Analytical Method Development and Dermal Absorption of 4-Amino-3-Nitrophenol (4A3NP), a Hair Dye Ingredient under the Oxidative or Non-Oxidative Condition.

The chemical 4-amino-3-nitrophenol (4A3NP) is classified as an amino nitrophenol and is primarily utilized as an ingredient in hair dye colorants. In Korea and Europe, it is exclusively used in non-oxidative or oxidative hair dye formulations, with maximum allowable concentrations of 1% and 1.5%, respectively. Despite this widespread use, risk assessment of 4A3NP has not been completed due to the lack of proper dermal absorption data. Therefore, in this study, both the analytical method validation and in vitro dermal absorption study of 4A3NP were conducted following the guidelines provided by the Korea Ministry of Food and Drug Safety (MFDS). Before proceeding with the dermal absorption study, analytical methods were developed for the quantitation of 4A3NP through multiple reaction monitoring (MRM) via liquid chromatography-mass spectrometry (LC-MS) in various matrices, including swab wash (WASH), stratum corneum (SC), skin (SKIN, comprising the dermis and epidermis), and receptor fluid (RF). These developed methods demonstrated excellent linearity (R2 = 0.9962-0.9993), accuracy (93.5-111.73%), and precision (1.7-14.46%) in accordance with the validation guidelines.The dermal absorption of 4A3NP was determined using Franz diffusion cells with mini-pig skin as the barrier. Under both non-oxidative and oxidative (6% hydrogen peroxide (H2O2): water, 1:1) hair dye conditions, 1% and 1.5% concentrations of 4A3NP were applied to the skin at a rate of 10 µL/cm2, respectively. The total dermal absorption rates of 4A3NP under non-oxidative (1%) and oxidative (1.5%) conditions were determined to be 5.62 ± 2.19% (5.62 ± 2.19 µg/cm2) and 2.83 ± 1.48% (4.24 ± 2.21 µg/cm2), respectively.

Repeated-dose toxicity and toxicokinetic study of isobutylparaben in rats subcutaneously treated for 13 weeks.

Parabens have historically served as antimicrobial preservatives in a range of consumables such as food, beverages, medications, and personal care products due to their broad-spectrum antibacterial and antifungal properties. Traditionally, these compounds were believed to exhibit low toxicity, causing minimal irritation, and possessing limited sensitization potential. However, recent evidence suggests that parabens might function as endocrine-disrupting chemicals (EDCs). Consequently, extensive research is underway to elucidate potential human health implications arising from exposure to these substances. Among these parabens, particular concerns have been raised regarding the potential adverse effects of iso-butylparaben (IBP). Studies have specifically highlighted its potential for inducing hormonal disruption, significant ocular damage, and allergic skin reactions. This study aimed to evaluate the prolonged systemic toxicity, semen quality, and estrus cycle in relation to endocrine disruption endpoints, alongside assessing the toxicokinetic behavior of IBP in Sprague-Dawley rats following a 13-week repeated subcutaneous administration. The rats were administered either the vehicle (4% Tween 80) or IBP at dosage levels of 2, 10, and 50 mg/kg/day for 13 weeks. Blood collection for toxicokinetic study was conducted on three specified days: day 1 (1st), day 30 (2nd), and day 91 (3rd). Systemic toxicity assessment and potential endocrine effects were based on various parameters including mortality rates, clinical signs, body weights, food and water consumption, ophthalmological findings, urinalysis, hematological and clinical biochemistry tests, organ weights, necropsy and histopathological findings, estrus cycle regularity, semen quality, and toxicokinetic behavior. The findings revealed that IBP induced local irritation at the injection site in males at doses ≥ 10 mg/kg/day and in females at 50 mg/kg/day; however, systemic toxicity was not observed. Consequently, the no-observed-adverse-effect level (NOAEL) for IBP was determined to be 50 mg/kg/day in rats of both sexes, indicating no impact on the endocrine system. The toxicokinetics of IBP exhibited dose-dependent systemic exposure, reaching a maximum dose of 50 mg/kg/day, and repeated administration over 13 weeks showed no signs of accumulation.

