is proposed. Furthermore, our morphology scoring system is reported in detail as protocol to further enhance study design harmonization.

Evaluating a county-based healthy nail salon recognition program.

OBJECTIVES: The City of San Francisco, California established a recognition program for nail salons that use safer nail products and receive worker safety training. This pilot study examined whether participating salons had reduced levels of toluene, methyl methacrylate (MMA), and total volatile organic compounds (TVOC), and improved knowledge and behavior compared to control salons. METHODS: We conducted personal air monitoring and administered surveys assessing knowledge and behaviors of two workers from each of six intervention salons and five control salons. We conducted assessments before and after the worker training. RESULTS: Although non-significant, there was a reduction in toluene (-46% vs. 0%) and TVOC (-19% vs. +47%), but an increase in MMA (+113% and +72%) among intervention salons compared to control salons. Awareness of dibutyl phthalates in nail products increased (+55%) among intervention salons between surveys. CONCLUSIONS: A government-administered nail salon recognition program may reduce chemical exposures and increase work-related knowledge.

Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment.

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350µg/L is proposed using a default relative source contribution for water of 20%.

European solvent industry group generic exposure scenario risk and exposure tool.

The European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) was developed to facilitate the safety evaluation of consumer uses of solvents, as required by the European Union Registration, Evaluation and Authorization of Chemicals (REACH) Regulation. This exposure-based risk assessment tool provides estimates of both exposure and risk characterization ratios for consumer uses. It builds upon the consumer portion of the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) tool by implementing refinements described in ECETOC TR107. Technical enhancements included the use of additional data to refine scenario defaults and the ability to include additional parameters in exposure calculations. Scenarios were also added to cover all frequently encountered consumer uses of solvents. The TRA tool structure was modified to automatically determine conditions necessary for safe use. EGRET reports results using specific standard phrases in a format consistent with REACH exposure scenario guidance, in order that the outputs can be readily assimilated within safety data sheets and similar information technology systems. Evaluation of tool predictions for a range of commonly encountered consumer uses of solvents found it provides reasonable yet still conservative exposure estimates.

Measurement, standards, and data needs for CO2 capture materials: a critical review.

The commercial deployment of cost-effective carbon capture technology is hindered partially by the lack of a proper suite of materials-related measurements, standards, and data, which would provide critical information for the systematic design, evaluation, and performance of CO2 separation materials. Based on a literature search and conversations with the carbon capture community, we review the current status of measurements, standards, and data for the three major carbon capture materials in use today: solvents, solid sorbents, and membranes. We highlight current measurement, standards and data activities aimed to advance the development and use of carbon capture materials and major research needs that are critical to meet if innovation in carbon capture materials is to be achieved. The review reveals that although adsorbents are considered to have great potential to reduce carbon capture cost, there is no consensus on the experimental parameters to be used for evaluating sorbent properties. Another important finding is the lack of in situ experimental tools for the structural characterization of solid porous materials during CO2 adsorption, and computational methods that would enable a materials-by-design approach for their development.

Degradation of a pharmaceutical in HPLC grade methanol containing trace level formaldehyde.

An anomalous peak was observed in the HPLC/UV analysis of a developmental drug product. High resolution LC/MS revealed that the mass of this degradant was 12 Da greater than the drug substance, corresponding to a net gain of a single carbon atom. The degradant was reproduced by incubating the drug substance with formaldehyde, followed by isolation using normal phase chromatography and structure elucidation by NMR. It was determined to be an analytical artifact caused by the nucleophilic reaction of the drug substance with trace levels of formaldehyde in the methanol diluent. Typical formaldehyde levels in various grades of methanol were determined, leading to the adoption of spectrophotometric purity solvent to mitigate the recurrence of this artifact. This work demonstrates that even ppm levels of impurities in solvents can cause significant degradation of drug product and the HPLC grade solvents are not always suitable for HPLC analysis in drug product development.

International Conference on Harmonisation; final recommendation for the revision of the permitted daily exposure for the solvent cumene according to the maintenance procedures for the guidance Q3C Impurities: Residual Solvents; availability. Notice.

The Food and Drug Administration (FDA) is announcing the availability of a final recommendation for the revision of the permitted daily exposure (PDE) for the solvent cumene according to the maintenance procedures for the guidance for industry entitled ``Q3C Impurities: Residual Solvents.'' The recommendation was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Extraction of antioxidants from spruce (Picea abies) bark using eco-friendly solvents.

