No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Safety Assessment of Tromethamine, Aminomethyl Propanediol, and Aminoethyl Propanediol as Used in Cosmetics
Abstract
The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of tromethamine, aminomethyl propanediol, and aminoethyl propanediolas used in cosmetics. All 3 ingredients are reported to function in cosmetics as pH adjusters, and tromethamine and aminomethyl propanediol are also reported to function as fragrance ingredients. The Panel reviewed relevant animal and human data related to these ingredients, along with a previous safety assessment of aminomethyl propanediol. The Panel concluded that tromethamine, aminomethyl propanediol, and aminoethyl propanediol are safe in cosmetics in the practices of use and concentration as given in this safety assessment.
... TEOA is applied as antiacne preparation in t salicylate. AMPD may react with the methyl esters of the organic acids form [40]. TRIS and TIPA may be used in the synthesis of surface-active agents as e agents and emulsion stabilizers in pharmaceutical applications [41,42]. TIPA idly with acids forming amine salts [41]. ...
... AMPD and TIPA enable pH neutra cosmetic preparations, e.g., lotions, aerosols, and tonics [40,41]. TRIS is admin the treatment of salicylates, barbiturates, and methanol intoxications, and it m for plasma alkalization [42]. NaOH and alcoholamines are used in pharmace could serve as potential ingredients of the preparation for external applicatio tion of selected alkaline components may enhance the aqueous solubility of C maceutical preparation. ...
... AMPD may react with the methyl esters of the organic acids forming amides [40]. TRIS and TIPA may be used in the synthesis of surface-active agents as emulsifying agents and emulsion stabilizers in pharmaceutical applications [41,42]. TIPA reacts rapidly with acids forming amine salts [41]. ...
The application of cryptotanshinone (CT), a diterpenoid obtained from the root of Salviae miltiorrhiza, is significantly hindered due to its poor aqueous solubility. The aim of the present research was to develop an optimal solvent for analytical and preparative procedures of prospective dermal hydrogel formulations with CT. The influence of pH, temperature, and cosolvent presence on the solubility of CT was examined. Various components were applied to increase CT solubility, i.e., ethanol, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, 2,2′,2″-nitrilotriethanol, and triisopropanoloamine. The concentration of CT was analyzed by spectral and chromatographic methods, including UV–vis and HPLC methods. The increased solubility of CT was demonstrated in alkaline solvents with ethanol as a cosolvent. CT solutions doped with alcoholamines are more stable compared to CT solutions doped with NaOH.
... Based on previous studies and our observations of selected alcoholamines, we chose AMPD for further research. Its molecular weight is 105.14, pKa = 8.76 at 25 • C, it is soluble in water and alcohol [13]. We prepared aqueous solutions of AMPD with concentrations of 0.5% to 2.5%. ...
... They are used in the production of creams, ointments, shampoos, emulsions, lotions, and tonics. They are also widely used in pharmaceutical technology as auxiliary substances and derivatives for the production of medicines [12][13][14]. ...
... 0.1M aqueous solutions were made. These alcoholamines are used as auxiliary or active substances in medical or cosmetic preparations [12][13][14]. The choices were also based on earlier studies of the interaction of alcoholamines with sebum [9,10]. ...
Alcoholamines are widely used as auxiliary substances in various topical preparations. Their impact on the components of skin sebum allows them to be used in preparations that cleanse the skin of sebum in hair follicles. We measured the effects of various concentrations of aqueous solutions of AMPD (2-amino-2-methyl-1,3-propanediol) on model skin sebum. The volume of reacted sebum was calculated using two methods: optical assessment of the interaction of alcoholamines with the components of model skin sebum and determination of the reacted volume of model skin sebum based on the measurements of changes in the pH of the AMPD solutions. Both methods showed that the most favorable AMPD concentration for model sebum penetration was approximately 1–2%. Lower values of alcoholamine caused premature exhaustion from the solution. Excessively high concentrations resulted in the formation of a dense layer of products hindering effective skin cleansing.
... AMPD, an organic primary amine, is freely soluble in water and alcohols [5]. It is commonly used in cosmetic formulations, particularly in eye-area products at a concentration of 2% [6,7]. Ethanol has been used as solvent or co-solubilizer of organic ingredients including diterpenoid tanshinones [8][9][10][11]. ...
(1) Background: The aim of the work was to investigate the influence of selected physico-chemical factors on the solubility and release rate of CT (cryptotanshinone) in alcohologels. (2) Methods: The alcohologels of methylcellulose (MC), hydroksyethylcellulose (HEC), polyacrylic acid (PA) and polyacrylic acid crosspolymer (PACP) with CT were prepared and/or doped with native potato starch (SN) and modified citrate starches (SM2.5 and SM10). The analytical methods included evaluation of CT release profiles, Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and electrospray ionization mass spectrometry (ESI-MS), and scanning electron microscope (SEM) images were performed. (3) Results: The release and decomposition kinetics of CT in relation to the phosphate buffer solution (PBS) and methanol were observed. The amount of cryptotanshinone (CT) released into PBS was significantly lower (2.5%) compared to its release into methanol, where 22.5% of the CT was released into the model medium. The addition of SM2.5 to the alcohologel significantly increased the CT content to 70% in the alcohologel preparation containing NaOH (40%), and this enhanced stability was maintained for up to two months. The ATR-FTIR exhibited interactions between PA and 2-amino-2-methyl-1,3-propanediol (AMPD) as well as between PA and NaOH in case of the alcohologels. Moreover, it indicated the interaction between CT and NaOH. PXRD diffractograms confirmed the FTIR study. (4) Conclusions: The study observed the influence of a number of factors on the solubility and release rate of CT, as: alkalizers and their concentration, SM2.5 addition. The transition of CT in the presence of NaOH to the tanshinone V sodium (T-V sodium) form was suspected.