Prediction of skin sensitization using machine learning.

As global awareness of animal welfare spreads, the development of alternative animal test models is increasingly necessary. The purpose of this study was to develop a practical machine-learning model for skin sensitization using three physicochemical properties of the chemicals: surface tension, melting point, and molecular weight. In this study, a total of 482 chemicals with local lymph node assay results were collected, and 297 datasets with 6 physico-chemical properties were used to develop Random Forest (RF) model for skin sensitization. The developed model was validated with 45 fragrance allergens announced by European Commission. The validation results showed that RF achieved better or similar classification performance with f1-scores of 54% for penal, 82% for ternary, and 96% for binary compared with Support Vector Machine (SVM) (penal, 41%; ternary, 81%; binary, 93%), QSARs (ChemTunes, 72% for ternary; OECD Toolbox, 89% for binary), and a linear model (Kim et al., 2020) (41% for penal), and we recommend the ternary classification based on Global Harmonized System providing more detailed and precise information. In the further study, the proposed model results were experimentally validated with the Direct Peptide Reactivity Assay (DPRA, OECD TG 442C approved model), and the results showed a similar tendency. We anticipate that this study will help to easily and quickly screen chemical sensitization hazards.

Analytical method development and dermal absorption of 2-amino-5-nitrophenol (2A5NP), a hair dye ingredient under oxidative condition.

Although 2-amino-5-nitrophenol (2A5NP) is one of the ingredients of hair dye, there has been no information on the dermal absorption rate of 2A5NP. 2A5NP is managed at less than 1.5% in Korea and Japan. In this study, analytical methods were developed and validated using high-performance liquid chromatography (HPLC) in various matrices of wash, swab, stratum corneum (SC), skin (dermis + epidermis), and receptor fluid (RF). Validation results were acceptable based on Korea Ministry of Food and Drug Safety (MFDS) guideline. The HPLC analysis showed a good linearity (r2 = 0.9992-0.9999), a high accuracy (93.1-110.2%), and a good precision (1.1-8.1%) in accordance with the validation guideline. Franz diffusion cell was used to determine dermal absorption of 2A5NP using mini pig skin. 2A5NP (1.5%) was applied to skin at 10 µl/cm2. For certain cosmetic ingredients such as hair dye with short exposure time, an interim wash step (after 30 min) was added during the study. After application for 30 min and 24 h, skin was wiped off with swab and SC was collected using tape stripping. RF was sampled at 0, 1, 2, 4, 8, 12, and 24 h. Total dermal absorption rate of 2A5NP (1.5%) was determined to be 13.6 ± 2.9%.

Urinary Metabolomics in Young Soccer Players after Winter Training Season.

During the off-season, soccer players in Korea attend the winter training season (WTS) to build running stamina for the next season. For young soccer players, proper recovery time is needed to prevent injury or muscle damage. In this study, urinary metabolites in young players after 1, 5, and 10 days of the WTS were analyzed using nuclear magnetic resonance spectroscopy (NMR) combined with multivariate analysis to suggest appropriate recovery times for improving their soccer skills. After NMR analysis of the urine samples obtained from young players, 79 metabolites were identified, and each group (1, 5, or 10 days after WTS) was separated from the before the WTS group in the target profiling analysis using partial least squares-discriminant analysis (PLS-DA). Of these, 15 metabolites, including 1-methylnicotinamide, 3-indoxylsulfate, galactarate, glutamate, glycerol, histamine, methylmalonate, maltose, N-phenylacetylglycine, trimethylamine, urea, 2-hydroxybutyrate, adenine, alanine, and lactate, were significantly different than those from before the WTS and were mainly involved in the urea, purine nucleotide, and glucose-alanine cycles. In this study, most selected metabolites increased 1 day after the WTS and then returned to normal levels. However, 4 metabolites, adenine, 2-hydroxybutyrate, alanine, and lactate, increased during the 5 days of recovery time following the WTS. Based on excess ammonia, adenine, and lactate levels in the urine, at least 5 days of recovery time can be considered appropriate.

