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Final report on the safety assessment of benzalkonium chloride
Abstract
Benzalkonium Chloride is a mixture of alkylbenzyldimethylammonium chlorides. The ingredient is used in cosmetic products as a foaming cleansing and bactericidal agent at concentrations up to 5.0%. The compound was nonmutagenic in several different cell assays. It is a skin and ocular irritant at concentrations greater than 0.1%. This cosmetic ingredient is not a sensitizer to normal humans at concentrations of 0.1%, but may be to individuals with diseased skin. It is concluded that Benzalkonium Chloride can be safely used as an antimicrobial agent at concentrations up to 0.1%.
... Dung dịch sát khuẩn thường bao gồm một số thành phần như: ethanol, isopropanol, npropanol, sodium lactate, fragrance… [1]. Ngoài ra, để diệt các vi khuẩn cứng đầu, một số chất sát khuẩn cũng được bổ sung vào thành phần dung dịch này, trong đó có nhóm benzalkonium chloride (BAC) [1,2]. Benzalkonium chloride hay Benzyldimethyloctyl ammonium chloride (BAC-C8) và benzyldimethyldodecylammonium chloride (BAC-C12) (Hình 1) là các chất hoạt động bề mặt có chứa nguyên tử cation bậc bốn, được thay thế bằng các chuỗi alkyl C8 và C12, các hợp chất này được sử dụng rộng rãi trong công nghiệp dược phẩm làm chất khử trùng chống vi sinh vật. ...
... Benzalkonium chloride hay Benzyldimethyloctyl ammonium chloride (BAC-C8) và benzyldimethyldodecylammonium chloride (BAC-C12) (Hình 1) là các chất hoạt động bề mặt có chứa nguyên tử cation bậc bốn, được thay thế bằng các chuỗi alkyl C8 và C12, các hợp chất này được sử dụng rộng rãi trong công nghiệp dược phẩm làm chất khử trùng chống vi sinh vật. BAC có thể được sử dụng một cách an toàn như một diệt vi khuẩn trong dung dịch sát khuẩn ở nồng độ lên tới 0,1% [2]. Tuy nhiên, theo Quyết định EU 2016/1950 và Quy định về các sản phẩm diệt khuẩn (EU) số 528/2012 [3,4], BAC không còn được chấp thuận sử dụng trong một số sản phẩm diệt khuẩn, như nước sát trùng rửa tay và làm sạch cơ thể. ...
Benzyldimethyloctylammonium chloride (BAC-C8) and Benzyldimethyldodecyl ammonium chloride (BAC-C12) are bactericidal surfactants which widely used in the pharmaceutical industry as anti-microbial disinfectants in skin antiseptic solution. According to current international regulations, the standard of finished antiseptic solution must have regulations on the limit of preservatives when used in the formulation. In this study, simultaneous determination of BAC-C8 and BAC-C12 was performed by capillary electrophoresis using capacitively coupled contactless conductivity detection (CE-C4D) with analytical conditions including: fused silica capillary (50 µm ID.) with effective length of 40 cm, background electrolyte solution of 100 mM acetic acid (Ace) added 30% acetonitril (ACN); hydrodynamic sample injection at height of 10 cm in 20 s; separation voltage of +15 kV. The detection limit of BAC-C8 and BAC-C12 were 1.5 mg/L and 3.5 mg/L, respectively. This method has been applied to determine the content of BAC-C8 and BACC12 in the disinfectant solution samples.
... Despite the outstanding properties of QS, the remarkable cytotoxicity of quaternary ammonium surfactants, including Stk, could represent a challenge in their in vivo application [65,66]. Therefore, to assess QS biocompatibility, we first performed cell viability assays on MCF-7 cells treated with two different concentrations of blank QS, i.e., 10 and 2 µg/mL (Stk/Chol); see Section 2.6.1 for details. ...
... More importantly, the entrapment of Br-Sq-C12 into the QSs does not interfere with the ability of the dye to generate ROS rapidly, an essential requirement for PDT activity. Despite the outstanding properties of QS, the remarkable cytotoxicity of quaternary ammonium surfactants, including Stk, could represent a challenge in their in vivo application [65,66]. Therefore, to assess QS biocompatibility, we first performed cell viability assays on MCF-7 cells treated with two different concentrations of blank QS, i.e., 10 and 2 μg/mL (Stk/Chol); see Section 2.6.1 for details. ...
Photodynamic therapy is a non-invasive therapeutic strategy that combines external light with a photosensitizer (PS) to destroy abnormal cells. Despite the great progress in the development of new photosensitizers with improved efficacy, the PS’s photosensitivity, high hydrophobicity, and tumor target avidity still represent the main challenges. Herein, newly synthesized brominated squaraine, exhibiting intense absorption in the red/near-infrared region, has been successfully incorporated into Quatsome (QS) nanovesicles at different loadings. The formulations under study have been characterized and interrogated in vitro for cytotoxicity, cellular uptake, and PDT efficiency in a breast cancer cell line. The nanoencapsulation of brominated squaraine into QS overcomes the non-water solubility limitation of the brominated squaraine without compromising its ability to generate ROS rapidly. In addition, PDT effectiveness is maximized due to the highly localized PS loadings in the QS. This strategy allows using a therapeutic squaraine concentration that is 100 times lower than the concentration of free squaraine usually employed in PDT. Taken together, our results reveal the benefits of the incorporation of brominated squaraine into QS to optimize their photoactive properties and support their applicability as photosensitizer agents for PDT.
... Bactisure (Zimmer-Biomet, Warsaw, IN) is an acetic acid, benzalkonium chloride (BZK)-based surgical lavage solution (ethanol 1%, acetic acid 0.6%, sodium acetate 0.2%, BZK 0.013%, and water). The component BZK is a quaternary ammonium cationic detergent that acts as a surfactant and as an antibacterial agent at 0.1% concentration [22]. The manufacturer claims that the solution does not harm human tissue [22][23][24]. ...
... The component BZK is a quaternary ammonium cationic detergent that acts as a surfactant and as an antibacterial agent at 0.1% concentration [22]. The manufacturer claims that the solution does not harm human tissue [22][23][24]. However, no outside clinical research supports this statement. ...
Introduction:
Multiple irrigation solutions are used in orthopedic surgeries although there are limited studies on their lasting effects on human tissues. The purpose of this work was to investigate the cytotoxic effects of the irrigation solutions Bacitracin, Clorpactin (sodium oxychlorosene), Irrisept (0.05% chlorhexidine gluconate), and Bactisure (ethanol 1%, acetic acid 0.6%, sodium acetate 0.2%, benzalkonium chloride 0.013%, and water) on 3D cultures of human fibroblasts.
Methods:
Two independent experiments with 6 replicates were performed for the following conditions: Control (saline), bacitracin, Clorpactin, Irrisept, and Bactisure. Human fibroblast cell sheets were exposed to these solutions (1 or 2 min), followed by three washes with warm saline. Cell sheets were then cultured for additional 5- and 7-day posttreatment. Cell viability was measured using the alamarBlue (AB) assay. The more cytotoxic the irrigant, the lower the AB reduction.
Results:
For 1-min exposure time, significant differences in AB reduction were noted in Clorpactin, Irrisept, and Bactisure groups compared to control at both 5 days (Clorpactin p = 0.0003, Irrisept p = 7.31 × 10-15, Bactisure p = 6.86 × 10-14) and 7 days posttreatment (all groups p < 0.0001). The results were similar in the 2-min exposure groups. Bacitracin-treated fibroblasts displayed no significant difference at all measurement times compared to control.
Discussion:
Impacts of irrigation solution exposure on cell viability were varied. Irrisept and Bactisure showed the highest cell toxicity even after a brief exposure (1 min), while bacitracin and Clor-pactin exposure showed smaller impacts on cell viability as compared to saline controls. This in vitro study provided insight into the effects of the irrigants on human cells and provides the groundwork essential to move to in vivo studies. Our findings raised the concern that some irrigation solutions may have negative impacts on wound healing and healthy cellular response.
... Hence, in this paper, a kind of BC dry film with antimicrobial properties was developed by using benzalkonium chloride as the antimicrobial agent. Benzalkonium chloride is a sort of antimicrobial cationic surfactant, which was widely used in commercial wound dressings and had a strong role against Grampositive bacteria (Elder, 1989). Some properties of BC dry film including swelling ratio, slow release of benzalkonium chloride and antimicrobial effect were investigated in order to achieve good performances in acute traumas treatment for the future. ...
... Five different concentrations of the benzalkonium chloride solution including 0.026%, 0.051%, 0.077%, 0.102% and 0.128% (w/w) were chosen to prepare the antimicrobial BC dry films. The concentration range investigated here was based on the common concentrations of benzalkonium chloride solution used in the treatment of wound, skin and mucous membrane as well as the sterilization of medical devices (Elder, 1989). The effects of concentration of the benzalkonium chloride solution on the antimicrobial activity were evaluated by the disc diffusion method and the results were shown in Fig. 1. ...