... The molecular feature C 4 H 11 NO 2 may represent diethanolamine or aminoethyl propanediol. Both are used in the production of cosmetics [46,47], and both are possible xenobiotics [48,49]. The former has been associated with Escherichia coli [48], while the latter with the baker's yeast Saccharomyces cerevisiae [49]. ...
Accurate diagnosis of dry eye disease (DED) is challenging, and even today there is no gold standard biomarker of DED. Hypothesis-free global metabolomic studies of tears from DED patients have great potential to discover metabolites and pathways affected in the pathophysiology of DED, and to identify possible future biomarkers. These metabolites and biomarkers could be important for diagnosing and monitoring disease as well as for new therapeutic targets and strategies. As DED is associated with dry mouth, this study aimed to perform metabolomic analyses of tears and saliva from patients with decreased tear film break-up time but normal Schirmer test, and age-matched controls with both tear production and stability within physiological range. We applied strict inclusion criteria to reduce sampling bias in the metabolomic analyses and selected only age-matched females with Schirmer test values between 10–15 mm/5 min. The tear film analysis arm included 19 patients (with tear film break-up time 0–5 s) and 12 controls (with tear film break-up time 10–30 s), while the salivary analysis arm consisted of a subset which included 18 patients and six controls. Metabolomic analyses were performed using liquid chromatography and high-resolution mass spectrometry. Analyses using a global database search detected a total of 56 metabolites in tear samples that were significantly different between the groups. Of these, several have known associations with DED. These metabolites are present in meibum and have anti-oxidative characteristics or associations with the ocular microbiome, and altered concentrations suggest that they may play a significant role in DED associated with decreased tear film stability. In saliva, hypotaurine levels were lower among patients with tear film instability. In this pilot study, we found different levels of several metabolites in patients with decreased tear film break-up time that may have associations with DED. Future studies are required to replicate our findings and clarify the exact roles of these metabolites.
... They are used to obtain creams, shampoos, washing preparations and others. They are also often used as gelling agents in polymer preparations [34][35][36]. In an earlier research, Musial and Kubis demonstrated another interesting feature of alcoholamines. ...
Due to its high instability and rapid degradation under adverse conditions, tetracycline hydrochloride (TC) can cause difficulties in the development of an effective but stable formulation for the topical treatment of acne. The aim of the following work was to propose a hydrogel formulation that would ensure the stability of the antibiotic contained in it. Additionally, an important property of the prepared formulations was the activity of the alcoholamines contained in them against the components of the model sebum. This feature may help effectively cleanse the hair follicles in the accumulated sebum layer. A series of formulations with varying proportions of anionic polymer and alcoholamine and containing different polymers have been developed. The stability of tetracycline hydrochloride contained in the hydrogels was evaluated for 28 days by HPLC analysis. Formulations containing a large excess of TRIS alcoholamine led to the rapid degradation of TC from an initial concentration of about 10 µg/mL to about 1 µg/mL after 28 days. At the same time, these formulations showed the highest activity against artificial sebum components. Thanks to appropriately selected proportions of the components, it was possible to develop a formulation that assured the stability of tetracycline for ca. one month, while maintaining formulation activity against the components of model sebum.
... Aminomethyl propanol is a synthetically produced pH adjuster that is classed as an aliphatic alcohol. It is commonly used in topical formulations due to its safety profile when used in low concentrations [68,69]. Citric acid is a weak alpha hydroxy acid (AHA) that is naturally occurring in plants and animals. ...
The aim of this chapter is to provide an overview of basic and tailored topical moisturisers and discuss how and why they form the backbone for the management of psoriasis. Our discussion begins by describing the main characteristics of psoriasis and by indicating how alterations in the skin’s integrity and barrier function contribute to the initial development of psoriasis and subsequent changes in psoriasis phenotype. Next, we address the evolution of topical moisturisers to ever more sophisticated and beneficial products, and describe the key biophysical effects exerted on the psoriatic skin by their active ingredients, as well as the myriad benefits offered by fundamental and specialty ingredients. Furthermore, we delineate how topical moisturiser formulation modalities can help to improve compromised skin barrier function and to alleviate the symptoms of psoriasis, cosmetically and/or therapeutically as well as discuss the associated concerns and challenges encountered along the way.
... Trisaminomethane (Tris) is also known as pharmaceutical registered under the name THAM, and is a biological buffer agent that regulates acid-base regulation 45,46 . The so-called 'no observed adverse effect level' (NOAEL) for repeated oral intake of Tris is 4000 mg/kg body weight 47 . Therefore, a single dose of 1.1 mg Tris in the quenching agent is not considered as being harmful. ...