Analytical Method Development and Dermal Absorption of Pyrogallol, a Hair Dye Ingredient.

Pyrogallol is an ingredient in hair dye. Its concentration in hair dye is managed at less than 2.0% in Korea. There have been no reports on the dermal absorption rate of pyrogallol. The two purposes of this study were to develop an analytical method and determine the dermal absorption rate of pyrogallol. An analytical method was developed and validated by high-performance liquid chromatography (HPLC) analysis of various matrices including swabs (SWAB), skin (SKIN, dermis + epidermis), stratum corneum (SC), and receptor fluid (RF). Linearity (r2 = 0.9993-0.9998), accuracy (92.1-108.2%), and precision (0.5-9.5%) met the validation criteria in guidelines. A Franz diffusion cell was used to determine the dermal absorption of pyrogallol using the skin of mini pigs. Pyrogallol (2.0%) was applied to the skin (10 µL/cm2). For the actual hair dye conditions, the skin was wiped with a swab 30 min after application. Twenty-four hours later, it was wiped with a swab again and the SC was collected using tape stripping. All samples were extracted with water and analyzed. RF was recovered at 0, 1, 2, 4, 8, 12, and 24 h. The total dermal absorption rate of pyrogallol was determined to be 26.0 ± 3.9%.

A Metabolomics Approach to Sulforaphane Efficacy in Secondhand Smoking-Induced Pulmonary Damage in Mice.

Sulforaphane is an isocyanate abundantly present in cruciferous vegetables. In the present study, we aimed to investigate the effects of sulforaphane on secondhand smoking (SHS)-induced pulmonary damage in mice. Additionally, a metabolomic study was performed to identify biomarkers associated with pulmonary disease using proton nuclear magnetic resonance (1H-NMR) analysis. Male C57BL6J mice were divided into a control group, an SHS exposure group (positive control group, PC), and a sulforaphane treatment group exposed to secondhand smoke (SS) (n = 5 per group). The PC and SS groups were exposed to secondhand smoke in a chamber twice daily for four weeks. Mice in the SS group were orally administered sulforaphane (50 mg/kg) for four weeks during secondhand smoke exposure. Histopathological examination of the lungs revealed pulmonary damage in PC mice, including loss of bronchial epithelial cells, bronchial wall thickening, and infiltration of macrophages. In contrast, mice in the SS group showed little or no epithelial thickening, thereby exhibiting reduced lung damage. Mouse serum and lung tissues were collected and analyzed to determine changes in endogenous metabolites using 1H-NMR. After target profiling, we identified metabolites showing the same tendency in the serum and lung as biomarkers for SHS-induced pulmonary damage, including taurine, glycerol, creatine, arginine, and leucine. As a result of histopathological examination, sulforaphane might inhibit SHS-induced lung damage, and metabolite analysis results suggest potential biomarkers for SHS-induced pulmonary damage in mice.

Pharmacokinetics and the Dermal Absorption of Bromochlorophene, a Cosmetic Preservative Ingredient, in Rats.