A kind of antibacterial bacterial cellulose (BC) dry film was developed and characterized as a potential functional wound dressing for acute traumas treatment. To achieve this, a freeze-dried BC film was immersed in a benzalkonium chloride solution, which belongs to cationic surfactant type antimicrobial agent, followed by another freeze-drying step. Some physical and antimicrobial properties of the prepared BC films were investigated and the results showed that the drug-loading capacity of the BC dry film was about 0.116mg/cm2 when soaked in 0.102% benzalkonium chloride solution. High water absorbing capacity, an important quality for wound dressings was also achieved with a swelling ratio of 26.2 in deionized water and of 37.3 in saline solution. With respect to the antimicrobial effect, a stable and prolonged antimicrobial activity for at least 24h was obtained especially against Staphylococcus aureus and Bacillus subtilis, which were general Gram-positive bacteria that found on the contaminated wound.
... It has been used to maintain the sterility of a variety of prescription and over-the-counter products, such as cosmetics, infant care products, and pharmaceutical nasal sprays, ophthalmic solutions, and otic drops. 2 As reported in the Journal of American College of Toxicology, the Cosmetic Ingredient Review panel concluded that BKC can be safely used as an antimicrobial agent at concentrations up to 0.1%. 2 However, over the past several years, reports of damage to human nasal epithelia and/or exacerbation of rhinitis medicamentosa associated with intranasal products containing BKC have emerged. [3][4][5][6][7] The objective of this article was to review the published literature specific to these safety issues to determine whether sufficient, clinically significant data exist to confirm that intranasal products containing BKC cause actual damage to human nasal epithelia or exacerbate rhinitis medicamentosa. ...
... It has been used to maintain the sterility of a variety of prescription and over-the-counter products, such as cosmetics, infant care products, and pharmaceutical nasal sprays, ophthalmic solutions, and otic drops. 2 As reported in the Journal of American College of Toxicology, the Cosmetic Ingredient Review panel concluded that BKC can be safely used as an antimicrobial agent at concentrations up to 0.1%. 2 However, over the past several years, reports of damage to human nasal epithelia and/or exacerbation of rhinitis medicamentosa associated with intranasal products containing BKC have emerged. [3][4][5][6][7] The objective of this article was to review the published literature specific to these safety issues to determine whether sufficient, clinically significant data exist to confirm that intranasal products containing BKC cause actual damage to human nasal epithelia or exacerbate rhinitis medicamentosa. ...
Background:
For most multiuse aqueous nasal, ophthalmic, and otic products, benzalkonium chloride (BKC) is the preservative of choice. The American College of Toxicology has concluded that BKC can be safely used as an antimicrobial agent at concentrations up to 0.1%. BKC has been in clinical use since 1935 and is contained in a wide variety of prescription and over-the-counter products. However, over the past several years there have been conflicting reports of damage to human nasal epithelia and/or exacerbation of rhinitis medicamentosa associated with intranasal products containing BKC.
Objective:
We sought to review the published literature and determine whether there is sufficient, clinically significant data that would confirm that intranasal products containing BKC are likely to damage human nasal epithelia or exacerbate rhinitis medicamentosa.
Methods:
A literature search was conducted for in vivo and in vitro studies that evaluated the effects of BKC on human nasal epithelia.
Results:
A total of 18 studies (14 in vivo, 4 in vitro) were identified that evaluated short- and long-term exposure of concentrations of BKC in concentrations ranging from 0.00045% to 0.1%. Eight studies, including a 6-month and 1-year long-term treatment study, demonstrated no toxic effects associated with BKC, indicating that BKC was neither harmful to nasal tissue nor prone to exacerbate rhinitis medicamentosa. Furthermore, of the 10 studies that concluded that BKC resulted in degenerative changes in human nasal epithelia (eg, ciliary beat frequency, ciliary morphology, mucociliary clearance, epithelial thinning and/or destruction) or that BKC exacerbates rhinitis medicamentosa, only 2 (it was 2 according to the Results section) of these studies were supported by statistically significant differences between BKC and placebo or active control groups were compared. It is important to note that in both of these studies, the protocol incorporated the use or oxymetazoline in some or all of the subjects. Oxymetazoline is associated with rhinitis medicamentosa.
Conclusion:
Intranasal products containing the preservative BKC appear to be safe and well tolerated for both long- and short-term clinical use.
... Antimicrobial performance of the compound has been studied since the 1930s. It was used for preservation, antisepsis and disinfection [18,58]. However, a decrease in bacterial susceptibility and resistance to biocides has been reported since the 1950s, especially with quaternary ammonium compounds [59,60]. ...
... 35 Due to its limited irritancy data, products containing less than 0.5% BEC may be considered safer than products comprised higher BEC concentrations. 48,77 ...
The recent global pandemic has resulted in increased use of quaternary ammonium compounds (QACs). Currently, QACs are active ingredients in 292 disinfectants recommended by the US EPA for use against SARS-CoV-2. Among QACs, benzalkonium chloride (BAK), cetrimonium bromide (CTAB), cetrimonium chloride (CTAC), didecyldimethylammonium chloride (DDAC), cetrimide, quaternium-15, cetylpyridinium chloride (CPC), and benzethonium chloride (BEC) were all identified as potential culprits of skin sensitivity. Given their widespread utilization, additional research is needed to better classify their dermal effects and identify other cross-reactors. In this review, we aimed to expand our knowledge about these QACs to further dissect its potential allergic and irritant dermal effects on healthcare workers during COVID-19.
... QAS activity is similar to that of a negative control representing spontaneous revertants and does not exceed 2.5% of the positive control, even at the highest concentrations. According to literature, BAC does not induce mutagenicity in Ames test in the concentration range 10-100 µg/plate [51]. Not determined-insoluble 10 ...
A series of quaternary diammonium salts derivatives of 1,4:3,6-dianhydro-l-iditol were synthesized, using isommanide (1,4:3,6-dianhydro-d-mannitol) as a starting material. Both aromatic (pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), (3-carboxamide)pyridine; N-methylimidazole) and aliphatic (trimethylamine, N,N-dimethylhexylamine, N,N-dimethyloctylamine, N,N-dimethyldecylamine) amines were used, giving eight gemini quaternary ammonium salts (QAS). All salts were tested for their antimicrobial activity against yeasts, Candida albicans and Candida glabrata, as well as bacterial Staphylococcus aureus and Escherichia coli reference strains. Moreover, antibacterial activity against 20 isolates of S. aureus collected from patients with skin and soft tissue infections (n = 8) and strains derived from subclinical bovine mastitis milk samples (n = 12) were evaluated. Two QAS with octyl and decyl residues exhibited antimicrobial activity, whereas those with two decyl residues proved to be the most active against the tested pathogens, with MIC of 16–32, 32, and 8 µg/mL for yeast, E. coli, and S. aureus reference and clinical strains, respectively. Only QAS with decyl residues proved to be cytotoxic in MTT assay against human keratinocytes (HaCaT), IC50 12.8 ± 1.2 μg/mL. Ames test was used to assess the mutagenic potential of QAS, and none of them showed mutagenic activity in the concentration range 4–2000 µg/plate.
... Benzethonium chloride and methyl benzethonium chloride are quaternary ammonium salts whose antimicrobial activity has been studied since the 1930s. There are even early reports of synergistic antimicrobial and antifungal activity with acylated peptides (Liebert, 1985). Of note, colistin is a polymyxin peptide with a fatty acyl chain. ...
Biofilm-associated Pseudomonas aeruginosa infections remain a significant clinical challenge since the conventional antibiotic treatment or combination therapies are largely ineffective; and new approaches are needed. To circumvent the major challenges associated with discovery of new antimicrobials, we have screened a library of compounds that are commercially available and approved by the FDA (Prestwick Chemical Library) against P. aeruginosa for effective antimicrobial and anti-biofilm activity. A preliminary screen of the Prestwick Chemical Library alone did not yield any repositionable candidates, but in a screen of combinations with a fixed sub-inhibitory concentration of the antibiotic colistin we observed 10 drugs whose bacterial inhibiting activity was reproducibly enhanced, seven of which were enhanced by more than 50%. We performed checkerboard assays of these seven drugs in combination with colistin against planktonic cells, and analysis of their interactions over the complete combination matrix using the Zero Interaction Potency (ZIP) model revealed interactions that varied from highly synergistic to completely antagonistic. Of these, five combinations that showed synergism were down-selected and tested against preformed biofilms of P. aeruginosa. Two of the five combinations were active against preformed biofilms of both laboratory and clinical strain of P. aeruginosa, resulting in a 2-log reduction in culturable cells. In summary, we have identified synergistic combinations of five commercially available, FDA-approved drugs and colistin that show antimicrobial activity against planktonic P. aeruginosa (Clomiphene Citrate, Mitoxantrone Dihydrochloride, Methyl Benzethonium Chloride, Benzethonium Chloride, and Auranofin) as well as two combinations (Auranofin and Clomiphene Citrate) with colistin that show antibiofilm activity.