INTRODUCTION: Antioxidants are known to avert oxidation processes and they are found in trees and other plant materials. Tree bark is a major waste product from paper pulp industries; hence it is worthwhile to develop an extraction technique to extract the antioxidants. OBJECTIVE: To develop a fast and environmentally sustainable extraction technique for the extraction of antioxidants from bark of spruce (Picea abies) and also to identify the extracted antioxidants that are abundant in spruce bark. METHODOLOGY: A screening experiment that involved three different techniques was conducted to determine the best technique to extract antioxidants. The antioxidant capacity of the extracts was determined with DPPH (2,2-diphenyl-1-picrylhydrazyl) assay. Pressurised fluid extraction (PFE) turned out to be the best technique and a response surface design was therefore utilised to optimise PFE. Furthermore, NMR and HPLC-DAD-MS/MS were applied to identify the extracted antioxidants. RESULTS: PFE using water and ethanol as solvent at 160 and 180°C, respectively, gave extracts of the highest antioxidant capacity. Stilbene glucosides such as isorhapontin, piceid and astringin were identified in the extracts. CONCLUSION: The study has shown that PFE is a fast and environmentally sustainable technique, using water and ethanol as solvent for the extraction of antioxidants from spruce bark.

Tratamento de compostos orgânicos odoríferos tóxicos por biorreatores / Treatment of odorous toxic organic compounds by bioreactor

Introdução É importante o desenvolvimento de sistemas de controle de poluição do ar que sejam eficientes, além de aplicáveis à condição nacional e pra proteção da saúde humana, uma vez que os compostos do grupo BTEX são tóxicos. Objetivo - Avaliar o desempenho de sistema de tratamento biológico para vapores de BTEX e investigar as melhores condições de operação para os critérios de projeto adotados. Métodos. Trata-se de trabalho experimental com utilização de unidade piloto constituída de coluna de vidro (diâmetro interno de 80 mm e altura total de 1,2 m) tendo no seu interior um meio filtrante composto vegetal e anéis de Pall - que serviram de suporte para os microrganismos e onde se realizou a biodegradação. Foram monitorados parâmetros como temperatura, perda de carga, vazão, concentração dos gases na entrada e na saída, que constituíram a base para desenvolver intervenções e melhorar seu desempenho. A análise dos gases foi feita por fotoionização (PID) em aparelho portátil. Conclusões - Conclui-se que é viável o tratamento biológico para remoção do BTEX de efluentes gasosos, nas condições operacionais adotadas, com eficiência máxima de remoção em torno de 90 por cento . A máxima eficiência foi obtida para tempo de retenção de 2,4 min., carga superficial do gás de 11,9 m3/m2xh, carga mássica no leito de 67 g/m3xh e capacidade de eliminação de 4 g/m3xh. O uso de anéis de Pall misturados ao composto evitou que valores elevados de perda de carga. Foi relevante a participação da adsorção. A utilização de composto mostrou-se viável como alternativa para a biodegradação do BTEX, fortalecendo seu uso com essa prática ambiental.

Quantitative property-property relationships for computing occupational exposure limits and vapour hazard ratios of organic solvents.