The cosmetic industry has flourished in recent years. Accordingly, the safety of cosmetic ingredients is increasing. Bromochlorophene (BCP) is a commonly used cosmetic preservative. To evaluate the effects of BCP exposure, in vitro dermal absorption and in vivo pharmacokinetic (PK) studies were conducted using gel and cream formulations. The Franz diffusion cell system and rat dorsal skin were used for tests according to the Korea Ministry of Food and Drug Safety guidelines for in vitro skin absorption methods. After the dermal application (1.13 mg/cm2) of BCP in the gel and cream formulations, liquid chromatography-mass spectrometry (LC-MS/MS) was used to evaluate the amount of BCP that remained unabsorbed on the skin (WASH), and that was present in the receptor fluid (RF), stratum corneum (SC), and (epi)dermis (SKIN). The total dermal absorption rate of BCP was 7.42 ± 0.74% for the gel formulation and 1.5 ± 0.9% for the cream formulation. Total recovery in an in vitro dermal absorption study was 109.12 ± 8.79% and 105.43 ± 11.07% for the gel and cream formulations, respectively. In vivo PK and dermal absorption studies of BCP were performed following the Organization for Economic Cooperation and Development guidelines 417 and 427, respectively. When intravenous (i.v.) pharmacokinetics was performed, BCP was dissolved in glycerol formal and injected into the tail vein (n = 3) of the rats at doses of 1 and 0.2 mg/kg. Dermal PK parameters were estimated by the application of the gel and cream formulations (2.34 mg/kg of BCP as an active ingredient) to the dorsal skin of the rats. Intravenous and dermal PK parameters were analyzed using a non-compartmental method. The dermal bioavailability of BCP was determined as 12.20 ± 2.63% and 4.65 ± 0.60% for the gel and cream formulations, respectively. The representative dermal absorption of BCP was evaluated to be 12.20 ± 2.63% based on the results of the in vivo PK study.

Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model.

Prenatal exposure to valproic acid (VPA) has been implicated in the manifestation of autism spectrum disorder (ASD)-like behavioral and functional changes both in human and rodents including mice and rats. The objective of this study was to determine metabolomics profiling and biomarkers related to VPA-induced symptoms resembling ASD using proton nuclear magnetic resonance (1H-NMR) spectral data. VPA was administered to pregnant rats at gestation day 12.5 and effects measured subsequently in male 4-week-old offspring pups. The sociability of VPA-treated animals was significantly diminished and exhibited ASD-like behavior as evidenced by reduction of social adaptation disorder and lack of social interactions. To find biomarkers related to ASD, the following were collected prefrontal brain cortices, urine bladder and blood samples directly from heart puncture. In all samples, principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) displayed significant clustering pattern differences between control and treated groups. Valine, taurine, myo-inositol, 3-hydroxybutyrate and 1,3-dihydroxyacetone were significantly decreased in brain cortices in treated rats. Serum metabolites of glucose, creatine phosphate, lactate, glutamine and threonine were significantly increased in VPA-administered animals. Urinary metabolites of pimelate, 3-hydroxyisovalerate and valerate were significantly reduced in VPA-treated rat, whereas galactose and galactonate levels were elevated. Various metabolites were associated with mitochondrial dysfunction metabolism and central nervous system disorders. Data demonstrated that VPA-induced alterations in endogenous metabolites of serum, urine, and brain cortex which might prove useful as biomarkers for symptoms resembling ASD as a model of this disorder.

Effect of Application Amounts on In Vitro Dermal Absorption Test Using Caffeine and Testosterone.

Dermal absorption of chemicals is a key factor in risk assessment. This study investigated the effects of different amounts of application on dermal absorption and suggested an appropriate application dose for proper dermal absorption. Caffeine and testosterone were chosen as test compounds. An in vitro dermal absorption test was performed using a Franz diffusion cell. Different amounts (5, 10, 25, and 50 mg (or µL)/cm2) of semisolid (cream) and liquid (solution) formulations containing 1% caffeine and 0.1% testosterone were applied to rat and minipig (Micropig®) skins. After 24 h, the concentrations of both compounds remaining on the skin surface and in the stratum corneum, dermis and epidermis, and receptor fluid were determined using LC-MS / MS or HPLC. Dermal absorption of both compounds decreased with increasing amounts of application in both skin types (rat and minipig) and formulations (cream and solution). Especially, dermal absorptions (%) of both compounds at 50 mg (or µL)/cm2 was significantly lower compared to 5 or 10 mg (or µL)/cm2 in both rat and minipig skins. Therefore, a low dose (5 or 10 mg (or µL)/cm2) of the formulation should be applied to obtain conservative dermal absorption.