... Meanwhile, benzalkonium chloride showed some ocular toxicity and irritation properties with a possibility of penetration and accumulation in deep ocular structures (Baudouin et al., 2010;Desbenoit et al., 2013;Rosin and Bell, 2013). When applied to the skin from 2.5% to 10% concentrations for 24 h, benzalkonium chloride induced skin irritations to 50% of dermatitis patients in the 2.5%-concentration group and caused primary irritant dermatitis of all patients in the 10%-concentration group (Liebert, 1989). In another study, application of 0.02% benzalkonium chloride to the eyes of 51 human volunteers induced a slight hyperemia conjunctivae in only one person. ...
Benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea are commonly used preservatives in cosmetics. Recent reports suggested that these compounds may have cellular and systemic toxicity in high concentration. In addition, diazolidinyl urea and imidazolidinyl urea are known formaldehyde (FA) releasers, raising concerns for these cosmetic preservatives. In this study, we investigated the effects of benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea on ROS-dependent apoptosis of rat neural progenitor cells (NPCs) in vitro. Cells were isolated and cultured from embryonic day 14 rat cortices. Cultured cells were treated with 1-1,000 nM benzalkonium chloride, and 1-50 μM diazolidinyl urea or imidazolidinyl urea at various time points to measure the reactive oxygen species (ROS). PI staining, MTT assay, and live-cell imaging were used for cell viability measurements. Western blot was carried out for cleaved caspase-3 and cleaved caspase-8 as apoptotic protein markers. In rat NPCs, ROS production and cleaved caspase-8 expression were increased while the cell viability was decreased in high concentrations of these substances. These results suggest that several cosmetic preservatives at high concentrations can induce neural toxicity in rat brains through ROS induction and apoptosis.
... BAC was reported to produce a variety of adverse effects in humans (Figure 1). The Cosmetic Ingredient Review (CIR) (2008) panel concluded that this compound may be safely used as an antimicrobial agent at concentrations of up to 0.1% by weight (Liebert 1989). The Scientific Committee on Cosmetology (SCC) (2000) calculated the margin of safety [MOS = the no-observed-adverse-effect-level (NOAEL)/the systemic exposure dosage (SED)] of BAC as 372, based upon daily bioavailability when utilized in preservatives, intimate hygiene products, and in skin (non-rinse) and hair products (both non-rinse and rinse-off). ...
A risk assessment of benzalkonium chloride (BAC) was conducted based upon its toxicological profile and exposure evaluation. Since 1935, BAC has been used in a wide variety of products such as disinfectants, preservatives, and sanitizers. It is well-established that BAC is not genotoxic nor does it display tumorigenic potential, but safety concerns have been raised in local usage such as for ocular and intranasal applications. The Foundation of Korea Cosmetic Industry Institute (KCII) reported that in a hair conditioner manufactured as a cosmetic or personal product in South Korea, BAC was present at concentrations of 0.5-2%. The systemic exposure dosage (SED) was determined using the above in-use concentrations and a risk assessment analysis was conducted. The Margin of Safety (MOS) values for hair conditioners were calculated to be between 621 and 2,483. The risk of certain personal and cosmetic products was also assessed based upon assumptions that BAC was present at the maximal level of regulation in South Korea and that the maximal amount was used. The MOS values for the body lotion were all above 100, regardless of the application site. Collectively, data indicate that there are no safety concerns regarding use of products that contain BAC under the current concentration restrictions, even when utilized at maximal permitted levels. However, a chronic dermal toxicity study on BAC and comprehensive dermal absorption evaluation needs to be conducted to provide a more accurate prediction of the potential health risks to humans.
... Since its discovery in 1935, benzalkonium chloride (BC), has been one of the most commonly used quaternary ammonium compounds worldwide, although new generation variants of these compounds have been developed subsequently (Schaeufele 1984). BC is commonly used in cleaning products, swimming pool algaecides, sanitizers, and topical antiseptics (Schaeufele 1984) and is also used to inhibit microbial growth in products such as eyedrops, nasal sprays, and cosmetics (Liebert 1989). ...
Hydrolyzed protein lures are widely used to monitor fruit fly pests but are rapidly degraded by microbial activity and must be replaced frequently. To improve the stability of lures, the quaternary ammonium biocide, benzalkonium chloride (BC), was evaluated in mixtures with two hydrolyzed proteins commonly used to monitor Anastrepha spp. The mean number of Anastrepha obliqua adults captured during six consecutive weeks using Captor + borax with the addition of 240 mg BC/liter, not renewed during the test, was similar to Captor + borax that was replaced at weekly intervals and was more effective than Captor + borax without BC. Numbers of A. obliqua flies captured in 30% CeraTrap diluted in water containing 240 mg BC/liter were similar to those caught in traps baited with Captor + borax or 30% CeraTrap without BC in the first 9 d of evaluation but was significantly more effective than both lures after 56 d. After >2 mo of use, 30% CeraTrap containing 240 mg BC/liter remained as effective as newly prepared 30% CeraTrap. The addition of BC to lures reduced surface tension of liquid lures by ~40–50%. However, when BC was increased to 720 mg BC/liter, only a small additional reduction in surface tension was observed and higher concentrations of BC did not increase capture rates. These findings could contribute to reduced costs for trapping networks and the development of long-lasting formulations of liquid protein lures for bait stations and mass-trapping targeted at major tephritid pests.
... Furthermore, a cosmetic ingredient review panel concluded that benzalkonium chloride can be safely used as preservative at concentrations up to 0.1% (Liebert, 1989). ...
De mucosa vormt een beschermende barrière tegen micro-organismen en schadelijke stoffen. Bijgevolg is het belangrijk om voor chemische producten en farmaceutische formulaties die met de mucosa in contact komen na te gaan of ze mucosale irritatie en beschadiging veroorzaken. De regelgevende instanties vereisen over het algemeen dat de lokale tolerantie van producten in vertebraten wordt beoordeeld. Het gebruik van vertebraten voor veiligheidstests wordt echter sterk in vraag gesteld. Bijgevolg is er een grote belangstelling voor de ontwikkeling van alternatieve methodes zoals in vitromethodes en voor het gebruik van lagere organismen als testorganismen. Alvorens een alternatieve methode door onderzoekers en regelgevers wordt aanvaard, moeten de relevantie en de betrouwbaarheid van de test onderzocht worden met behulp van referentiestoffen (Hoofdstuk 1 en Hoofdstuk 2). In dit raam werd een alternatieve mucosale irritatietest ontwikkeld die gebruik maakt van naaktslakken (namelijk Arion lusitanicus). De naaktslak werd gekozen als testorganisme, omdat de mucosa zich aan de buitenzijde van de slak bevindt en omdat de mucosa van de slak histologisch lijkt op de humane mucosa. De mucusproductie van de slakken werd geselecteerd als eindpunt om de potentieel irriterende effecten van een substantie te evalueren; de vrijstelling van proteïnen en enzymen uit de lichaamswand van de slakken werd gekozen om de weefsel-beschadiging te beoordelen. Dit onderzoek beoogde de optimalisatie en validatie van de testprocedure en het predictiemodel van de mucosale irritatietest voor de evaluatie van de oogirritatie en -beschadiging die kunnen veroorzaakt worden door een éénmalige blootstelling aan chemische producten. Een ander objectief was de optimalisatie van de vijf dagen procedure voor de evaluatie van de lokale tolerantie van vaste, halfvaste en vloeibare formulaties bestemd voor herhaalde toediening (Hoofdstuk 1 en Hoofdstuk 2). In Hoofdstuk 3 werden referentiechemicaliën (waarvan gegevens over oogirritatie bij konijnen beschikbaar waren) gebruikt om de mucosale irritatie testprocedure te optimaliseren en valideren voor de evaluatie van oogirritatie en -beschadiging. De resultaten van deze studie tonen dat de testprocedure kan worden verkort tot één dag door de testconcentratie van de tweede contactperiode te verhogen tot 3.5%. Er werd een predictiemodel ontwikkeld dat de chemicaliën eerst klasseert op basis van de hoeveelheid mucus die geproduceerd wordt tijdens een 60 minuten durende behandeling met een 1% verdunning van het chemische product. De chemicaliën die dit eindpunt niet beïnvloeden worden geklasseerd op basis van de weefselbeschadiging