Detailed knowledge on the fate of dietary components inside the human intestinal tract is lacking. Access to this inner world of digestion is now possible through novel human gastrointestinal sampling capsules. Due to the novelty of such devices, no methodology has been published to stabilise and analyse the resulting samples. A complicating factor is that excretion of such capsules in faeces may take days, while degradation of the dietary components continues. Therefore a stabilising reagent should be pre-loaded in the capsule to ensure the measurement of a representative sample. Considering the small volume of recovered samples, analytical methods must be optimized to collect as many data as possible from little material. We present a complete workflow for stabilising and analysing the fermentation status of dietary fibres in such samples, including microbiota, fibre degradation, and short chain fatty acids. The final quenching reagent was designed based on safety and effectiveness to inhibit fructo- and galacto-oligosaccharides degradation and short chain fatty acids production by human ileostomy microbiota, and subsequently validated in faecal samples. The final composition of the stock quenching reagent is 175 mM Tris, 525 mM NaCl, 35 mM EDTA, 12% SDS, and 8 M urea at pH 8.5.
Temporary tattoos and dyes constitute a great analytical challenge in relation to the regulatory control of their ingredients. Most of these commercial products are not labeled according to their content and their chemical nature is highly diverse. Therefore, it is necessary to analyze these complex samples to evaluate the potential presence of metallic impurities, to ensure the safety of cosmetic products contributing to health protection. This study proposes a multi-analytical methodology, which includes handheld X-ray fluorescence (h-XRF) and X‐ray diffraction (XRD), complemented by variable pressure scanning electron microscopy coupled with energy-dispersive X‐ray spectrometry (VP-SEM–EDS) to fully characterize 34 commercial samples of jagua and henna tattoos and dyes. The approach allowed the identification of the main constituents providing complementary compositional data and differences between sample types were established. In addition, information on the degree of natural pigments homogeneity was also obtained. The results’ discussion considering the current European cosmetics regulation may be useful to support the drafting of safety requirements and specific regulation.
THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37°C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule.
In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia.
THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function.
Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein; THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration.
The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) × base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient).
When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH ≤7.20), the use of THAM within a ‘therapeutic window’ is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi.
THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.
The consumer exposure to the vast majority of cosmetic products is limited to dermal contact. Even spray applications tend to be topically exposed to skin or hair. Besides this skin contact, spray products require additional considerations in regard to potential inhalation for building a robust and reliable safety assessment. Over the years, cosmetic industry developed prediction models for the best estimate of inhalation exposure combining data from computer simulation programs available in the market, individual real measured data and last but not least the experience from the market. Such attempt is driven by the toxicological profile of individual used ingredients. The focus of this review is on the determination of inhalation exposure, and the derivation of safe exposure levels for cosmetic spray products. Many of the methods employed to ensure product safety of cosmetic sprays in accordance with the general requirements of the EC Cosmetics Directive are based on industry experience which are not necessarily consistent across companies. This paper presents an approach to compile common principles for risk assessment and thus contribute to standardisation of safety assessment methodologies utilized for spray product evaluation without interfering with the flexibility of the individual safety assessor. It is based on the experience within the author's companies and may be useful as a support document as well for SME (Small and Medium Enterprises) companies safety assessors. In this respect it can be seen as one fundamental step in a tiered approach of cosmetic spray safety evaluation.
Synopsis
This preliminary study was undertaken to provide data from which a more comprehensive investigation to establish the safety in‐use of cosmetic talcs could be designed. Methods for collecting and analysing respirable talc generated during the use of loose face powder and adult and baby dusting powders were established.
Respirable particles in the air were separated from larger size particles by means of a cyclone and were collected on membrane filters. The collected dust was dissolved in acid and the solution was analysed for magnesium by atomic absorption spectroscopy. From the results the concentrations of talc in the air samples were calculated.
The method was used to monitor the in‐use levels of a range of cosmetic talcs. Mean concentrations in air sampled for 5 min from the start of use of Chinese grades and Italian 00000 grades of talc formulated for use as loose face powder, adult dusting powder and baby dusting powder were 0.48, 1.13 and 0.21 mg m ⁻³ , respectively. Higher levels were found with micronised adult dusting powder (mean concentration 1.9 mg m ⁻³ ).
There was no evidence that the presence of perfume in the talc or the ambient relative humidity in the range 54–74% during use affected the levels of respirable talc, but high relative humidity <90% reduced the amount of respirable talc.
Utilisation des talcs cosmetiques: étude préliminaire des teneurs en talc respirable
Metalworking fluids (MWFs) are well-known causes of occupational contact dermatitis in machinists.
To gain information about skin sensitizers in MWFs and to compare it with the information in safety data sheets (SDSs).
A total of 17 samples of MWF concentrates were analysed for skin sensitizers known or suspected to be used in MWF. Alkanolamines, formaldehyde, isothiazolinones, methyldibromo glutaronitrile (MDBGN), and iodopropynyl butylcarbamate (IPBC) were separated by liquid chromatography. Resin acids of colophonium (colophony) were separated by gas chromatography. The substances were identified with mass spectrometric detection and ultraviolet detection.
Of the MWFs, 15 contained 6-39% of alkanolamines, mostly monoethanolamine and triethanolamine. Formaldehyde was detected in all MWFs: the concentrations of total formaldehyde ranged between 0.002% and 1.3%. Benzisothiazolinone and octylisothiazolinone were detected in one fluid each. IPBC was detected in nine MWFs, and the highest concentration was 0.09%. Methylisothiazolinone and MDBGN were not detected in any of the fluids. Resin acids of colophonium were detected in seven MWFs in concentrations ranging from 0.41% to 3.8%. On the whole, the allergens analysed were poorly declared in the SDSs.
