Abstract Owing to their volatility, the most important occupational exposure route for low-molecular-weight amines is considered to be inhalation. However, dermal exposure is also possible in many workplace situations. There are limited data available on the dermal uptake of these amines through human skin, and existing exposure standard skin notations are typically based on acute toxicity animal studies or by chemical analogy. This gap in knowledge is in part due to a lack of standardized approach for assessing dermal uptake. We describe a relatively simple protocol for the determination of permeation of low-molecular-weight amines through human skin in vitro. Using isopropylamine as a test amine, it was found that isopropylamine vapour has limited capacity to absorb into, or penetrate through, the epidermal layer of human skin, even at lethal atmospheric concentrations. This protocol can be adapted for a range of exposure scenarios, including clothing effects, and may be used to determine whether skin notations are warranted. amines, dermal exposure, isopropylamine, skin permeation, vapour Introduction Amines are a group of organic compounds used widely as raw materials or chemical intermediates in the manufacturing of other chemicals, pharmaceuticals, polymers, textiles, dyes, adhesives, solvents and pesticides (Cavender, 2001; Namieśnik et al., 2003; Fournier et al., 2008). The differing physical properties and a large range of uses result in the potential for the presence of amine vapours in workplace atmospheres. Amine compounds are associated with a variety of health problems for exposed workers depending on the individual toxicity of the particular amine. As a general observation, aliphatic amines are known to have acute oral toxicity with certain compounds having led to occupational asthma in chemical workers (Ng et al., 1995; Agius, 2000), and particular primary aliphatic amines reportedly exhibit high skin corrosivity and are strong mucous membrane irritants (Greim et al., 1998; Patnaik, 2007). The wide range of industrial settings in which amines are used results in the potential exposure to these chemicals in work environments. Due to the volatile nature of most amines, the primary exposure route is via inhalation; however, dermal exposure is also a potential route of exposure in many workplaces (Wellner et al., 2008). A small number of worker studies (Riffelmann et al., 1996; Korinth et al., 2006, 2007) and human in vitro studies (Lundh et al., 1997; Wellner et al., 2008) on skin absorption have been reported for a limited range of aromatic amines. Despite the limited data surrounding the potential for dermal uptake, many amines with occupational exposure standards contain a skin notation (SK, SEN or DSEN). The documentation for those amines with a skin notation suggests that most are based on LD50 animal studies or by analogy to other amines. Based on this evidence, there is a significant gap in knowledge surrounding the dermal uptake of many industrial amines, particularly aliphatic amines. The accepted ‘gold standard’ approach for skin absorption studies is using human tissue and an in vitro diffusion system (OECD, 2004). This approach for occupationally relevant short-term exposures could provide valuable data in supporting skin notations for these chemicals or provide empirical evidence for the assigning of skin notations to low-molecular-weight amines where a skin notation does not currently exist due to insufficient evidence (i.e. isopropylamine). Amines are traditionally challenging compounds to monitor in air, especially primary and secondary amines, due to their high reactivity and resulting susceptibility to oxidation and degradation (Andersson et al., 1985). Direct analytical detection of amines using high-performance liquid chromatographic (HPLC) methods is hampered by the low ultraviolet (UV) absorptivity of the amine functional group (Kamarei et al., 2011). Therefore, the conventional approach is to coat diffusive (passive) air samplers with a derivatizing agent that forms a more stable compound, upon reaction with amines, while also enhancing the sensitivity of analytical detection. The most commonly employed derivatizing agents for HPLC–UV determination are dansyl chloride and 1-naphthylisothiocyanate (NITC) (Andersson et al., 1985; Levin et al., 1989; Lindahl et al., 1993). The Occupational Safety and Health Administration (OSHA) Sampling and Analytical Methods utilize both of these derivatizing agents depending on the particular amine under investigation (OSHA, 1982; 1986). For skin permeation studies, an adapted approach is required to analytically determine from aqueous solutions the concentration of amine penetrating the skin over time. This article describes the successful adaptation of an accepted OSHA sampling and analytical method for an aliphatic amine in air, for application to aqueous samples for use in skin permeation studies. Using an in vitro diffusion cell technology with dynamic vapour delivery system, we examined the kinetics of skin absorption of isopropylamine (as a representative aliphatic amine) through human epidermis for short-term exposures relevant to occupational