die wordt veroorzaakt door de eerste behandeling en door een tweede behandeling met een 3.5% verdunning van het product. Herhaald testen van 28 chemicaliën in vijf afzonderlijke experimenten toonde een goede intralaboratorium reproduceerbaarheid. Slechts vier chemicaliën werden zowel niet-irriterend als R36 geklasseerd in de herhaalde experimenten, terwijl geen enkele chemische stof zowel niet-irriterend als R41 geklasseerd werd. Wanneer de 28 chemicaliën werden ingedeeld in niet-irriterende of irriterende stoffen, werden een gevoeligheid en specificiteit van respectievelijk 94% en 75% bekomen. Bovendien werden 71% van de 28 chemische producten correct voorspeld in de drie EU oogirritatiecategorieën. Evaluatie van de data van de 28 chemicaliën en 12 bijkomende chemicaliën leerde dat chemische producten met verdovende eigenschappen over het algemeen verschillend geklasseerd worden met de mucosale irritatietest dan met de oogirritatietest bij konijnen. Laurylzuur (een chemische stof die mechanische beschadiging veroorzaakt), natriumlaurylsulfaat en Triton X-100® werden ook verschillend geklasseerd. Voor de meeste van de verschillend geklasseerde chemicaliën zijn de resultaten bekomen met de mucosale irritatietest echter in overeenstemming met beschikbare in-vivogegevens of resultaten bekomen met andere alternatieve oogirritatietests. In Hoofdstuk 4 werden de effecten van slakkenpopulatie en -species op de eindpunten van de test en op de oogirritatieclassificatie nagegaan. Vergelijking van de resultaten van één Belgische en twee Zwitserse A. lusitanicus populaties leert dat de geografische en ecologische oorsprong van de geteste populaties noch de mucusproductie, noch de score voor weefselbeschadiging beïnvloedt. De species specifieke effecten op de testeindpunten werden onderzocht door de gegevens van Belgische A. lusitanicus slakken te vergelijken met gelijkaardige gegevens van Belgische L. flavus en L. maximus slakken. L. flavus en L. maximus produceerden meer mucus dan A. lusitanicus, zodat de grenswaarden van de mucusproductie moesten worden verhoogd. De resultaten tonen bijgevolg aan dat de testprocedure en het predictiemodel dienen geoptimaliseerd en gevalideerd te worden als andere slakkenspecies gebruikt worden in plaats van A. lusitanicus. In Hoofdstuk 5 werd de lokale tolerantie geëvalueerd van bioadhesieve poeders bestemd voor herhaalde buccale toediening (die Amioca® zetmeel en lineair polyacrylzuur of Carbopol® 974P bevatten). Hiervoor werd de vijf dagen procedure van de mucosale irritatietest – die bij het begin van dit onderzoek aangewend werd voor de evaluatie van de lokale tolerantie van nasale bioadhesieve poeders – gebruikt. Er werd een predictiemodel ontwikkeld dat de formulaties klasseert in vier irritatiecategorieën op basis van de totale mucusproductie en in vier weefselbeschadiging-categorieën op basis van de vrijstelling van proteïnen en enzymen. De test liet toe om het concentratie-effect van ingrediënten van buccale poederformulaties te evalueren. Het vernet polyacrylzuur (Carbopol® 974P) veroorzaakte meer mucosale irritatie en beschadiging dan het lineaire polyacrylzuur. Bovendien nam het irriterend en beschadigend vermogen toe met een stijgende concentratie aan polyacrylzuur. De resultaten zijn in overeenstemming met beschikbare (pre)klinische data over de buccale tolerantie. Deze concentratie-respons experimenten kunnen een zeer nuttig hulpmiddel zijn bij de selectie van concentraties van componenten die bestemd zijn voor de ontwikkeling van geneesmiddelen. Hoofdstuk 6 beschrijft de optimalisatie van de vijf dagen procedure van de mucosale irritatietest voor de evaluatie van de lokale tolerantie van bioadhesieve poeders bestemd voor herhaalde oculaire toediening en hun ingrediënten. De resultaten toonden aan dat een herhaalde behandeling met 20 mg poeder op vijf opeenvolgende dagen – gelijkaardig aan de procedure gebruikt in Hoofdstuk 5 – best discrimineert tussen de gegevens over de mucusproductie en de proteïnen- en enzymen-vrijstelling van de negatieve en positieve controleslakken. DDWM en DDWM/SLS 80/20 werden respectievelijk als negatieve en positieve controle gekozen. Een herhaalde behandeling met de ingrediënten DDWM, natriumstearylfumaraat of Amioca® resulteerde niet in irritatie van de mucosa van de slakken. Ciprofloxacine HCl en gentamycinesulfaat werden als mild irriterende componenten geklasseerd. Vancomycine HCl induceerde sterke irritatie van de mucosa. Behandeling met elk van de voorgaande componenten resulteerde in minimale beschadiging van de mucosa. De poeders die DDWM, 5% Carbopol® 974P, 1% natriumstearylfumaraat en tot 10% ciprofloxacine HCl bevatten werden geklasseerd als niet-irriterende formulaties. De poeders die Amioca®, 1% natriumstearylfumaraat, 5% gentamycinesulfaat, 5% vancomycine HCl en 4.45% of 13.35% Carbopol® 974P bevatten werden geklasseerd als mild irriterende poeders. De lokale tolerantiedata van de geteste poeders en hun ingrediënten bekomen met de mucosale irritatietest zijn in goede overeenstemming met bestaande in-vivodata over de oculaire tolerantie. In Hoofdstuk 7 werd de vijf dagen procedure van de mucosale irritatietest geoptimaliseerd voor de evaluatie van de lokale tolerantie van suppositoria. De resultaten tonen aan dat een herhaalde behandeling met 50 mg fijngemalen suppositorium goed discrimineert tussen de gegevens over de mucusproductie en de proteïnen- en enzymenvrijgave van de negatieve en positieve controleslakken. Novata® B en Novata® B/SLS 90/10 werden respectievelijk als negatieve en positieve controle gekozen. Het predictiemodel ontwikkeld voor bioadhesieve poeders werd gebruikt om de suppositoria te klasseren. Een herhaalde behandeling van de slakken met Novata® B, Suppocire® AM of Colitofalk® suppositoria – die elk een vette suppobasis bevatten – resulteerde niet in irritatie of beschadiging van de mucosa van de slakken. Pentasa® suppositoria – met PEG als basis – en PEG 1500/PEG 4000 3/7 werden respectievelijk als mild en sterk irriterende formulaties geklasseerd. Noch Pentasa®, noch PEG 1500/PEG 4000 3/7 resulteerde in beschadiging van de mucosa. De lokale tolerantiedata van de geteste suppositoria bekomen met de mucosale irritatietest zijn in goede overeenstemming met beschikbare (pre)klinische data over de rectale tolerantie. Hoofdstuk 8 behandelt de optimalisatie van de vijf dagen procedure van de mucosale irritatietest voor de evaluatie van de lokale tolerantie van halfvaste vaginale formulaties. Op basis van de resultaten werd 100 mg geselecteerd als testhoeveelheid om de mucosale tolerantie van halfvaste formulaties te beoordelen. 5% HEC gel en Conceptrol® werden respectievelijk als negatieve en positieve controle gekozen. Er werd een predictiemodel opgesteld dat de irritatiecategorie van halfvaste formulaties voorspelt. Een herhaalde behandeling van de slakken met 5% HEC gel, Monistat® 7 of gelen die tot 10 mM dapivirine bevatten induceerde geen mucosale irritatie. Replens® en K-Y® jelly werden respectievelijk als mild en matig irriterende formulaties geklasseerd. Geen van voorgaande formulaties induceerde mucosale beschadiging. Het irriterend vermogen van de halfvaste formulaties die N-9 als enige actief bestanddeel bevatten (Gynol II®, Gynol II® Extra Strength, Advantage S®, Conceptrol® en Delfen®) nam toe met toenemende concentratie aan N-9. Deze formulaties induceerden milde, matige of sterke beschadiging van de mucosa van de slakken. Protectaid® werd geklasseerd als een sterk irriterende formulatie die milde mucosale beschadiging veroorzaakt. Voor alle geteste halfvaste formulaties met uitzondering van Protectaid® zijn de data bekomen met de mucosale irritatietest in goede overeenstemming met bestaande invivodata over de vaginale tolerantie. De overschatting van de irriterende en beschadigende eigenschappen van Protectaid® door de mucosale irritatietest kan verklaard worden door het feit dat we enkel de gel testten die aanwezig is in de Protectaid® spons. Gebruik van de Protectaid® spons door vrouwen resulteert echter in een beperktere blootstelling aan de gel. In Hoofdstuk 9 werd nagegaan of de vijf dagen procedure van de mucosale irritatietest kan gebruikt worden voor de evaluatie van de lokale tolerantie van vloeibare nasale formulaties. Er werd een predictiemodel ontwikkeld dat de irritatiecategorie van vloeibare formulaties voorspelt. Een herhaalde behandeling van de slakken met Naaprep® of Luffeel® induceerde geen mucosale irritatie. Flixonase Aqua werd geklasseerd als een mild irriterende formulatie, terwijl Nasonex®, Nesivine® en Allergodil® geklasseerd werden als matig irriterende formulaties. Geen van voorgaande formulaties induceerde beschadiging van de mucosa van de slakken. Syntaris® induceerde sterke irritatie en milde beschadiging van de mucosa. De lokale tolerantiedata van de geteste vloeibare nasale formulaties bekomen met de mucosale irritatietest zijn in goede overeenstemming met (pre)klinische data over de nasale tolerantie.