Vapour Hazard Ratio (VHR) is used in solvent substitution to select the best replacement option regarding overexposure potential of solvents. However, VHR calculations are limited by the availability of Occupational Exposure Limits (OELs). The overall objective of this study was to develop quantitative property-property relationship (QPPR) approaches for computing OELs, in view of supporting the derivation of VHRs for solvents without OELs. QPPRs were developed for estimating OELs using a database of 88 solvents which have health-based Time-Weighted Average (TWA) OELs published by the American Conference of Governmental Industrial Hygienists (ACGIH). Three surrogates of biotic lipid : air partition coefficients [n-octanol : air (K(oa)), olive oil : air (K(oila)) and fat : air (K(fa))] were selected for evaluating the descriptive/predictive relationship with OELs for solvents with local modes of action. For solvents with systemic modes of action, the prediction of OEL needs to consider quantitative differences in toxicokinetics (i.e. kinetic variability factor, KVF) and toxicological potency (i.e. effective internal concentration, EIC). The n-octanol : water (K(ow)), the oil : water (K(oilw)) and the fat : water (K(fw)) partition coefficients were selected for evaluating the relationship with EICs. For local modes of action, K(oa) is the most accurate predictor of OELs [OEL (ppm) = 10(((-0.45 x log K(oa)) + 3.65)); n = 21, r²= 0.71, PRESS/SSY = 0.36, F = 45.5 with p < 0.001] and the mean (±SD) (range) of the recommended to predicted OELs was 1.04 ± 0.61 (0.2-2.5). For systemic modes of action, KVFs and EICs vary in a range from 0.73 to 41.4 µmol L⁻¹ and 1.20-848 µmol L⁻¹, respectively. K(ow) is an accurate predictor of calculated EICs [EIC (µmol L⁻¹) = 10 (((-1.16 x log K(ow)) + 3.65)); n = 27, r²= 0.88, PRESS/SSY = 0.12, F = 181 with p < 0.001] and 50% of the predicted OEL values were within a factor of two of the recommended TWA OELs. Overall, 61% and 87% of the predicted VHRs were within a factor of two and five, respectively, of the calculated VHRs. The QPPR models developed in this study represent potentially useful tools for estimating provisional OELs for solvents lacking such guideline values. These provisional OELs are developed only to support initial estimations of VHR for dealing with the challenge of solvent substitution where relative values rather than absolute values of OEL and vapour pressure guide the hygienist in making pragmatic decisions for managing occupational health hazards.

Efficacy of an extraction solvent used to quantify albumin deposition on hydrogel contact lens materials.

OBJECTIVES: Extracting proteins from conventional hydrogel (CH) and silicone hydrogel (SH) contact lens materials using a mixture of trifluoroacetic acid/acetonitrile (TFA/ACN) is a well-established procedure for quantifying individual and total protein deposited on contact lenses. The purpose of this study was to determine the efficacy of TFA/ACN in extracting albumin from SH and a CH group IV lens material using an in vitro model. METHODS: One CH group IV lens material (etafilcon A) and five different SH lens materials (lotrafilcon A, lotrafilcon B, balafilcon A, galyfilcon A, and senofilcon A) were incubated in both simple albumin solution and a complex artificial tear protein solution containing 125I-labeled albumin. All the lens materials were incubated for 14 days at 37 degrees C with constant rotations. Following the incubation period, radioactive counts were determined and the lenses were placed in an appropriate volume of the extraction solvent. After the specified time, the lenses were removed and radioactive counts were determined again to calculate the amount of albumin remaining on the lenses post-extraction. RESULTS: Extraction efficiencies for albumin from the artificial tear protein solution were 97.2% +/- 2 for etafilcon A, 77.3% +/- 6.2 for lotrafilcon A, 73.5% +/- 5.6 for lotrafilcon B, 81.5% +/- 5.8 for balafilcon, 91.2% +/- 3.4 for galyfilcon A, and 89.2% +/- 3.4 for senofilcon A. Results were similar for the albumin extracted after incubating in the simple albumin solution. CONCLUSIONS: Although TFA/ACN is efficient at extracting albumin deposited on etafilcon lenses, it does not extract all the albumin that is deposited on SH lenses and alternative extraction procedures should be sought.

Topical formulations of metaflumizone plus amitraz to treat flea and tick infestations on dogs.

A topical spot-on solution was developed for treating pets that contained of active ingredients metaflumizone and amitraz and intended for use as an ectoparasiticide. The formulation vehicle system was designed by balancing the following three attributes of various solvents: evaporation/drying, surface spreading, and percutaneous absorption. The solvents were selected by evaluating the solubilization capacity of individual solvents with respect to the above active ingredients. The evaporation rates of various solvent systems were then determined. The visual observations of the treatment sites was also performed a day after treating the dogs to understand the cosmetic effect of various solvent systems. The lead formulations dried off within a day after application with no noticeable residue at the treatment site, while others produced appreciable powdery residue or a large wet and oily spot. The stability of the lead formulations was also evaluated over 2 years to demonstrate a 2-year shelf life of this product.

Investigation of fatty acid esters to replace isopropyl myristate in the sterility test for ophthalmic ointments.