Metabolomics approach to biomarkers of dry eye disease using 1H-NMR in rats.

Dry eye disease (DED) is a chronic and progressive lesion on the ocular surface and induces symptoms, such as burning sensation, itchy eyes, heavy eyes, tired eyes, dry feeling, facial flushing, and blurred vision. The present study was performed to develop DED biomarkers using metabolomics in a rat model. DED was induced by injecting scopolamine and exposing rats to a dry condition. Scopolamine (12 mg/kg/day for 7 days) was subcutaneously injected to male Sprague-Dawley rats. The rats were placed in dry condition with air-flow and dehumidifier. Tear volume and tear breakup time (TBUT) were measured, and eyes were examined through fluorescein staining to assess DED. Mucosal damage and immune reactions were also determined. Plasma and urinary endogenous metabolites were determined using 1H-NMR analysis. Compared with control tear and TBUT levels were significantly decreased in the DED group whereas corneal damage was significantly increased. The levels of interleukins (IL-6) and IL-1ß significantly elevated in the cornea and lacrimal glands in the DED group. TNF-α was numerically increased but not significantly different between groups. Pattern recognition using principal component analysis (PCA) and orthogonal projections to latent structure-discriminant analysis (OPLS-DA) of the NMR spectra in global profiling revealed different clusters between DED and control groups. Target profiling demonstrated that PCA and OPLS-DA score plots were separated between DED and controls in plasma and urine. Subsequently, 9 plasma metabolites were selected to examine different clustering between groups, and 26 urinary metabolites were also selected. Plasma metabolites showed a non-significant rising tendency in the DED group. Urinary phenylalanine, phenylacetate, pantothenate, glycine, succinate, methanol, valine, propylene glycol, histidine, threonine, lactate, and acetate were significantly different between control and DED rats. These results may contribute to understanding the metabolic regulation that is involved in DED and might be useful for potential biomarkers related to DED in rats.

Effects of anti-wrinkle and skin-whitening fermented black ginseng on human subjects and underlying mechanism of action.

The aim of this study was to determine the effects of anti-wrinkle and skin-whitening of fermented black ginseng (FBG) in human subjects and to examine underlying biochemical mechanisms of action. A clinical study was performed to evaluate efficacy and safety using a 1% FBG cream formulation. Twenty-three subjects were recruited and instructed to apply control or FBG creams each on half of their face twice daily for 8 weeks. After 8 weeks, FBG cream significantly reduced the appearance of eye wrinkles compared to prior to exposure and control cream. Skin color was significantly brightened using FBG cream in comparison with a control cream. To determine the mechanism of actions involved in anti-wrinkle and skin-whitening effects various concentrations of FBG were applied to human fibroblast CCD-986sk and mouse melanoma B16F1 cells. Collagen synthesis in CCD-986sk cells was improved significantly at 1, 3, 10, or 30 µg/ml of FBG. At 30 µg/ml, FBG significantly inhibited (73%) collagenase, and matrix metalloproteinase-1 (MMP-1) compared to control. Tyrosinase activity and DOPA (3,4-dihydroxy-L-phenylalanine) oxidation were significantly decreased at all tested concentrations. Melanin production in B16F1 cells was concentration-dependently reduced from 15% to 60% by all concentrations of FBG. These results suggested that a 1% FBG cream exerted anti-wrinkle and skin-whitening effects.

Effects of anti-wrinkle and skin-whitening fermented black ginseng on human subjects and underlying mechanism of action.