The content of total formaldehyde was not declared in any SDS. IPBC, a relatively new allergen, seems to be common in MWFs. Isothiazolinones may be relevant allergens of machinists, and they should be analysed in MWFs in case other sources are not identified. The occupational relevance of positive patch test results to MWF ingredients in machinists is difficult to determine if information in the SDSs is relied upon.
Aminomethyl propanol and aminomethyl propanediol are substituted aliphatic alcohols that function as pH adjusters in cosmetic products at concentrations less than 10%; additionally, aminomethyl propanediol is a fragrance. Extensive oral toxicity data are reviewed, with fewer inhalation toxicity data. Dermal toxicity data are presented that demonstrate, for example, that a mascara with 1.92% aminomethyl propanediol does not cause dermal irritation or allergic contact sensitization, suggesting that the maximum reported use concentration of 2% in mascara would be safe. Although these ingredients are primary amines that are not substrates for N-nitrosation, they may contain secondary amines as impurities in finished products that may undergo N-nitrosation. These ingredients should not be included in cosmetic formulations containing N-nitrosating agents. The Cosmetic Ingredient Review Expert Panel concludes that aminomethyl propanol and aminomethyl propanediol are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.
1. 1. Varying degrees of metabolic lacticacidosis were noted in 20 patients during prolonged hypothermic perfusions employed for the repair of a variety of congenital cardiac defects. 2. 2. The acidosis developed during the rewarming phase of perfusion as a result of lean tissue hypoxia with the production of anaerobic metabolites. 3. 3. An accumulation of lactic acid in the 20-hour-old heparinized priming blood was also found to contribute significantly to the lacticacidemia. 4. 4. An amine proton acceptor (2-amino-2-hydroxymethyl-1, 3-propanediol) was used to buffer the acidosis in all cases, and was added to blood in the extracorporeal circuit 15 minutes prior to termination of cardiopulmonary bypass. 5. 5. Small quantities of Tris buffer (equivalent to a dose of 75 to 100 mg. per kilogram body weight) were administered to 7 patients (Groups I and II), and produced either a minimal or transient response. 6. 6. A larger quantity of buffer (equivalent to 150 mg. per kilogram body weight) was employed in the treatment of 13 patients comprising Groups III and IV; rapid and sustained increments in arterial pH, plasma CO 2 content, and CO 2 combining power were obtained. 7. 7. This study suggests that Tris buffer is a safe and effective agent for use in the management of metabolic acidosis associated with profound hypothermia and cardiopulmonary bypass.
The mechanism of acute toxicity of TRIS-buffer was investigated in pentobarbital-anaesthetized Wistar-rats. An infusion of 0.5 mmol/kg · min TRIS, either pH 10.9 or pH 7.4, was tolerated for 60–70 min before death. TRIS concentration in plasma increased linearly to 53.7±9.09 mmol/l after 60 min (¯x±sx), indicating slow uptake of the drug into tissues. Blood pressure, heart rate, ECG and Na+- and K+-concentrations in plasma and erythrocytes were not influenced by TRIS. A small rise of plasma osmolarity by 39±4.7 mosmol/l after 30 min seemed unimportant for toxicity. With alkaline TRIS a metabolic alkalosis developed and the compensatory arrest of ventilation caused a sudden drop of arterial pO2 to 48±9 mm Hg after 50 min. A similar, though more gradual, decline of pO2 was observed with neutralized TRIS without concomitant changes of acid-base status. Artificially ventilated rats, with constant arterial pO2, tolerated an infusion of neutralized TRIS for at least 90 min. With TRIS of either pH plasma glucose concentration was nearly halved after 30 min. Addition of glucose (50 mg/ml) to the infusion neither prevented this effect nor increased the survival time. From these results we conclude that the main lethal action of TRIS is a depression of ventilation that, in the case of neutralized TRIS, may be related to an intracellular alkalosis.
An nephrektomierten Sprague-Dawley-Ratten wurde die zeitabhängige Verteilung von ¹⁴C-Trispuffer zwischen Extra- und Intrazellulärraum über 24 Stunden bei einem konstanten Plasma-pH-Wert um 7,4 ermittelt.
• Es dauert mindestens 6-12 Stunden, bis ein Gleichgewicht in der Verteilung zwischen ECR und ICR eintritt. Tris dringt in den Intrazellulärraum nur sehr langsam ein, was im Gegensatz zu der in der Klinik vertretenen Meinung steht.
• Die Ausstromkurve wies einen multiexponentiellen Verlauf auf, was darauf hindeutet, daß sich Tris sehr unterschiedlich in den verschiedenen Körpergeweben verteilt.
• Das Verteilungsgleichgewicht, das nach 6-12 Stunden zwischen beiden Körperkompartimenten besteht, erreicht bei weitem nicht das theoretisch vorausberechnete. Bei einem Plasma-pH-Wert von 7,4 und einem „mean whole body pHi” von 6,88 müßte die Verteilung zwischen ECR und ICR 1:11 und nicht, wie hier gefunden, 1:4 betragen. Hieraus wird geschlossen, daß auch ionisiertes Tris in den Intrazellulärraum eindringt. Tris kann die in diese Substanz gesetzten Erwartungen nicht voll erfüllen.
Summary
The distribution of ¹⁴C labelled THAM (tris-hydroxy-methylaminomethane) was determined between intra- and extracellular space of nephrectomised Sprague-Dawley rats as a function of time at constant plasma pH of 7.4. The following results were obtained:
• An equilibrium in the distribution of THAM between ECS and ICS will not occur before 6-12 hours after administration. This indicates that THAM permeates very slowly into the intracellular compartment, which is in contrast to the general assumption that it quickly diffuses into the intracellular space to restore the intracellular acidosis.
