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RESISTANCE OF GLOVES AND PROTECTIVE CLOTHING MATERIALS TO PERMEATION OF CYTOSTATIC SOLUTIONS.

INTRODUCTION

The growing incidence of cancers leads to an increased use of cytostatics, thus raising the numbers of health care workers exposed to them during the performance of their duties. The professionals at greatest risk of exposure to cytostatics are nurses, physicians, and pharmacists working at oncological hospital wards and at pharmacies compounding such medications [1-5]. It is estimated that the worldwide population of health care and pharmaceutical workers exposed to cytostatics amounts to 5.5 million [6].

Under typical workplace conditions, cytostatics are mostly absorbed through the skin and mucosae. The manipulation of medications, the opening of ampoules, the preparation of injection solutions, and the removal or air from the syringe may cause some of the medicine to be released into the air and absorbed through the respiratory system, while accidental contamination of the skin may lead to transdermal absorption. Furthermore, cytostatics may also enter the body through the skin in the process of cleaning objects and surfaces contaminated with urine or vomit by patients undergoing chemotherapy, as well as during direct contact with the patients.

Previous research has demonstrated the presence of airborne cytostatics in a number of hospital areas. These substances have also been found in the urine of nurses and pharmacists [4]. The presence of cytostatics has been detected in compounding rooms, examination rooms, nurses' lounges, and doctors' lounges. An airborne cytostatic (cyclophosphamide) has been found in laundries cleaning the clothes, towels, and bedding of patients treated with these medications [6]. A study conducted in Swedish oncological hospitals [7] reported a cytostatic (cisplatin) in the blood of nurses. In turn, an investigation of Canadian hospital pharmacies [8] showed that more than 60% of the tested surfaces were contaminated with a cytostatic (methotrexate--MTX). Methotrexate has also been found on the surface of tools [9] and on protective gloves used in oncological wards in British hospitals [10].

Research has shown that individuals who professionally deal with cytostatics are also exposed to their harmful activity. Therefore, medical personnel should wear appropriate protection devices preventing the absorption of those substances [11-13]. Thus, it is necessary to study the protective properties of materials used in the production of personal protective equipment (PPE) with a particular focus on protective gloves and clothing to ascertain that they meet the requirements. Personal protective equipment should be used whenever workers may be exposed to hazardous substances, also with a view upon preventing congenital defects in the case of children [14, 15].

The objective of the work was to determine the resistance of selected glove and clothing materials to permeation of solutions of the tested cytostatics (docetaxel, fluorouracil, and doxorubicin).

MATERIAL AND METHODS

Materials

The study involved the determination of barrier properties of selected clothing and glove materials used for chemical protection: natural rubber latex, acrylonitrile-butadiene rubber and chloroprene rubber for gloves as well as a layered material composed of a non-woven polyester (PES), a polypropylene (PP) film, and a non-woven PP for protective coats. The glove materials were coded A, B, and C, respectively, and the clothing material was coded D.

The tested materials were subjected to the following preliminary tests to determine their characteristics:

- thickness according to the standard EN ISO 5084: 1996 [16],

- surface density according to the standard PN-EN 12127: 1997 [17],

- puncture resistance according to the standard EN 863 1995 [18],

- abrasion resistance according to the standard EN 388: 2003 [19].

The Table 1 shows the properties of the studied materials.

Chemicals

Taking into consideration the diverse types of cytostatics used in the treatment of cancers in Poland and the results of a questionnaire survey concerning health care units compounding chemotherapy medications for oncological wards [15], the following cytostatics were selected:

- 5-fluorouracil--a topoisomerase inhibitor,

- docetaxel--an inhibitor of the mitotic spindle,

- doxorubicin--an antimetabolite and a natural antibiotic.

The cytostatics were tested in the form of solutions. Commercially available cytostatic preparations were prepared by dilution in saline using the maximum cytostatic concentration that can be administered to the patient. The test substances used in the permeation study were prepared using the following reagents:

- docetaxel: 10 mg x [ml.sup.-1] in saline solution with the addition of ethanol, 10 ml vial (Ebewe Pharma),

- doxorubicin: 1 mg x [ml.sup.-1] in saline solution, 25 ml (Ebewe Pharma),

- 5-fluorouracil: 50 mg x [ml.sup.-1] in saline solution, 20 ml vial (Ebewe Pharma).

- 0.9% sodium chloride (NaCl) solution, 500 ml (saline solution) (Kaliclear).

The respective phases used in high-performance liquid chromatography (HPLC) were prepared with the following reagents:

- ammonium acetate (C[H.sub.3]COON[H.sub.4]) (Merck),

- disodium phosphate ([Na.sub.2]HP[O.sub.4]) (POCH S.A.),

- orthophosphoric acid ([H.sub.3]P[O.sub.4]) (POCH S.A.),

- triethylamine (TEA) (Sigma-Aldrich),

- acetonitrile (ACN) (Merck),

- methanol (C[H.sub.3]OH) (Merck).

Experimental stand

The experimental stand consisted of:

- a Merck-Hitachi Elite LaChrom liquid chromatograph with an L2200 autosampler and a DAD L-2450 diode array detector,

- a C18 analytical column (RP-18 endcapped Purospher Star) with dimensions of 250x4.6 mm and a particle size of 5 [micro]m with a guard column,

- a permeation cell in which the samples were placed (Figure 1),

- a peristaltic pump with a flow rate of 0-2100 ml x [min.sup.-1],

- an analytical scale with an accuracy of 0.1 g,

- a disc micrometer with a disc diameter of 10 mm and a pressure of 4.9 Pa.