settings. We demonstrate a dermal exposure procedure and analytical method with the potential to be applied to the detection of a wide range of amine-containing compounds that will facilitate future studies into the skin absorption properties of other common amines in occupational environments. Methods Chemicals and chromatography standards Isopropylamine is an example of a low-molecular-weight aliphatic amine. It is commonly used as an intermediate in the synthesis of dyes, rubber accelerators, insecticides, bactericides, textile specialities, surface-active agents and pharmaceuticals. Liquid isopropylamine (>99.9%, Sigma–Aldrich, Australia) was used to create a dynamic vapour atmosphere for skin exposure experiments. NITC (95%, Sigma–Aldrich, Australia) was used to prepare chromatography standards and for the derivatization of isopropylamine post-exposure. Dimethylformamide (DMF) (analytical grade, Sigma–Aldrich, Australia) was used in the preparation of isopropylamine–NITC derivative chromatography standards. HPLC solvents used were acetonitrile (>99.5%, Sigma–Aldrich, Australia) and Milli-Q water. A stock standard isopropylamine–NITC thiourea derivative (3.39 mg ml−1) was prepared according to the procedure outlined in the Occupational Health and Safety Administration (OSHA) Sampling and Analytical Methods for isopropylamine (OSHA, 2003). First, 57.8 mg of NITC was weighed into a 10-ml flask, then 33.9 mg of isopropylamine was added dropwise on top of the NITC in the flask followed by the further addition of 87.1 mg of NITC to the flask. The flask was then left for 1 h to allow all of the amine to react with the NITC. The flask was subsequently half filled with DMF and allowed to sit for a further 30 min to allow complete dissolution of the formed derivative. Finally, the flask was made to the mark with DMF to produce the final stock standard. Chromatography standards were then prepared by serial dilution of the stock standard in HPLC-grade acetonitrile containing excess NITC (1 mg ml−1) covering a calibration range of 0.034–22.71 µg ml−1. Optimized sample analysis The final method for the analysis of isopropylamine in aqueous solution was adapted from the published OSHA Sampling and Analytical Method for isopropylamine (OSHA, 2003). Namely, 1 ml of sample in 50% ethanol was added to 1 ml of 0.1% wt/vol sodium hydrogen carbonate solution to adjust the overall pH and placed in a 50°C water bath for 5 min to equilibrate. Afterwards, 500 µl of 0.5% wt/vol NITC solution was added, mixed well and returned to the 50°C water bath for a further 30 min to derivatize. Subsequent HPLC–UV analyses were performed using a Perkin-Elmer solvent manager and isocratic LC pump connected to a Shimadzu SPD-20A UV-Vis absorbance detector controlled by Perkin-Elmer TotalChrom (v18.104.22.168.1) software. Samples were manually injected, and separation was achieved on a Phenomonex Kinetex® C18 column (150 × 4.6 mm × 5 µm). The chromatographic conditions for all analyses were as follows: mobile phase comprising 57% acetonitrile, 43% Milli-Q water and 0.1% orthophosphoric acid, flow rate of 0.8 ml min−1, injection volume of 20 µl and a detection wavelength of 280 nm. The limit of detection of the analytical method was 0.02 µg ml−1 of isopropylamine (0.034 µg ml−1 isopropylamine–NITC derivative). Skin permeation experiments Skin permeation experiments were performed in vitro using static Franz diffusion cells modified for flow-through gas delivery to the surface of the skin as outlined previously (Gaskin et al., 2014; Heath et al., 2017). Freshly excised human abdominal skin was obtained from cosmetic reduction surgery, with donor consent and ethics approval (SACHR ethics approval #273.10). Epidermis was harvested from full thickness skin within 1 h of excision from the donor, as described previously (Gaskin et al., 2014). Skin electrical resistance testing was performed to provide a rapid assessment of barrier integrity in vitro pre- and post-skin exposure (Lawrence, 1997; Diembeck et al., 1999; Davies et al., 2004; Gaskin et al., 2014). Denim (thickness 0.772 ± 0.011 mm) was chosen as a representative of typically worn ‘street clothing’. For the application of denim on to skin, cut squares (4 cm2) of fabric were added onto skin already mounted on the Franz cell. Isopropylamine vapour was delivered to the skin surface using a custom-built dynamic atmosphere generator, the design of which has been published previously (Pisaniello, 1988; Gaskin et al., 2014). Briefly, liquid isopropylamine was injected using a syringe pump into a mixing chamber and a volatilized fraction subsequently diluted with purified air to achieve the test atmosphere concentration (3000 p.p.m.). Isopropylamine vapour was exposed across the surface of the skin for short-term exposure times (≤30 min). In addition to bare skin exposure for intervals up to 30 min, denim was added on top of the skin to understand the interaction effects of non-protective ‘street clothing’ on skin permeation outcomes. Similarly, it was considered important to understand the effects of ventilating the skin with fresh air (open to atmosphere) post-exposure up to a period of 60 min total (i.e. 30-min