... Benzalkonium chloride (BAC) is a quaternary ammonium compound which has been used in clinical applications since 1935 [3]. It has been also used as the antiseptic compound in a variety of products, such as cosmetics, infant care products and ophthalmic solutions [12]. The major advantage of QASs is the possibility to use them in formulations for rinse-free applications. ...
Background Quaternary ammonium salts (QASs) formulations are the disinfectants of choice for hospitals. The advantage of formulation containing QAS is the possibility of their usage as rinse free-solutions e.g. for hands. Long lasting and widespread industrial usage of (QAS) increase number of resistant pathogens not only to these but also other drugs. Thus, it is important to elucidate the chemical composition – activity relationships in order to create highly effective mixtures having synergistic activity. Material and Methods Antimicrobial activity of three different quaternary ammonium salts (cocamidopropyl betaine, dimethyl amine oxide and benzalkonium chloride) have been tested separately and as mixtures. Experiments were performed according to CSN PN-EN Standards on reference strains. Minimal inhibitory concentrations (MIC) were obtained for Escherichia coli ATCC 10536 (PCM 1144), Enterococcus hirae ATCC 10541 (PCM 2559), Staphylococcus aureus ATCC 6538 (PCM 2602), Pseudomonas aeruginosa ATCC 15442 (PCM 2563), Candida albicans (ATCC 10231) and Listeria monocytogenes. Results The highest antimicrobial activity had benzalkonium chloride, the lowest activity cocamidopropyl betaine. Mixtures showed increased antimicrobial activity. Conclusions For the tested compounds there is positive correlation between critical micelle concentration and activity. Synergistic activity was found for mixture of compounds. Key words bacteria • minimal inhibitory concentration • quaternary ammonium salts • yeast Streszczenie Wstęp Do dezynfekcji w szpitalach bardzo często używa się obecnie środków zawierających czwartorzędowe sole amoniowe (CAS). Niestety, szeroko rozpowszechnione stosowanie tych związków, spowodowało narastającą oporność patogennych szczepów, powiązaną z opornością również na innego rodzaju substancje. Z tego powodu ważne jest poszukiwanie nowych strukturalnie środków dezynfekcyjnych lub ich nowych połączeń w mieszaninach, a także badanie powiązań pomiędzy składem chemicznym a aktywnością przeciwdrobnoustrojową. Materiały i Metody W pracy zostały przebadane przeciwdrobnoustrojowe właściwości trzech rodzajów czwartorzędowych soli amoniowych (betainy kokamidopropylowej, tlenku dimetyloaminy i chlorku benzalkoniowego). Doświadczenia przeprowadzono także na mieszaninach tych preparatów. Wyznaczono minimalne stężenia hamujące według normy CSN PN-EN dla szczepów standardowych: Escherichia coli ATCC 10536 (PCM 1144), Enterococcus hirae ATCC 10541 (PCM 2559), Staphylococcus aureus ATCC 6538 (PCM 2602), Pseudomonas aeruginosa ATCC 15442 (PCM 2563), Candida albicans (ATCC 10231) oraz Listeria monocytogenes. Wyniki Chlorek benzalkoniowy wykazywał najwyższą, a betaina kokamidopropylowa najniższą aktywność przeciwdrobnoustrojową. W mieszaninach rosła aktywność związków. Konkluzje Wyniki wskazują pozytywną korelację pomiędzy krytycznym stężeniem micelizacji a aktywnością przeciw testowanym szczepom. Słowa kluczowe bakterie • czwartorzędowe sole amoniowe • drożdże • minimalne stężenie hamujące
... These substances have similar physicochemical features as imidazolium ILs, but have been studied in greater detail because of their application as preservatives in eye medicines and cosmetics among various other applications. Benzalkonium chlorides have been shown to be cytotoxic in cultures of human conjunctival cells and of mouse lymphoma cells [22]. Xue et al. [21] investigated the uptake and distribution in rats of benzalkonium chlorides with alkyl chains of predominantly C 12 and C 14 . ...
In order to assist an integrated development of ionic liquids (ILs), a study on the sorption, distribution, and cytotoxicity of a series of 1-alkyl-3-methyl imidazolium tetrafluoroborates with C6 rat glioma cells has been performed. Cellular sorption and distribution among three cellular fractions (cytosol, nuclei, and membranes) were analysed by reversed-phase HPLC (RP-HPLC). Compounds with longer 1-alkyl substituents were sorbed with higher enrichment factors and sorption coefficients per protein than those with shorter 1-alkyl chains. The 1-octyl-3-methyl imidazolium cation (C8MIM) was enriched 17-folds whereas C6MIM and C4MIM were enriched by factors of 3.5 and 2.3, respectively. After fractionation of cells by centrifugation, about 8% of C8MIM was found in the nuclear fractions. The cytotoxicity as estimated by the tetrazolium reductase assay was increasing with the lengths of the 1-alkyl chains from C4MIM to C10MIM. Consistently, cell proliferation rates were decreasing with increasing lengths of the 1-alkyl chains. The results reveal the correlations between lipophilicity, cellular sorption, and cytotoxicity.
... 43 Benzalkonium chloride has been used in cosmetic and therapeutic products since 1935 and has been declared by the American College of Toxicology to be safe for use in cosmetics at a concentration of 0.1%. 44 Triclosan is a synthetic, nonionic, broad spectrum, chlorinated bisphenol antiseptic that has been used in personal care products for more than 30 years. 45 Triclosan containing cleansers and the addition of triclosan to an emollient has been recognised as an effective way to treat large areas of atopic eczema. ...
Atopic eczema is one of the most common skin disorders in young children and also affects adults. Staphylococcus aureus infection is the most frequent complication of atopic eczema and is involved in the worsening of the disease. Antibiotic therapy against S. aureus has been an important component of treatment for atopic eczema but there are concerns about antibiotic overuse and increasing bacterial resistance. This has led some clinicians to recommend the use of homemade remedies such as bleach baths as an adjunctive treatment for patients with infected atopic eczema, despite the fact that there have been few published studies in this area. Balancing safety concerns with efficacious treatment is of particular importance in the paediatric population. This review discusses the historical use of bleach in medicine as well as its recent use for atopic eczema. Further, the chemistry and safety of bleach as well as alternative therapies are examined.
... The relationship between the LDM-MTT assay and Draize eye test results for cosmetic ingredients = UV absorbers (4); = surfactants(19); = macromolecules (10); = humectants(7); = oils(20); = medicants(13).= true-positive (11); = false-positive (25); = true-negative (37); = false-negative (0). ...
A tier evaluation system for the identification of cosmetic ingredients that are not ocular irritants was applied to 59 cosmetic ingredients, for which in vivo data were available. The tier system employs monolayer cultures of SIRC cells, an established cell line originally derived from rabbit cornea, and a threedimensional living dermal model (LDM; MATREX(TM)), which consists of human dermal fibroblasts in a contracted collagen lattice. The effects of ingredients on monolayer cultures of SIRC cells were determined by Crystal Violet staining (in the SIRC-CVS assay), and the effects on the LDM were measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (in the LDM-MTT assay). The classifications of eye irritancy predicted by the in vitro system were compared with previously reported data obtained with the in vivo Draize rabbit eye test. The in vivo classification was based on appearance of corneal damage, or a maximal average score (MAS) of 15 as the cut-off point. The SIRC-CVS assay was effective in the prediction of compounds that would be non-irritants at a concentration of 10%, while the subsequent LDM-MTT assay could predict non-irritancy at various lower and higher concentrations, including 10%. The tier system gave very few false-negative predictions, though false positives were unavoidable. Performing the LDM-MTT assay with an additional 73 ingredients gave similar results in the prediction of non-irritancy at various concentrations. Our findings indicate that the tier system may be suitable for the safety assessment of eye irritancy of ingredients intended to be used in cosmetics and medicated cosmetics in Japan.
Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mis-match for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.
Biofouling is a critical problem for water treatment and desalination membranes because it significantly reduces process efficiency. Here, we present a new facile strategy for the fabrication of anti-biofouling polyamide (PA) thin film composite (TFC) membranes that involves the addition of the biocidal cationic surfactant, benzalkonium chloride (BAC), to an amine monomer solution during interfacial polymerization. The optimal addition of BAC effectively promotes and uniformizes amine diffusion toward the organic phase by reducing organic–aqueous interfacial tension and improving solution wettability on the support, producing a denser and more permeable PA structure. Moreover, BAC was strongly integrated into the PA matrix, presumably via strong chemical interactions between BAC and PA (i.e., electrostatic, hydrophobic, π–π stacking, and cation–π interactions), which enhanced the surface hydrophilicity and anti-bacterial activity of the membrane. Consequently, the BAC-incorporated TFC (BAC-TFC) membrane exhibited significantly enhanced reverse osmosis separation and anti-biofouling performance in comparison with the control TFC membrane. When compared with the conventional surfactant, sodium dodecyl sulfate, BAC resulted in remarkably improved biofouling resistance with comparable performance enhancement. Furthermore, the strong incorporation of BAC into PA led to the long-term durability of the BAC-TFC membrane in terms of its separation and anti-biofouling performance.