• THAM disappears from the extracellular space in a multiexponential fashion, indicating that it equilibrates with the different body tissues at largely variable rates.
• The equilibrium which occurs between both body compartments 6-12 hours after THAM application does not agree with the values which are expected for transfer of only the nonionised substance. At plasma pH 7.4 and a ”mean whole body pHi” of 6.88, THAM is distributed with a distribution ratio of 4 (ICS/ECS), a value quite different from the value of 11 which would be expected for exclusive nonionic diffusion. Thus THAM is also transferred across the cell membrane in ionised form.
These results indicate that the influx of THAM into the intracellular space is too slow (when compared to the renal elimination kinetics) to influence intracellular pH significantly by direct buffer action. Moreover, only a fraction of THAM enters the intracellular space in the nonionised form, thus reducing (to an even greater extent) the direct effect of THAM on the intracellular acid-base equilibrium.
Surfactants are used as additives in topical pharmaceuticals and drug delivery systems. The biocompatibility of amino acid-based surfactants makes them highly suitable for use in these fields, but tests are needed to evaluate their potential toxicity. Here we addressed the sensitivity of tumor (HeLa, MCF-7) and non-tumor (3T3, 3T6, HaCaT, NCTC 2544) cell lines to the toxic effects of lysine-based surfactants by means of two in vitro endpoints (MTT and NRU). This comparative assay may serve as a reliable approach for predictive toxicity screening of chemicals prior to pharmaceutical applications. After 24-h of cell exposure to surfactants, differing toxic responses were observed. NCTC 2544 and 3T6 cell lines were the most sensitive, while both tumor cells and 3T3 fibroblasts were more resistant to the cytotoxic effects of surfactants. IC(50)-values revealed that cytotoxicity was detected earlier by MTT assay than by NRU assay, regardless of the compound or cell line. The overall results showed that surfactants with organic counterions were less cytotoxic than those with inorganic counterions. Our findings highlight the relevance of the correct choice and combination of cell lines and bioassays in toxicity studies for a safe and reliable screen of chemicals with potential interest in pharmaceutical industry.
Aminomethyl propanol and aminomethyl propanediol are substituted aliphatic alcohols that function as pH adjusters in cosmetic products at concentrations less than 10%; additionally, aminomethyl propanediol is a fragrance. Extensive oral toxicity data are reviewed, with fewer inhalation toxicity data. Dermal toxicity data are presented that demonstrate, for example, that a mascara with 1.92% aminomethyl propanediol does not cause dermal irritation or allergic contact sensitization, suggesting that the maximum reported use concentration of 2% in mascara would be safe. Although these ingredients are primary amines that are not substrates for N-nitrosation, they may contain secondary amines as impurities in finished products that may undergo N-nitrosation. These ingredients should not be included in cosmetic formulations containing N-nitrosating agents. The Cosmetic Ingredient Review Expert Panel concludes that aminomethyl propanol and aminomethyl propanediol are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.
Exposure to compounds in consumer products can be assessed using the computer program ConsExpo (Consumer Exposure). Given the huge number of consumer products, it is not possible to calculate the exposure for each separate product, so a limited number of groups containing similar products are defined. The information for each group of products is described in a fact sheet. Paint, cosmetics, children's toys and pest control products are examples of fact sheets which have been published already. This fact sheet covers the use of cleaning products by consumers. In the fact sheet 36 product categories are described including laundry detergents, dishwashing products, abrasives and toilet cleaners. To assess exposure of compounds in the cleaning products default values for all 36 product categories have been determined. Een snelle, transparante en gestandaardiseerde blootstellingsschatting van reinigingsmiddelen is dankzij een nieuwe factsheet voor het computerprogramma ConsExpo nu mogelijk. ConsExpo 4.0 is een computerprogramma, dat gebruikt kan worden om de blootstelling van mensen aan stoffen in consumentenproducten uit te rekenen. Hierbij wordt rekening gehouden met verschillende blootstellingsroutes (dus via de huid, via inhalatie en via orale opname). Bij het ConsExpo programma hoort ook een database, waarin standaardwaarden voor vele product typen en voor een groot aantal blootstellingsscenarios worden aangeboden. De beschrijving van deze achtergrondinformatie bij deze standaardwaarden wordt gerapporteerd in zogenoemde 'factsheets'. In dit rapport, factsheet reinigingsmiddelen, is de meest recente informatie bijeengebracht om de blootstelling aan stoffen uit reinigingsmiddelen te berekenen. De verschillende typen reinigingsmiddelen zijn verdeeld in 36 categorien, bijvoorbeeld wasmiddelen, afwasmiddelen, schuurmiddelen en toiletreinigers. Voor iedere categorie wordt de samenstelling en gebruik van producten uit die categorie beschreven. Daarnaast wordt aangegeven welk model of modellen van ConsExpo het meest geschikt is om de blootstelling uit te rekenen en worden voor alle gegevens die nodig zijn voor de berekening standaardwaarden ingevuld. Naast deze factsheet reinigingsmiddelen zijn er ook factsheets voor ongediertebestrijdingsmiddelen, verf, cosmetica en desinfectantia.