exposure plus 30-min ventilation). A minimum of three replicates for each variable at each exposure time was gained. Results Analytical method optimization The analytical method for the determination of isopropylamine in aqueous solutions was optimized from the OSHA Sampling and Analytical Method for isopropylamine (OSHA, 2003) and a previous report on the derivatization of biogenic amines using NITC (Jain et al., 2015). Complete reaction of isopropylamine with NITC to form the thiourea derivative in receptor fluid samples was achieved by optimizing the pH and temperature. The final optimum conditions were 1-ml receptor fluid, 1-ml 0.1% wt/vol sodium hydrogen carbonate and 0.5-ml 0.5% wt/vol NITC at 50°C. Subsequent separation of the thiourea derivative from endogenous compounds in post-exposure samples was achieved using a modified 57% acetonitrile, 43% Milli-Q water with 0.1% orthophosphoric acid mobile phase and a flow rate of 0.8 ml min−1. Isopropylamine vapour skin permeation Exposure of human epidermis up to 30 min to 3000 p.p.m. isopropylamine vapour resulted in a negligible fraction penetrating the skin (0.12 ± 0.02 μg), but evidence of skin absorption over short exposure times (11 ± 0.24 μg at 30 min) (Table 1). Post-exposure skin electrical resistance assessment showed reduced barrier integrity, but the epidermis remained intact as evidenced by the low permeation outcomes. Post-exposure ventilation (30 min) of the skin resulted in a 5-fold reduction in isopropylamine skin absorption (2.2 ± 1.7 μg) for 30-min exposures. Ventilation also corresponded to a greater than 2-fold increase in isopropylamine skin penetration (0.31 ± 0.10 μg); however, the total fraction was still considered negligible. The presence of denim fabric on top of skin provided 10-fold protection against skin absorption (1.6 ± 0.24 μg) for up to 30-min exposures. Denim itself demonstrated significant ‘sink’ capacity to absorb isopropylamine vapour (86 ± 24 μg at 30 min). Table 1. Maximum cumulative skin permeation (μg) of isopropylamine vapour under various exposure conditions. Exposure time (min) Bare skin Skin + ventilation Skin + denim Cumulative skin penetration 20 <0.10 nd nd 30 0.12 (±0.02) 0.31 (±0.10) <0.10 Cumulative skin absorption 20 4.4 (±2.8) nd nd 30 11 (±3.8) 2.2 (±1.7) 1.6 (±0.24) Exposure time (min) Bare skin Skin + ventilation Skin + denim Cumulative skin penetration 20 <0.10 nd nd 30 0.12 (±0.02) 0.31 (±0.10) <0.10 Cumulative skin absorption 20 4.4 (±2.8) nd nd 30 11 (±3.8) 2.2 (±1.7) 1.6 (±0.24) Mean values (± SD). nd, not determined. View Large Table 1. Maximum cumulative skin permeation (μg) of isopropylamine vapour under various exposure conditions. Exposure time (min) Bare skin Skin + ventilation Skin + denim Cumulative skin penetration 20 <0.10 nd nd 30 0.12 (±0.02) 0.31 (±0.10) <0.10 Cumulative skin absorption 20 4.4 (±2.8) nd nd 30 11 (±3.8) 2.2 (±1.7) 1.6 (±0.24) Exposure time (min) Bare skin Skin + ventilation Skin + denim Cumulative skin penetration 20 <0.10 nd nd 30 0.12 (±0.02) 0.31 (±0.10) <0.10 Cumulative skin absorption 20 4.4 (±2.8) nd nd 30 11 (±3.8) 2.2 (±1.7) 1.6 (±0.24) Mean values (± SD). nd, not determined. View Large Discussion We successfully adapted an air sampling method for application to skin permeation studies, by optimizing the aqueous derivatization conditions for isopropylamine and NITC. Furthermore, by using an in vitro diffusion cell technology with dynamic vapour delivery system and human tissue, we examined the kinetics of skin absorption of isopropylamine for short-term exposures relevant to occupational settings. We have demonstrated a simple dermal exposure procedure and analytical method with the potential to be applied to the detection of a wide range of other low-molecular-weight amines. This approach has the potential to provide a standardized testing protocol for the evaluation of skin permeation of volatile amines to produce comparison metrics and subsequently assist in determining the suitability for skin notations. Direct analytical detection of amines is hampered by the low UV absorptivity of the amine functional group. This study optimized a derivatization method for isopropylamine with NITC to form a stable thiourea derivative in aqueous solutions prior to HPLC–UV analysis. Previous studies have shown that acidic pH gives rise to incomplete derivatization as a result of protonated amines that act as weak nucleophiles towards their addition to the isothiocyanate group of NITC (Sahasrabuddhey et al., 1999; Jain et al., 2015). Therefore, the pH of the receptor fluid samples (post-exposure) in this study were increased via the addition of 0.1% wt/vol sodium hydrogen carbonate to deprotonate and increase the nucleophilicity of isopropylamine in solution. In addition to pH, temperature is also known to effect the rate at which derivatization occurs (Jain et al., 2015). Subsequent optimization of the temperature allowed for the complete derivatization of aqueous isopropylamine to be achieved within 30 min. Isopropylamine does not currently have a skin notation due to insufficient experimental evidence to support one. This study provides the first outcome on kinetics of skin