The aim of this study was to determine the effects of anti-wrinkle and skin-whitening of fermented black ginseng (FBG) in human subjects and to examine underlying biochemical mechanisms of action. A clinical study was performed to evaluate efficacy and safety using a 1% FBG cream formulation. Twenty-three subjects were recruited and instructed to apply control or FBG creams each on half of their face twice daily for 8 weeks. After 8 weeks FBG cream significantly reduced appearance of eye wrinkles compared to prior to exposure and control cream. Skin color was significantly brightened using FBG cream in comparison with control cream. To determine the mechanism of actions involved in anti-wrinkle and skin-whitening effects various concentrations of FBG were applied to human fibroblast CCD-986sk and mouse melanoma B16F1 cells. Collagen synthesis in CCD-986sk cells was improved significantly at 1, 3, 10, or 30 µg/ml of FBG. At 30 µg/ml, FBG significantly inhibited (73%) collagenase, and matrix metalloproteinase-1 (MMP-1) compared to control. Tyrosinase activity and DOPA (3,4-dihydroxy-L-phenylalanine) oxidation were significantly decreased at all tested concentrations. Melanin production in B16F1 cells was concentration-dependently reduced 15% to 60% by all concentrations of FBG. These results suggested that a 1% FBG cream exerted anti-wrinkle and skin-whitening effects.

Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats.

Polyhexamethylene guanidine phosphate (PHMG-p) was used as a humidifier disinfectant in Korea. PHMG induced severe pulmonary fibrosis in Koreans. The objective of this study was to elucidate mechanism of pulmonary toxicity caused by PHMG-p in rats using multi-omics analysis. Wistar rats were intratracheally instilled with PHMG-p by single (1.5 mg/kg) administration or 4-week (0.1 mg/kg, 2 times/week) repeated administration. Histopathologic examination was performed with hematoxylin and eosin staining. Alveolar macrophage aggregation and granulomatous inflammation were observed in rats treated with single dose of PHMG-p. Pulmonary fibrosis, chronic inflammation, bronchiol-alveolar fibrosis, and metaplasia of squamous cell were observed in repeated dose group. Next generation sequencing (NGS) was performed for transcriptome profiling after mRNA isolation from bronchiol-alveoli. Bronchiol-alveoli proteomic profiling was performed using an Orbitrap Q-exactive mass spectrometer. Serum and urinary metabolites were determined using 1H-NMR. Among 418 differentially expressed genes (DEGs) and 67 differentially expressed proteins (DEPs), changes of 16 mRNA levels were significantly correlated with changes of their protein levels in both single and repeated dose groups. Remarkable biological processes represented by both DEGs and DEPs were defense response, inflammatory response, response to stress, and immune response. Arginase 1 (Arg1) and lipocalin 2 (Lcn2) were identified to be major regulators for PHMG-p-induced pulmonary toxicity based on merged analysis using DEGs and DEPs. In metabolomics study, 52 metabolites (VIP > 0.5) were determined in serum and urine of single and repeated-dose groups. Glutamate and choline were selected as major metabolites. They were found to be major factors affecting inflammatory response in association with DEGs and DEPs. Arg1 and Lcn2 were suggested to be major gene and protein related to pulmonary damage by PHMG-p while serum or urinary glutamate and choline were endogenous metabolites related to pulmonary damage by PHMG-p.

Pragmatic Approach to Design Silicon Alloy Anode by the Equilibrium Method.

Silicon fascinates with incredibly high theoretical energy density as an anode material and considered as a primary candidate to replace well-established graphite. However, further commercialization is hindered by the abnormal volume changes of Si in every single cycle. Silicon embedded in a buffer matrix using the melt-spinning process is a promising approach; however, its metastable nature significantly reduces the microstructure homogeneity, the quality of the composition, and, therefore, the electrochemical performances. Herein, we developed a new approach to design a high-performance Si-alloy with improved microstructure uniformity and electrochemical properties. Namely, annealing at a certain temperature of the melt-spun amorphous alloy ribbon allowed us to evenly distribute Si nanocrystallites in the microstructure with control of average grain size. As a result, the Si-alloy electrode delivers an initial discharge capacity of 900 mAh g-1 and exhibits a high coulombic efficiency of >99% from the second cycle with a capacity retention of ∼98% after 100 cycles. This study provides powerful insights and evidence for the successful application of the proposed approach for commercial purposes.