Syrian golden hamster received intratracheal instillations of 0.125, 0.25, 0.50 or 1.0 mg benzo[a]pyrene (B[A]P) in a mixture of Tris buffer and physiological saline once weekly for life. Papillary polyps, squamous cell papillomas and carcinomas developed in both the larynx and trachea. In addition, bronchiogenic adenomas, adenocarcinomas and squamous cell carcinomas were induced in the lung. The highest incidence of respiratory tract tumours (83%) was seen in hamsters receiving 0.25 mg B[a]P. The results of these investigations are statistically evaluated and discussed.
The mass concentration of potentially respirable particles produced during routine application of talcum powder were determined. Tests were conducted both on adults exposed to talc over the whole body area and infants exposed in the napkin area. The total exposure time, the amount of the powder used and the average talc concentration in the air in the region of the nares were measured. These average talc concentrations were compared with the threshold limit value (TLV) which is considered safc for industrial talc workers, and also with chronic exposure levels for experimentally exposed hamsters in which no adverse reactions were seen. The average adult exposure was 600 times less than the TLV and 500 times less than the level at which no adverse effects were seen in chronically exposed hamsters. Likewise, the average infant exposure was over 2000 times less than the TLV and over 1800 times less than the hamster no-effect level.
Rats were anaesthetized with halothane and artificially ventilated. After bilateral nephrectomy and implantation of arterial and venous catheters, arterial plasma pH (pHe) was adjusted by infusion of HCl or sodium bicarbonate to 7.2, 7.4, or 7.5 and kept constant throughout the experiment. The distribution of tris between intra- and extracellular compartments was determined as a function of time up to 24 h after infusion of 14C-labelled tris and 3H inulin in five skeletal muscle groups, heart, liver, spleen, and brain tissue. The following results were obtained: Tris diffuses very slowly into the intracellular space of the investigated tissues. For different arterial plasma pH, the intracellular tris concentration is quite different. It rises more rapidly and reaches higher levels in alkalemia. Five different skeletal muscle groups showed the same rates of rise of intracellular tris at the same pHe. Tris diffuses almost immediately into liver cells, the rates being slower in spleen, heart, skeletal muscle and brain, in that order. Only in the liver did intracellular tris concentration reach a steady state, at levels higher than theoretically predicted, suggesting that ionic tris also is permeable. In other tissues, lack of steady states at the end precluded similar conclusions. It can be concluded that the clinical importance of tris therapy is in its elimination of H+ ions from the extracellular space and in the generation of bicarbonate that then penetrates the intracellular compartment.
Babies with respiratory distress syndrome can be divided into two groups with a good and bad prognosis on the basis of an initial arterial oxygen tension measurement taken when breathing 100% oxygen, providing a measure of the extent of V-A shunting. Following intravenous THAM given early in the course of the illness, there is a considerable and often sustained rise in arterial oxygen tension in the bad prognosis group which can best be accounted for by a diminution in such shunting. The alteration in calculated shunt induced by THAM injection suggests that reversible hypoperfusion is a factor in the aetiology of the pulmonary changes seen in the respiratory distress syndrome.
The use of THAM during peritoneal dialysis for the extraction of CO2, and weak acids in dogs was compared with other dialyzing media. The rapid passage of THAM across the peritoneum is a limiting factor and to avoid reaching toxic levels, the total amount administered of a 0.075M THAM dialysate should not exceed 22 mM per kilogram per 24 hours. Dialysate pR and THAM concentration fell rapidly during the first 30 minutes and then more gradually, while dialysate CO2, content increased markedly, THAM dialysate acting as a “C02 trap.” After 3 hours 47 per cent of the THAM administered was excreted in the urine and there was a moderate diuresis of alkaline urine. After six 30 minute periods of dialysis the rate of passage of pentobarbital into the dialysate was three times greater with THAM solution than with Ringer solution and more than one and one half times greater than with NaHC03. Comparable results for the three media were obtained during the extraction of phenobarbital. The amount of sodium salicylate extracted into the three dialyzing media was similar, but the production of an alkaline urine with THAM administration enhanced salicylate excretion. Three times more salicylate was excreted in the urine during THAM administration than with Ringer solution and one and one half times more than with NaHCO3. Peritoneal dialysis with THAM should have clinical applications for the removal of exogenous or endogenous weak acids.
A short-term bacterial assay system for determining the mutagenic potential of environmental substances was developed and validated. Genotoxic activity was demonstrated for selected substances from 10 categories of chemical agents. The RK test results were obtained with one Escherichia coli assay strain that was transiently exposed to, and then removed from the test substance prior to the selection step for mutant cells. The RK test employs a hitherto unused short-term assay technique for selecting forward mutations in the wild-type selector strain cells. The cells of the selector strain are killed upon shifting to 42 degrees C as a consequence of thermal derepression and subsequent expression of the replication genes from an integrated 10-kilobase fragment of phage lambda. Cells that acquire mutations in the responsible killing genes are detected by their colony-forming ability at 42 degrees C. A substance is determined to be genotoxic if it is capable of increasing the forward mutation frequency for appearance of these mutant cells. Toxicity of the agent is independently evaluated by examining its effect on the viability of the selector strain at 30 degrees C, when the viral replication genes remain repressed. The flexible assay protocol enables determination of the effect of pH on mutagenic activity, the requirement for metabolic activation, and assays of nearly insoluble or highly toxic substances.