Designing secure, resilient, and scalable IoT networks is challenging because of heterogeneity, resource-constrained devices, and no guarantees of reliable network connectivity, which requires the implementation of new secure communication protocols with assurance compliance with security levels requirements of applications. In this context, one major question is how to map the multiple adaptive chaos-based security protocols to Class of Fog Applications (CoFA) on Fog integrated Cloud architecture. The approach to identifying the levels of chaos-based security protocols and discriminate the applications arriving at the Fog into CoFA for secure communication by keeping the important constraints like how much public channel is secure, how much time it takes to communicate from one node to another, and the rate at which synchronization error reaches close to zero. This paper thus introduces a set of CoFA for Fog applications and the associated level of chaos-based security protocols for secure communication. We have introduced dynamical adaptive chaos masking methodology for secure transmission wherein, we have divided into four sets of adaptive, secured communication protocol which starts with level one: security consists of non-identical chaotic (one master and one slave), level two: consist of non-identical hyper-chaotic (one master, one slave), level three: with non-identical complex hyper-chaotic system and, level four with hyper-chaotic complex and real hyper-chaotic (two masters, two slaves). We compared existing literature and state of the art; we found that our technique best results in synchronization error recovery and time duration. To the best of our knowledge, such mapping of CoFA with level-based secure communication protocols for Fog integrated Cloud architecture is introduced the first time. In the analysis phase, hyper-chaotic is more complex than a chaotic, similarly hyper-chaotic complex, with more complexity than hyper-chaotic and chaotic, ensuring more robust and secure transmission on a public channel.In this study, a chaotic system
with a hyperchaotic system is used to increase the security of the chaotic communication
system, which has not been previously implemented for this purpose in the literature for Fog integrated Cloud architecture. The
used chaotic system includes chuas system, modified jerk system and genesio-tesi system. Also, to map Fog request to the respective levels of security, a CoFA was introduced. These properties increase the complexity of the chaotic system and the security level.
The sliding adaptive mode control method is preferred for the synchronization part of the secure
communication.
Benzalkonium chloride is widely used in disinfectants. Several toxicological and fatal cases have been reported; however, little is known about its kinetics and distribution. We investigated the kinetic characteristics and distribution of benzalkonium cation (BZK) based on the length of the alkyl chains C12, C14, and C16. Rats were treated intravenously with BZK solution (dose, 13.9 mg/kg) containing equal amounts of the three homologues. Kinetic parameters in the blood were assessed, and BZK distribution in the blood and tissues was examined both in rapid intravenous (IV) and drip intravenous (DIV) administrations. BZK concentrations were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). BZK with longer alkyl chains showed lower elimination tendencies and remained in the blood for a longer duration. Concentrations of BZK were higher in the heart, lung, spleen, and kidney than those in the blood, and lower in the brain and fat. In both the IV and DIV groups, the lung, liver, spleen, and fat samples showed higher concentrations of the longer alkyl chains (BZK-C12< -C14< -C16), and the opposite trend was observed in the kidney (BZK-C16< -C14< -C12). Only the heart and muscle samples displayed the homologues in ratios comparable to the original administered solutions. Differences between IV and DIV groups could be identified by comparing concentrations of BZK homologues in the heart, lung, spleen, and kidney samples. We found that the kinetics and distribution of BZK were influenced by the alkyl chain length, and analysing each BZK homologues in blood and tissue samples may provide useful information.
The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 21 parabens as preservatives in cosmetic products. All of these ingredients are reported to function in cosmetics as preservatives; however, 5 are reported to also function as fragrance ingredients. The Panel reviewed relevant data relating to the safety of these ingredients under the reported conditions of use in cosmetic formulations. The Panel concluded that 20 of the 21 parabens included in this report are safe in cosmetics in the present practices of use and concentration described in this safety assessment when the sum of the total parabens in any given formulation does not exceed 0.8%. However, the available data are insufficient to support a conclusion of safety for benzylparaben in cosmetics.
Polyvinyl alcohol (PVA) is a hydrophilous and semi-crystallized. It has attracted much relevancy due to its pretty chemical endurance, fine thermal determination, decent physical specialities, wonderful bio-compatibility and cheapness. Gelatin (G) is a natural polymer and that are interesting materials for biomedical applications. Electrospinning is a simple method that provides very porous nanofiber production with high surface area. It is possible to produce biomedical, filtration, energy storage and protective materials by using electrospinning method. Benzalkonium chloride (BAC) is a kind of anti-microbial cationic surface-active agent, which has been pretty used in merchant wound dressings and has a powerful status toward Gr+ bacteria. In this study, nanofibers were produced from electrospinning of BAC, PVA and G containing solutions at various concentrations. The fibers of obtained nanofiber structure were uniform, continuous and intensive. The optimum parameters in terms of good mechanical and antibacterial properties were determined. S2 sample, electrospun from 11.63% PVA + 1.0% G +1.0% BAC containing solution, had the best morphological and mechanical properties due to having the thinnest fiber diameter (51±13nm) and the highest vertical strength (4.299MPa) and horizontal strength (4.058MPa). It also had antibacterial activity against all the bacteria tested (E. coli, P. aeruginosa, B. subtilis and S. aureus). Due to owning good mechanical and antibacterial properties, S2 sample can have many uses in medical sector.
Recently, the importance of inhalation toxicity assessment increased due to recent humidifier disinfectant-associated deaths in children. Benzalkonium chloride (BAC) is currently used as a cationic surfactant and germicide in food industry processing lines and as a hand sanitizer. Animal models are mainly used as a method of evaluating the inhalation toxicity of a hazardous substance, but that approach requires considerable amounts of time and cost. As a replacement for animal experiments, in vitro cell culture can be used to assess toxicity. However, such culture does not reflect the natural microenvironment of the lung, particularly its dynamic nature. In this study, we simulated normal breathing levels (tidal volume 10%, 0.2 Hz) through surface elongation of an elastic membrane in a dynamic culture system. The low-cost dynamic system provided easy control of breathing rate during lung cell culture. We assessed the toxicity using different concentrations of BAC (0, 2, 5, 10, 20, and 40 μg/mL) under static and dynamic culture conditions. Following 24 h of exposure to BAC, cellular metabolic activity, cell membrane integrity, interleukin-8 (IL-8) and reactive oxygen species (ROS) levels, and the total amount of protein in cells were analyzed. Our results showed that significant differences in cellular metabolic activity, as well as IL-8 and ROS profiles, between static and dynamic cell growth conditions, following BAC exposure.
ResumeBut
A la perimenopause, l’augmentation des risques cardiovasculaires, cancereux et des pathologies gynecologiques influence tout particulierement le choix d’une methode contraceptive. L’objectif de cet article est d’evaluer l’interet des spermicides a cette etape de la vie des femmes.
Materiels et methodes
Les criteres d’eligibilite des differentes methodes contraceptives selon les recommandations nationales et internationales, ainsi qu’une revue bibliographique de l’efficacite et des effets indesirables des deux principaux spermicides (chlorure de benzalkonium et nonoxynol-9) chez les femmes de plus de 40 ans, sont presentes.
Resultats
D’apres les recommandations, aucune methode contraceptive n’est contre-indiquee apres l’âge de 40 ans. L’efficacite des spermicides est tres variable selon les publications et ce quel que soit l’âge des utilisatrices. Ils semblent appropries chez les femmes en perimenopause surtout celles ayant une contre-indication aux autres methodes contraceptives ou ne souhaitant pas les utiliser. L’effet lubrifiant de certains spermicides pourrait constituer un avantage supplementaire.
Conclusion
Les spermicides devraient etre inclus dans l’offre de methodes contraceptives proposees aux femmes apres 40 ans. Les informations disponibles sur les mecanismes d’action, l’efficacite et la tolerance de ces agents devraient leur etre communiquees. La realisation d’etudes d’efficacite et d’acceptabilite des spermicides dans cette population apparait cependant indispensable.
Personal hygiene and cleanliness continue to represent important strategies for the maintenance of good health. Yet the introduction, within the community, of personal care products containing antimicrobial chemicals merits further review. While use of antimicrobial chemicals is both valid and appropriate in the healthcare setting where the potential for infection is great, its benefit in the community is unclear. In this chapter, we discuss personal care products containing the antimicrobial chemicals triclosan, triclocarban, and benzalkonium chloride, assessing their effectiveness for reducing disease in the community setting and growing concerns regarding the potential hazards to individuals and communities, especially the threat of emerging antibiotic resistance.