Genome-scale metabolic reconstruction and in silico analysis of the rice leaf blight pathogen, Xanthomonas oryzae.

Xanthomonas oryzae pv. oryzae (Xoo) is a vascular pathogen that causes leaf blight in rice, leading to severe yield losses. Since the usage of chemical control methods has not been very promising for the future disease management, it is of high importance to systematically gain new insights about Xoo virulence and pathogenesis, and devise effective strategies to combat the rice disease. To do this, we reconstructed a genome-scale metabolic model of Xoo (iXOO673) and validated the model predictions using culture experiments. Comparison of the metabolic architecture of Xoo and other plant pathogens indicated that the Entner-Doudoroff pathway is a more common feature in these bacteria than previously thought, while suggesting some of the unique virulence mechanisms related to Xoo metabolism. Subsequent constraint-based flux analysis allowed us to show that Xoo modulates fluxes through gluconeogenesis, glycogen biosynthesis, and degradation pathways, thereby exacerbating the leaf blight in rice exposed to nitrogenous fertilizers, which is remarkably consistent with published experimental literature. Moreover, model-based interrogation of transcriptomic data revealed the metabolic components under the diffusible signal factor regulon that are crucial for virulence and survival in Xoo. Finally, we identified promising antibacterial targets for the control of leaf blight in rice by using gene essentiality analysis.

Risk assessment of volatile organic compounds (VOCs) detected in sanitary pads.

Disposable sanitary pads are a necessity for women's health, but safety concerns regarding the use of these products have created anxiety. The aim of this study was to conduct a risk assessment of 74 volatile organic compounds (VOCs), which were expected to be contained within sanitary pads. Of the 74 VOCs, 50 were found in sanitary pads retailed in Korea at concentrations ranging from 0.025 to 3548.09 µg/pad. In order to undertake a risk assessment of the VOCs, the toxicological database of these compounds in the United States Environmental Protection Agency (USEPA), Agency for Toxic Substances and Disease Registry (ATSDR), National Toxicology Program (NTP) and World Health Organization (WHO) was searched. Ethanol was found to exhibit the highest reference dose (RfD) while 1,2-dibromo-3-chloro-propane displayed the lowest RfD. Consequently, a worst-case exposure scenario was applied in this study. It was assumed that there was the use of 7.5 sanitary napkins/day for 7 days/month. In the case of panty liners or overnight sanitary napkins, the utilization of 90 panty liners/month or 21 overnight sanitary napkins/month was assumed, respectively. In addition, 43 kg, the body weight of 12 to 13-year-old young women, and 100% VOCs skin absorption were employed for risk assessment. The systemic exposure dose (SED) values were calculated ranging from 1.74 (1,1,2-trichloroethane) ng/kg/day to 144.4 (ethanol, absolute) µg/kg/day. Uncertainty factors (UFs) were applied ranging from 10 to 100,000 in accordance with the robustness of animal or human experiments. The margin of exposure (MOE) of 34 VOCs was more than 1 (acceptable MOE > 1). Applicable carcinogenic references reported that the cancer risk of five VOCs was below 10-6. Based on our findings, evidence indicates that the non-cancer and cancer risks associated with VOCs detected in sanitary pads currently used in South Korea do not pose an adverse health risk in women.

Risk Assessment of Triclosan, a Cosmetic Preservative.