absorption for isopropylamine vapour, using a human in vitro model. The results suggest isopropylamine vapour has some capacity to absorb into the epidermal layer at very high atmospheric exposure concentrations (four times the lethal atmospheric concentration by inhalation) for relatively brief exposures (<30 min). Negligible isopropylamine was shown to penetrate the epidermal layer under the same conditions. Ventilating the skin with fresh air post-exposure resulted in less absorption into the epidermal layer (5-fold reduction) but doubled the mass of penetrated isopropylamine. Despite this observed increase in penetration, the fraction was still considered negligible and the outcomes indicate that the majority of the difference between the absorbed fraction in bare skin [11 (±3.8) µg] and ventilated skin [2.2 (±1.7) µg] was returned to atmosphere during the ventilation period. The presence of fabric on skin provided an initial barrier to skin absorption, but would be a potential source of secondary exposure due to its absorptive capacity. These results indicate it is unlikely that isopropylamine would have a significant dermal pathway at lower vapour concentrations for short-term exposures to intact or undamaged skin. Thus supporting the suggestion that using this methodology to evaluate skin permeability of other amines would be valuable, especially in cases where existing skin notations are a result of analogy to other amines rather than direct experimental data (i.e. diisopropylamine). Only two investigations into the dermal exposure of isopropylamine have been previously reported, both using an animal model. Myers and Ballantyne (1997) describe an animal study where applying 0.01 ml of undiluted liquid isopropylamine to the uncovered, clipped, ventral skin of rabbits for 30 min induced necrosis, while moderate capillary injection was found in one out of five animals following similar treatment with a 10% solution (in water) (no further details available) (Myers and Ballantyne, 1997). In an older study, isopropylamine scored an injury grade of 6 (i.e., necrosis) on a scale from 1 to 10 (Smyth et al., 1951). Both of these studies investigated multiple amines, provided limited empirical data and reflect the broader lack of knowledge regarding the dermal absorption properties of isopropylamine in the scientific literature. Limited in vitro studies have been reported for the dermal absorption of other amines for example liquid dimethylethylamine (Lundh et al., 1997) and a range of liquid aromatic amines including aniline, o-toluidine, 4,4′-methylenedianiline and N-phenyl-2-naphthylamine (Wellner et al., 2008). Lundh et al. determined that uptake of liquid dimethylethylamine (applied as 1% solution) through human skin was of far less importance than simultaneous inhalation exposure of the vapour. In contrast, Wellner et al. reported that the percutaneous absorption of several aromatic amines may significantly contribute to overall exposure to aromatic amines in the workplace. Neither study investigated the dermal exposure of amine vapours. Conclusions This study is the first demonstration of dynamic amine vapour generation for in vitro skin permeation studies using isopropylamine as a model aliphatic amine. In addition, we successfully adapted an air sampling method for the determination of isopropylamine in aqueous solutions. High isopropylamine vapour exposure concentrations (3000 p.p.m.) for short timeframes resulted in some skin absorption and negligible skin penetration. Denim was found to provide protection of the skin but was a sink for isopropylamine and may contribute to further dermal absorption over time. This study reports the first empirical data to assist in determining if a skin notation may be warranted for isopropylamine. Furthermore, it provides a standardized protocol for more extensive future investigations into the skin absorption kinetic profiles of a wide range of occupationally relevant amine vapours using a simple in vitro system and HPLC-UV analytical detection method. Declaration for Publication This research was supported by the Australian Department of Prime Minister and Cabinet, as part of a larger program of work (Grant No. CB-4433). The authors declare no conflict of interest relating to the material presented in this article. References Agius RM. ( 2000) Why are some low-molecular-weight agents asthmagenic. Occup Med ; 15: 369– 84. Google Scholar PubMed Andersson K, Hallgren C, Levin J-Oet al. ( 1985) Determination of ethylenediamine in air using reagent-coated adsorbent tubes and high-performance liquid chromatography on the 1-naphthylisothiourea derivative. Am Ind Hyg Assoc J ; 46: 225– 29. Google Scholar CrossRef Search ADS Cavender FL. ( 2001) Aliphatic and alicyclic amines. In Bingham E, Cohrssen B, editors. Patty’s toxicology . New York: John Wiley & Sons, Inc. Davies DJ, Ward RJ, Heylings JR. ( 2004) Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies. 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Annals of Work Exposures and Health (formerly Annals Of Occupational Hygiene) – Oxford University Press
Published: Feb 23, 2018
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