Any contraceptive method prescribed to a breastfeeding woman should be not only adapted to her physiological condition after delivery and to the health of her newborn, but should also meet her expectations. According to the French guidelines, combined hormonal contraception is prohibited up to 6 weeks after delivery in breastfeeding women and is not recommended within 6 months. Intrauterine devices and oral progestin alone may be utilized only from the fourth week after delivery. Spermicides have a privileged indication in breastfeeding women. Indeed, they have no restriction in national and international guidelines. In France, spermicides primarily include myristalkonium chloride and benzalkonium chloride that does not pass into maternal milk according Liebert [31]. In addition to their safe use, the lubricant effect of some specialties can be useful. Spermicides can be used in combination with a condom as well as with the lactational amenorrhea method. The acceptability and success of spermicides in breastfeeding woman depends largely on the information of users, their motivation and understanding of the conditions of use.
This test was performed to evaluate the acute oral toxicity and skin irritation of Lamia-Kill, disinfectant, containing 20% benzalkonium chloride and 10% citric acid. In acute oral toxicity, Lamia-Kill was orally administered at dose levels of 2,000, 1,000, 500, 250 and 0 mg/kg body weight. After single oral administration to both sexes of SD rats, the rats were observed for 14 days. In primary skin irritation test, New Zealand white rabbits were dermally treated with Lamia-Kill for 24 hr and observed for 3 days. All rats treated with Lamia-Kill were induced no toxic signs in mortalities, clinical findings, body weights and gross findings. Also, the disinfectant did not induce any adverse reactions such as erythema and edema on intact skin sites for the most part rabbits, but on abraded skin sites, some rabbits showed very slight erythema on 24 hr after topical application. With the results of this study, Lamia-Kill have no effect on acute toxicity and side effect in SD rats and was classified as a practically non-irritating material based on the score 0.50 of primary irritation index.
Cynomolgus monkeys were treated for 28 days with fluticasone propionate aqueous nasal spray (FPANS) 8 × 0.1 ml/day, which contained 0.02% benzalkonium chloride (BKC). Rats were treated for 1 hour/day for 28 days with a beclomethasone dipropionate aqueous nasal spray (BDPANS) essentially similar to the commercial preparation (Allen and Hanburys Ltd, Middlesex, England), which contained 0.01% BKC. Control animals received 5% glucose (monkeys) or air (rats). Sections of nasal mucosa were examined at 4 different levels by light microscopy. Counts of ciliated cells were made and scanning and transmission electron microscopy was performed on target sites that had been directly exposed to treatment (inferior turbinate of monkeys and intermediate turbinate of rats). No reduction in the number of ciliated cells or microscopical changes were seen in the nasal epithelium of the animals, and in particular there was no damage to the ultrastructure of the ciliated cells, the cilia themselves or their basal bodies that was related to treatment. The findings were compared with the results of previous in vitro and in vivo studies. Although ciliostasis has been reported with BKC in in vitro models, where mucus is relatively depleted, such results should be interpreted with caution since BKC repeatedly applied to the nasal respiratory epithelium in vivo has not caused damage to the ciliated epithelial cells. The animals received greater exposure to BKC-containing corticosteroids than patients who are treated with the aqueous nasal sprays for allergic rhinitis. The lack of any morphological damage supports previous findings that no damage to ciliated cells occurs in patients treated with FPANS or BDPANS.
Unlabelled:
Free N Clear is a sanitizing agent composed of United States Pharmacopeial Convention grade benzalkonium chloride (BAC), acetic acid, and methylparaben. Free N Clear is proposed for use as a sanitizing agent at a 1: 50 dilution (2% solution), which contains approximately 100 ppm BAC. As part of a program to assess its safety, a 2% solution of Free N Clear (diluted Free N Clear) was administered by gavage to Sprague-Dawley rats for 91d and tested for genetic toxicity in vitro and in vivo. In the 91d study, the no observable adverse-effect level of diluted Free N Clear in male and female Sprague-Dawley rats is 5000 mg/kg bw/day, the highest dose administered. Diluted Free N Clear was not mutagenic in a bacterial reverse mutation assay that tested concentrations extending into the toxic range, and did not increase the frequency of micronucleated polychromatic erythrocytes in bone marrow cells of male or female Sprague-Dawley rats when tested at the maximum permissible dose volume of 20 mL/kg bw. The results support safety of Free N Clear, when used at the concentration proposed for use.
Practical application:
The significance of these findings will allow for the development of Free N Clear as a potential sanitizing agent for food.
To develop a novel cancer vaccine using the targeting system of antigen protein to antigen-presenting cells (APCs) for efficient and safe cancer therapy.
The novel delivery system was constructed with antigen protein, benzalkonium chloride (BK), and γ-polyglutamic acid (γ-PGA), using ovalbumin (OVA) as a model antigen protein and evaluating its immune induction effects and utilities for cancer vaccine.
BK and γ-PGA enabled encapsulation of OVA and formed stable anionic particles at nanoscale, OVA/BK/γ-PGA complex. Complex was taken up by dendritic cell line DC2.4 cells efficiently. We subcutaneously administered the complex to mice and examined induction of IgGs. The complex induced not only Th2-type immunoglobulins but also Th1-type immunoglobulins. OVA/BK/γ-PGA complex inhibited tumor growth of E.G7 cells expressing OVA regularly; administered OVA/BK/γ-PGA complex completely rejected tumor cells.
The novel vaccine could be platform technology for a cancer vaccine.
Accidental ingestion or injection of household products sometimes occurs due to their accessibility, but the toxic manifestations have not been well characterized when they are internally administered. The aim of this study was to investigate the toxic effects induced by ingestion or injection of different ionic surfactants and disinfectants in rats. The test drugs involved benzalkonium and benzethonium (BZK and BZT, both cationic surfactants used as disinfectants), alkyldiaminoethylglycine (AEG, an amphoteric surfactant used as a disinfectant), linear alkylbenzenesulfonate (LAS, an anionic surfactant), polyoxyethylene cetylether (PEC, a nonionic surfactant), chlorhexidine (CHX, not a surfactant but a disinfectant) and saline (control). Male Sprague-Dawley rats were administered one of the test drugs orally (p.o.), intravenously (i.v.) or intraarterially (i.a.). The fatal effects appeared rapidly (<30 min) in i.v.-administered rats, while taking hours (>5 h) in i.a./p.o.-administered rats after a dose of around LD(50) , although the progress and degree of toxic effects varied among the drugs tested. In intravascular administration, BZK and BZT were fatal at doses of 15-20 mg kg(-1) . Higher concentrations in lung and kidney than in blood were determined. CHX showed a high toxic effect compared with cationic surfactants. The rats administered anionic (LAS) or amphoteric (AEG) surfactant died in less than 24 h at doses over 100 mg kg(-1) . In p.o. administration, the toxic effects were concentration/dose-dependent, and all rats administered high doses of surfactants except for PEC died at 5-20 h. The overall toxic ranks could be: cationic surfactant/CHX> anionic/amphoteric surfactant > nonionic surfactant.
The living skin equivalent (LSE) is an organotypic co-culture composed of human dermal fibroblasts in a collagen-containing matrix overlaid with human keratinocytes that have formed a stratified epidermis. This model system was used as a dermatotoxicity model in vitro for studying the effects of test samples topically applied to the air-exposed epidermis. Using the colorimetric thiazolyl blue (MTT) conversion assay as a measure of mitochondrial function, the extent of cytotoxicity induced by several well-characterized chemical irritants was evaluated in the LSE. For the seven chemical irritants tested, the concentrations that inhibited MTT conversion by 50% were approximately those threshold concentrations at which irritation was seen in human skin. In addition, nine chemicals that were classified as non-irritating to human skin, including solids and water-insoluble substances, exhibited minimal or no inhibition of MTT conversion when tested at full strength. Time- and dose-dependent release of the pro-inflammatory mediators, prostaglandin E2, prostacyclin and interleukin-1-alpha (IL-1alpha) was seen in LSE exposed to two known chemical irritants, morpholine and hydroxylamine sulphate, but not in LSE exposed to a minimally irritating test sample. The permeability constants (K(p) values) for water, caffeine, hydrocortisone, oestradiol and benzoic acid were determined in the LSE. In all cases the LSE was more permeable than human skin with K(p) values ranging from 0.56 +/- 0.10 x 10(-3) cm/hr for hydrocortisone to 29 +/- 5 x 10(-3) cm/hr for water penetration. The data suggest that organotypic skin cultures can be used as model systems for studying certain aspects of chemically induced dermal irritation. Using rates of water penetration as the most meaningful assessment of barrier competence, the LSE is approximately 30-fold more permeable than human skin. Although incomplete as a percutaneous absorption model, the presence of this partial barrier does influence the responses of cells in the LSE to topically applied chemicals.