The influence of Tris buffer on plasma glucose and insulin concentrations was investigated in pentobarbital-anesthetized (60 mg/kg i.p.) Wistar rats. A bolus injection of neutralized Tris (5 mmol/kg; pH 7.4) caused a transient increase of plasma insulin concentration (+ 130 +/- 20 microU/ml; means +/- S means, n = 6) but did not change the glucose concentration. A continuous infusion of Tris (0.5 mmol/kg X min for 90 min) reduced the plasma glucose concentration from 8.7 +/- 0.42 to 5.1 +/- 0.33 mmol/l after 30 min. The plasma insulin concentration was elevated during the first 20 min (maximum +122 +/- 21 microU/ml after 10 min). In streptozotocin-diabetic rats (75 mg/kg i.v., 48 h prior to the experiments) an infusion of Tris changed neither glucose nor insulin concentration in plasma. The results indicate that in the rat Tris-induced hypoglycemia is always associated with a transient stimulation of insulin secretion.
To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg = 1 mmol/kg;pH 7.4) and to 20 patients suffering from metabolic acidosis (109--376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,beta = 5.6 h) and patients with intact renal function (t0.5,beta = 16.3--45.6 h). The final volume of distribution (V beta) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.
Intraperitoneal injection of lipopolysaccharide (LPS) was used to elicit a sublethal, shock-like condition in mice. LPS, 2.5 mg/kg i.p., induced hypothermia, elevated serum TNF-alpha levels and lethality over a 48 h period in male CD-1 mice. The 5-lipoxygenase (LO) inhibitors, WY-50,295 tromethamine and zileuton (100 mg/kg p.o), significantly inhibited hypothermia at 4, 24 and 48 h after LPS. Interestingly, whereas cyclooxygenase (CO) inhibitors (ibuprofen, etodolac, naproxen and tenidap) at 40-80 mg/kg p.o. stimulated hypothermia at 4 h, they significantly reduced the later stages of hypothermia at 24-48 h. Rolipram (PDE-IV inhibitor) and dexamethasone significantly reduced hypothermia at 4-24 h and 1-24 h, respectively. All the anti-inflammatory agents significantly reduced elevated TNF-alpha levels at approximately 70 min post-LPS, except for ibuprofen. In conclusion, these anti-inflammatory standards indicate that LPS-induced shock involves multiple lipid mediators (PG's, LT's and possibly PAF) and secondary cytokine generation. This sublethal model of LPS-induced shock represents a sensitive model for estimating the efficacy of potential drug candidates for the treatment of endotoxic shock.
Mechanical hyperventilation of acidemic patients with acute lung injury (ALI) requires the use of high volumes and pressures that may worsen lung injury. However, permissive hypercapnia in the presence of shock, metabolic acidosis, and multi-organ system dysfunction may compromise normal cellular function. Tris-hydroxymethyl aminomethane (THAM) may be an effective method to control acidosis in this circumstance. Protonated THAM is excreted by the kidneys, so that carbon dioxide production is not raised. In an uncontrolled study, we administered THAM to 10 patients with acidosis (mean pH = 7.14) and ALI (mean lung injury score = 3.28) in whom adequate control of arterial pH could not be maintained during either eucapnic ventilation or permissive hypercapnia ventilation. THAM was given at a mean dose of 0.55 mmol/kg/h. Administration of THAM was associated with significant improvements in arterial pH and base deficit, and a decrease in arterial carbon dioxide tension that could not be fully accounted for by ventilation. Although further studies are needed to confirm these observations, THAM appears to be an effective alternative to sodium bicarbonate for treating acidosis during ALI.
Seven cats and three dogs, after ligature of the renal vessels, were given 27.3–13.7 µc/kg body wt. of C ¹⁴ -labeled 2-amino-2-hydroxymethyl-1, 3-propanediol or tris(hydroxymethyl)aminomethane (THAM). One milliliter per kilogram of 10% inulin was simultaneously administered. Arterial pH was maintained close to 7.40. At this pH, 30% of THAM (pK 7.82 at 37 C) is un-ionized. Samples of plasma were withdrawn at 15, 30, and 60 min and 2, 3, 4, 5, and 6 hr. Plasma inulin concentration reached a plateau within 1–2 hr and had distributed in 21% of body weight. No C ¹⁴ was detected in the expired CO 2 . After 15 min the volume of C ¹⁴ space was significantly larger ( P < 0.02 > 0.01) than the inulin space. Plasma radioactivity approached a plateau after 4 to 6 hr, at which time the C ¹⁴ was distributed into a volume corresponding to 55 ± 9% of body weight. If THAM is distributed evenly throughout body water and is not significantly degraded, it tends to equilibrate within 6 hr with the intracellular compartment.
Experimental and clinical studies have demonstmted that THAM is an effective titrating agent because of its buffering capacity, low toxicity, and mpid elimination. THAM has been used for the correction of acute acidosis during cardiac operation and extra corporeal circulation, cardiac arrest, and massive transfusions with ACD blood. Its use in chronic espiratory acidosis should be restricted to the acute decompensated phase and should be accompanied by mechanical ventilation. Other clinical indications for THAM administration include salicylate and barbiturate intoxication and the metabolic acidosis of diabetes. It is most effective when administered intravenously as a O.3M solution in amounts calculated to titrate excess acid in extracellular fluid.
THAM can be given orally as a salt in combination with a weak acid such as citrate. In this form, it is a gastric antacid and will also produce systemic alkalinization.