Several pharmacopoeias recommend the membrane filtration method for the sterility test of ophthalmic ointments. Isopropyl myristate, a fatty acid ester that exhibits high toxicity mainly against Gram-negative microorganisms, is indicated as a solvent for ointments. In this study, six fatty acid esters (diethyl adipate, diisopropyl adipate, ethyl laurate, ethyl myristate, methyl caprylate and isopropyl palmitate) were evaluated as solvents to replace isopropyl myristate in the sterility test for ophthalmic ointments. The logarithm of the partition coefficient (logP) of the fatty acid esters was calculated from the sum of the substituent hydrophobicity constants (pi) of the functional groups present in their molecules. The ability of the solvents to dissolve an ophthalmic ointment base was investigated. The D-value method was used to assess the antimicrobial activity of isopropyl palmitate, ethyl myristate, ethyl laurate and isopropyl myristate against Pseudomonas aeruginosa. Isopropyl palmitate was the least toxic solvent to this microorganism, since it had the highest D-value (171.1 min). No significant difference was observed between the D-values of ethyl myristate (89.4 min) and isopropyl myristate (92.5 min). Ethyl laurate exhibited the lowest D-value (27.2 min). Using gas chromatography coupled to mass spectrometry, other fatty acid esters were detected as the predominant impurities in the solvents, as well as acid contaminants in low or insignificant amounts.

Modeling aggregate exposures to glycol ethers from use of commercial floor products.

Computer modeling of aggregate exposure provides the capability to estimate the range of doses that can occur from product use and to understand the relative importance of different routes of exposure. This paper presents an assessment of aggregate occupational exposure to two glycol ethers used as solvents in floor maintenance products for industrial and institutional facilities, using a simulation tool named PROMISE. Three commercial floor-care products were assumed to be applied in sequence--a floor stripper, then a floor cleaner, and lastly a protective coating. The glycol ethers modeled were ethylene glycol butyl ether (EGBE) in the floor stripper and in the floor cleaner, and dipropylene glycol methyl ether (DPGME) in the coating. Modeling uncertainty was assessed through a comparison of the PROMISE inhalation exposure estimates with those from an independent model (MCCEM), and parameter uncertainty was investigated using PROMISE software's Monte Carlo simulation capabilities. Modeling results indicated that inhalation is the dominant exposure route. The predicted average air concentration and inhalation dose from PROMISE agreed with the second model (MCCEM) within 10%. Monte Carlo simulation indicated that the upper end of the aggregate-dose distribution for the scenario was more than 50% higher than the value of the point estimate. The modeled 8-h TWA concentrations for EGBE and DPGME were lower than the corresponding permissible exposure limits American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLV) by at least a factor of 20, indicating that under the assumed conditions workplace exposures to glycol ethers are below levels of concern.

Potential uses of petrochemical products can result in significant benzene exposures: MSDSs must list benzene as an ingredient.

According to 29 CFR1910.1200 (Hazard Communication Standard [HCS]), a material safety data sheet (MSDS) must list a carcinogen as an ingredient if its concentration in a product is 0.1% or more by weight. However, according to the HCS, when the concentration of a carcinogen in a product is less than 0.1% (by weight) it may not be necessary to list it as an ingredient on the MSDS. The standard stipulates that if potential uses of the product can result in exposures to the carcinogen that exceed the Occupational Safety and Health Administration (OSHA) permissible exposure limit or the ACGIH threshold limit value (TLV), then it must be listed. This article focuses on the failure of MSDSs to report benzene as a listed ingredient in products that incorporate petroleum-derived ingredients such as toluene and hexane. In the United States, approximately 238,000 people are occupationally exposed to benzene each year. Only rarely is benzene listed as an ingredient on MSDSs even though it often comprises more than 0.1% of petroleum solvents and, when its concentrations in petroleum-derived products are much less than 0.1%, inhalation exposures to benzene can be much higher that its OSHA PEL of one part per million (ppm) by volume (v/v) andACGIH TLV of/one-half ppm (v/v). As a consequence of benzene's omission from MSDSs as a listed ingredient, employers are frequently unaware of their requirement to implement 29 CFR 1910.1028 (Benzene Standard) and of the need to address employee exposures to benzene in the workplace. This article demonstrates that benzene should be listed as an ingredient on MSDSs, even at concentrations in benzene-containing products that are between one and two orders of magnitude below OSHA's 0.1% threshold. An exposure assessment methodology is presented that is applicable to employees whose conditions of exposure are similar to those in the published study. These workers make up a similar exposure group. The information and methodology presented here are germane to preparation of accurate MSDSs for benzene-containing products, employers who must comply with 29 CFR 1910.1028, and retrospectively estimating exposures to benzene.