The toxicity of well known irritants was investigated in rabbit and human skin organ cultures. Test chemicals were selected from various categories of irritants and included both water-soluble and water-insoluble compounds. Using a highly standardized protocol, test chemicals were applied topically at concentrations relevant to the in vivo situation. Toxicity was assessed by histomorphological examination, inhibition of conversion of the tetrazolium salt MTT, inhibition of epidermal cell proliferation and release of pro-inflammatory hydroxy fatty acids. Chemicals that are known to induce irritation in vivo invariably caused histopathological changes and inhibition of cell proliferation, whereas non-irritating chemicals did not; however, inhibition of MTT conversion and release of hydroxy fatty acids occurred with only a limited number of irritants. The response to the chemical irritants was different in rabbit and human skin cultures. Rabbit skin was slightly more sensitive to sodium dodecyl sulfate and benzalkonium chloride than human skin. Moreover, mineral oil enhanced epidermal cell proliferation in rabbit skin, but not in human skin. This study demonstrates that chemical irritants cause substance- and species-specific effects in skin organ cultures. It is therefore unlikely that irritant potential of chemicals from all irritant categories can be detected in vitro using one single parameter. A multiple endpoint approach and the inclusion of human tissue are recommended for optimal in vitro irritancy testing of chemicals.
The selection of reference compounds is crucial for a successful in vitro test development in order to proof the relevance of the test system. This publication describes the criteria and the selection strategy leading to a list of more than 130 chemicals suitable for test development within the ReProTect project. The presented chemical inventory aimed to support the development and optimization of in vitro tests that seek to fulfill ECVAM's criteria for entering into the prevalidation. In order to select appropriate substances, a primary database was established compiling information from existing databases. In a second step, predefined selection criteria have been applied to obtain a comprehensive list ready to undergo a peer review process from independent experts with industrial, academic and regulatory background. Finally, a peer reviewed chemical list containing 13 substances challenging endocrine disrupter tests, additional 50 substances serving as reference chemicals for various tests evaluating effects on male and female fertility, and finally 61 substances were identified as known to provoke effects on the early development of mammalian offspring. The final list aims to cover relevant and specific mode/site of actions as they are known to be relevant for various substance classes. However, the recommended list should not be interpreted as a list of reproductive toxicants, because such a description requires proven associations with adverse effects of mammalian reproduction, which are subject of regulatory decisions done by involved competent authorities.
Some deleterious effects on cartilage and even severe arthropathy have been reported after intra-articular corticosteroid injections. The objective of the present in vitro study was to determine if an injectable corticosteroid suspension is toxic to articular chondrocytes and synovial cells.
Human and bovine articular chondrocytes, bovine synovial cells, mouse C3H10T1/2 cells, and human osteosarcoma MG-63 cells were treated for thirty minutes in monolayer or suspension culture with an injectable corticosteroid suspension or its chemical components, including betamethasone sodium phosphate, betamethasone acetate, and benzalkonium chloride (as preservative). Cell viability was determined by means of microscopy or flow cytometry analysis.
In monolayer culture, the betamethasone corticosteroids per se did not cause cell death, whereas benzalkonium chloride caused death of articular chondrocytes. In suspension culture, betamethasone sodium phosphate at dosages of as high as 6 mg/mL did not cause significant death of human or bovine articular chondrocytes (p > 0.05). In contrast, benzalkonium chloride caused a death rate of 10.6% in human articular chondrocytes at a dosage of 10 microg/mL (p < 0.01), 21.0% at a dosage of 13.3 microg/mL (p < 0.01), and 99.3% and 99.4% at dosages of 20 and 200 microg/mL, respectively (p < 0.001 for both). Similarly, benzalkonium chloride caused death of bovine articular chondrocytes, bovine synovial cells, C3H10T1/2 cells, and MG-63 cells in a dose-dependent manner. When treated with a combination of betamethasone sodium phosphate and 200 microg/mL benzalkonium chloride, >99% of human or bovine articular chondrocytes were dead (p < 0.001).
The injectable corticosteroid suspension caused death in in vitro culture of human and bovine articular chondrocytes as well as bovine synovial cells because of its preservative benzalkonium chloride. The betamethasone corticosteroids per se did not cause significant chondrocyte death under the conditions tested.
A sensitive and simple high-performance liquid chromatography assay for benzalkonium chloride (BZK) in biological samples was developed. The biological samples, spiked with domiphen used as an internal standard, were purified by solid-phase extraction. The major homologues of BZK in pharmaceutical products (C(12) and C(14)) were eluted at 24 and 36 min using a YMC-Pack CN column (4.6 x 250 mm, 5 microm) with a mobile phase, mixture of acetonitrile and sodium acetate buffer (48:52), and monitored at 254 nm. The most dominant component C(12) was selected as an indicator to quantify BZK, and adjustment was then done based on the proportion of C(12) in the BZK product. Good linearity was obtained in the range of 0.1-3 microg, and the limit of detection was 20 ng as a loaded amount on column. The recoveries of BZK in serum and tissues ranged from 54 to 90%. In a practical case, 0.16 microg/ml of BZK was quantified in serum collected several hours after accidental ingestion. The method is simple, sensitive and reliable for determining BZK levels in practical biological samples.
Commercial grapefruit seed extracts (GSE) were extracted with chloroform. The solvent was evaporated, and the resulting solid was subsequently analyzed by high-performance liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI/MS), tandem mass spectrometry (ESI/MS/MS), and elemental analysis (by proton-induced X-ray emission analysis). Three major constituents were observed by HPLC and were identified as benzyldimethyldodecylammonium chloride, benzyldimethyltetradecylammonium chloride, and benzyldimethylhexadecylammonium chloride. This mixture of homologues is commonly known as benzalkonium chloride, a widely used synthetic antimicrobial ingredient used in cleaning and disinfection agents.
Quaternary ammonium compounds (QACs) are cationic surfactants that are widely used as disinfectants. In the present study, we tested two important representatives, namely, benzalkonium chloride (BAC) and dimethyldioctadecyl-ammonium bromide (DDAB) in four genotoxicity tests, namely, in the Salmonella/microsome assay with strains TA 98, TA 100 and TA 102, in the single-cell gel electrophoresis (SCGE) assay with primary rat hepatocytes and in micronucleus (MN) assays with peripheral human lymphocytes and with root tip cells of Vicia faba. In the bacterial experiments, consistently negative results were obtained in the dose range between 0.001 and 110 microg per plate in the presence and absence of metabolic activation while significant induction of DNA migration was detected in the liver cells. With BAC, a moderate but significant effect was found with an exposure concentration of 1.0 mg/l while DDAB caused damage at lower doses (0.3 mg/l). The effects were not altered when the nuclei were treated with formamidopyridine glycosylase, indicating that they are not due to formation of oxidized purines. The MN assays with blood cells were carried out under identical conditions to the SCGE experiments and a significant increase was seen at the highest dose levels (BAC: 1.0 and 3.0 mg/l; DDAB: 1 mg/l). Both compounds also caused significant induction of MN as well as inhibition of cell division in plant cells, the lowest effective levels were 1.0 and 10 mg/l for DDAB and BAC, respectively. Our findings show that both chemicals induce moderate but significant genotoxic effects in eukaryotic cells at concentrations which are found in wastewaters and indicate that their release into the environment may cause genetic damage in exposed organisms. Furthermore, the direct contact of humans to QAC-containing detergents and pharmaceuticals that contain substantially higher concentrations than those which were required to cause effects in eukaryotic cells in the present study should be studied further in regard to potential DNA-damaging effects in man.
Benzalkonium chloride (BZK) is a cationic surfactant used widely as a disinfectant, preservative and sanitizer in hospitals, at home and many public places. The toxicity of BZK is not well established although several human fatalities have been reported over the years. In this study, distribution and disposition of BZK following oral administration (PO) and intravascular (jugular vein (JV), femoral artery (FA), femoral vein (FV) and jugular artery (JA)) administration in rats were investigated along with pathological examinations. Toxic doses of 250 and 15 mg/kg of BZK were used for PO and intravascular administration, respectively. The fatal effects of BZK appeared soon in JV-, FV- or JA-rats, but took hours in PO or FA-rats. No rat receiving BZK via FA survived longer than 1 day. The PO-rats that aspirated BZK into their lungs had some systemic symptoms and higher blood and tissue concentrations of BZK. The blood BZK levels and kinetics were similar among the different routes of intravascular administration, but the lung and kidney levels were higher in JV-rats. Pathological examinations confirmed severe congestion and edema in the lungs and kidneys. These results suggest that (1) the toxic effects of BZK varied depending on the route of administration, (2) the degree of toxicity correlated with peak blood and tissue concentrations in orally dosed rats, (3) different toxicological progressions and manifestations were observed in FA- and JV-dosed rats even though these groups had similar blood concentration profiles, and (4) lung and kidney are reservoirs for BZK and considered to be the target organs of BZK.
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