Administration of 20% THAM citrate (pH 8.50) to dogs on a meat diet results in increase of the base content of the blood and in the production of an alkaline urine. Between 60 and 70% of the THAM administered is excreted daily in the urine indicating intestinal absorption. This treatment which was well tolerated over a 3-month period could have useful applications in clinical medicine.
Water-based metalworking fluids (MWFs) may cause both irritant and allergic contact dermatitis. Several well-known MWF allergens are available for patch testing, but considering the wide variety of possible components used in MWF, our diagnostic arsenal covers only a small part of potential allergens. We therefore selected 13 frequently used MWF components that might be sensitizers and had not yet been tested routinely. In 5 centres, 233 dermatitis patients with present or past occupational exposure to MWF were patch tested with this and other panels. Only 7 patients showed positive reactions to the study panel. Allergic reactions to the emulsifier diglycolamine [syn. 2-(2-aminoethoxy) ethanol] were seen in 5 patients, and 1 patient each reacted positively to 2-amino-2-ethyl-1,3-propanediol (AEPD) and methyldiethanolamine (MDEA). Clinical relevance of the reactions to diglycolamine was unequivocally proven by its presence in the MWF from the patients' workplace in 3 cases. Diglycolamine seems to be an important MWF allergen, independently from monoethanolamine and diethanolamine. A test concentration of 1% petrolatum (pet.) appears to be appropriate. The importance of AEPD and MDEA as MWF allergens still remains to be established. The lack of positive test reactions to the other MWF components tested may be due to their low-sensitizing potential or too low a patch test concentration being used.
Although many allergens in metalworking fluids (MWF) are identified, there are still some MWF components, which are not sufficiently investigated concerning their sensitizing properties.
To investigate sensitization to 10 frequently used MWF components, which are not part of the established MWF test series, in metalworkers with suspected occupational dermatitis due to MWF.
Oleyl alcohol, myristyl alcohol, dimethylolurea, 4,4'-methylenebis morpholine, imazalil, 1-amino-2-propanol (monoisopropanolamine; MIPA), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2,5-bis(n-octyldithio)-1,3,4-thiadiazole, zinc alkyl dithiophosphate and dibenzyl disulfide have been patch tested in 144 patients.
7 patients reacted positively to the formaldehyde releaser 4,4'-methylenebis morpholine, and 6 of these patients also reacted to formaldehyde and/or other formaldehyde releasers. 4 patients reacted positively to myristyl alcohol tested at 10% petrolatum (pet.). Additionally, 20 doubtful or irritant reactions occurred. 1 patient each reacted positively to oleyl alcohol, MIPA, and AEPD. None of the other test substances mentioned above elicited any clear-cut positive reaction. Patch testing with well-known MWF allergens showed proportions of positive reactions, which were comparable to those from other studies, e.g. 11% to monoethanolamine, 8% to colophonium and 3%-5% to various preservatives.
4,4'-methylenebis morpholine may be an important MWF allergen, although clinical relevance could not be stated definitely in every case. Myristyl alcohol should not be patch tested at 10% pet., but at a lesser concentration, due to irritant properties.
MI: The Dow Chemical Company
- Company Dow Chemical
International Cosmetic Ingredient Dictionary and Handbook
- T E Gottschalck
- H P Breslawec
Gottschalck TE, Breslawec HP. International Cosmetic Ingredient Dictionary and Handbook. 14th ed. Washington, DC: Personal Care Products Council; 2012.
Handbook of Data on Organic Compounds
- David R Lide
- G W A Milne
David R. Lide, G.W.A. Milne. Handbook of Data on Organic
Compounds. 3rd ed. Boca Raton, FL: CRC Press, Inc; 1994.
Percutaneous absorption of tromethamone [sic] hydrochloride: Study on human skin in invitro diffusion cells
- J Wepierre
- M S Noel-Hudson
Wepierre J, Noel-Hudson MS. Percutaneous absorption of tromethamone [sic] hydrochloride: Study on human skin in invitro
diffusion cells. University of Paris-SUD, Faculty of Pharmacy.
1993. http://ofmpub.epa.gov/oppthpv/Public_Search.PublicTabs?
SECTION¼1&epcount¼2&v_rs_list¼25422367,25227911.
Unpubished data submitted to the US Environmental Protection
Agency High Production Volume Information System (HPVIS).
REACH Regstration of TRIS AMINO (CAS No. 77-86 -1); Analogue Approach. Midland, MI: The Dow Chemical Company
- Knoell Consult
Knoell Consult. REACH Regstration of TRIS AMINO (CAS No.
77-86 -1);
Remingon's Pharmaceutical Sciences
- A Osol
- A R Gennaro
- M R Gibson
Osol A, Gennaro AR, Gibson MR, et al. Remingon's Pharmaceutical Sciences. 15th ed. Easton, PA: Mack Publishing Co.; 1975.
Summary: Evaluation of the Acute Cutaneous Tolerance of a Cosmetic Product (Mask for Hands Containing 3. 1% Tromethamine) on Adult Subjects: Single Patch Test Method Under Dermatological Control. Unpublished data submitted by Personal Care Products Council
- Anonymous
Anonymous. 2012. Summary: Evaluation of the Acute Cutaneous
Tolerance of a Cosmetic Product (Mask for Hands Containing 3.
1% Tromethamine) on Adult Subjects: Single Patch Test Method
Under Dermatological Control. Unpublished data submitted by
Personal Care Products Council. 1 pages.