Triclosan (TCS) is an antimicrobial compound used in consumer products. The purpose of current study was to examine toxicology and risk assessment of TCS based on available data. Acute toxicities of oral, transdermal and inhalation routes were low, and phototoxicity and neurotoxicity were not observed. Topical treatment of TCS to animal caused mild irritation. TCS did not induce reproductive and developmental toxicity in rodents. In addition, genotoxicity was not considered based on in vitro and in vivo tests of TCS. It is not classified as a carcinogen in international authorities such as International Agency for Research on Cancer (IARC). No-observed-adverse-effect level (NOAEL) was determined 12 mg/kg bw/day for TCS, based on haematoxicity and reduction of absolute and relative spleen weights in a 104-week oral toxicity study in rats. Percutaneous absorption rate was set as 14%, which was human skin absorption study reported by National Industrial Chemicals Notification and Assessment Scheme (NICNAS) (2009). The systemic exposure dosage (SED) of TCS has been derived by two scenarios depending on the cosmetics usage of Koreans. The first scenario is the combined use of representative cosmetics and oral care products. The second scenario is the combined use of rinse-off products of cleansing, deodorants, coloring products, and oral care products. SEDs have been calculated as 0.14337 mg/kg bw/day for the first scenario and 0.04733 mg/kg bw/day for the second scenario. As a result, margin of safety (MOS) for the first and second scenarios was estimated to 84 and 253.5, respectively. Based on these results, exposure of TCS contained in rinse-off products, deodorants, and coloring products would not pose a significant health risk when it is used up to 0.3%.

Analytical method development of methylisothiazolinone, a preservative, in rat plasma using LC-MS/MS.

Methylisothiazolinone (MI) is a preservative used in consumer products to control bacterial and fungal growth. MI can be toxic, act as a skin sensitizer and irritant, and initiate lung diseases; therefore, it is important to understand the mechanisms underlying the toxicity of MI in the body. In this study, we developed a method to analyze plasma MI by using an LC-MS/MS-coupled multiple reaction monitoring (MRM) technique, which follows the fragments of a target metabolite in rat plasma. The MRM transition of MI was m/z 116 ➔ 101, and the lower limit of quantification (LLOQ) was set at 10 ng/mL. Including the concentration of LLOQ, a seven-point calibration curve explained much of the variation in the response, and it was strongly linear (R2 = 0.9998); its intra- and inter-day accuracy and precision values were within 15% of the standard deviation (SD%) and along with the FDA and Korea Ministry of Food and Drug Safety guidelines. For intravenous (iv) pharmacokinetic studies of MI using rats, we developed an analytical method that was useful in detecting the profile of MI in the plasma. We also determined half-life, and area under the curve (AUC) of MI using a non-compartment model, and these might be useful for the study of toxic mechanisms of MI in the body.

Metabolomic and Transcriptomic Comparison of Solid-State and Submerged Fermentation of Penicillium expansum KACC 40815.

Penicillium spp. are known to harbor a wide array of secondary metabolites with cryptic bioactivities. However, the metabolomics of these species is not well-understood in terms of different fermentation models and conditions. The present study involved metabolomics profiling and transcriptomic analysis of Penicillium expansum 40815 under solid-state fermentation (SSF) and submerged fermentation (SmF). Metabolite profiling was carried out using ultra-performance liquid chromatography quadruple time-of-flight mass spectrometry with multivariate analysis, followed by transcriptomic analyses of differentially expressed genes. In principal component analysis, the metabolite profiling data was studied under different experimental sets, including SSF and SmF. The significantly different metabolites such as polyketide metabolites (agonodepside B, rotiorin, verrucosidin, and ochrephilone) and corresponding gene transcripts (polyketide synthase, aromatic prenyltransferase, and terpenoid synthase) were primarily detected under SmF conditions. In contrast, the meroterpenoid compounds (andrastin A and C) and their genes transcripts were exclusively detected under SSF conditions. We demonstrated that the metabolite production and its corresponding gene expression levels in P. expansum 40815 were significantly influenced by the varying growth parameters and the immediate environment. This study further provides a foundation to produce specific metabolites by regulating fermentation conditions.