Test method

The tested sample constituted a barrier between the upper and lower chambers of the permeation cell (Figure 1). A cytostatic solution was placed in the upper chamber, while a collection medium was circulated through the bottom chamber, sweeping the underside of the tested sample and collecting permeated cytostatic particles for chromatographic analysis. The presented method was developed based on the guidelines specified in the standard EN ISO 6529:2001 [20]. The tests were conducted pursuant to the Method A concerning liquid chemical substances in continuous contact.

Taking into consideration the toxicity of cytostatics, it was very important to minimize the amounts of those compounds used during the tests and left over after their completion. Consequently, the permeation cell presented in the standard EN ISO 6529:2001 [20] was modified to reduce the volume of cytostatic solutions used in the test (from 10 ml to 1.5 ml) and to decrease the flow of the collection medium (from 600 ml x [min.sup.-1] to 175 ml x [min.sup.-1]).

In the first step, the tested sample was placed between the upper and lower chambers of the permeation cell. Then, 1.5 ml of docetaxel solution at a concentration of 10 mgxml-1 was placed in the upper chamber, which marked the beginning of the test. A liquid collection medium was circulated through the bottom chamber at a flow rate of 175 ml x [min.sup.-1]). The bottom chamber with the inlet and outlet of the collection medium formed a closed circuit. The flow of the medium was forced by a peristaltic pump. The Photo 1 presents the permeation cell with a peristaltic pump as used in testing material resistance to cytostatic permeation [21].

At predetermined time intervals, 200 [micro]l of the collection medium was taken for chromatographic analysis. Those intervals ranged from 10 min to 480 min and coincided with the intervals defined in the standards EN 14605+A1:2009 [22] and EN 374-1:2003 [23] (10 min, 30 min, 60 min, 120 min, 240 min, 480 min), defining performance levels for gloves and clothes protecting against chemical substances. The test continued for 8 h.

The test results were expressed as the time to cytostatic breakthrough calculated as an arithmetic mean for 3 samples of a given type of material. Pursuant to the standard EN 6529:2001 [20], breakthrough time was defined as the moment when the amount of the chemical substance penetrating though the sample reached 2.5 [micro]g x [cm.sup.-2].

Analytical determination of cytostatics

The cytostatics were determined in 200 [micro]l of collection medium by means of high performance liquid chromatography (HPLC) using a Merck-Hitachi Elite LaChrom liquid chromatograph with a L2200 autosampler, a DAD L-2450 diode array detector, and a C18 analytical column (RP-18 endcapped Purospher Star) with dimensions of 250x 4.6 mm and a particle size of 5 [micro]m with a guard column.

The Table 2 gives the parameters of the chromatographic analysis for the studied cytostatics. The basic validation parameters are given in the Table 3.

Statistics

The barrier properties of the materials were analyzed based on the breakthrough times determined individually for each material-cytostatic solution system.

The statistical analysis shows highly significant differences between groups (H = 28.93, df = 9, p = 0.0007). However, only the results for the breakthrough of material D by docetaxel solution are significantly (p = 0.0027) lower than the other results, which did not differ from one another (p = 1.0000).

The analysis of results was conducted using the package PQStat v. 1.6.

Distributions of results were evaluated using the Kruskal-Wallis test and the post hoc Dunn test. Test probability of p < 0.05 was considered significant, and p < 0.01 was deemed highly significant.

RESULTS

The barrier properties of materials were analyzed based on the breakthrough times determined individually for each material-cytostatic solution system. The results concerning the resistance of glove and protective clothing materials to permeation of cytostatic solutions are given in the Figures 2-4. In the case of the layered material in the D-docetaxel solution system, in which cytostatic permeation was detected, the cumulative quantity of the permeated cytostatic was measured (Figure 4).

DISCUSSION

The tested materials made of natural rubber latex (code A), acrylonitrile-butadiene rubber (code B) chloroprene rubber (code C) as well as the layered clothing material composed of a non-woven PES, a PP film, and a non-woven PP (code D) were found to exhibit very good resistance to solutions containing 2 of the 3 selected cytostatics: doxorubicin and 5-fluorouracil (Figure 2). The applied concentrations of the studied cytostatics were equivalent to their maximum concentrations in preparations administered to patients. Throughout the time of the experiment, neither doxorubicin nor 5-fluorouracil penetrated the glove or clothing material samples (Figure 2), which implies a breakthrough time of more than 480 min. Pursuant to the relevant standards, EN 14605+A1:2009 [22] and EN 374-1:2003 [23], these results indicate the highest (sixth) performance level of PPE protecting against chemical substances.

Equally high resistance to permeation of docetaxel solution was found for materials A, B, and C, with a breakthrough time longer than 480 min. This means that in respect of docetaxel these materials also met the requirements of the highest performance level (Figure 3).

However, it was found that docetaxel penetrated the layered clothing material (D) much more readily than the glove material samples as the breakthrough time for material D was only 120 min (Figure 3). It may be assumed that this result is attributable both to the properties of the material and those of the cytostatic solution. Material D is quite thick (0.32 mm) and contains 2 non-woven layers creating a complex structure that may facilitate the accumulation of cytostatics. While the other materials are smooth membranes, it should be noted that material D is composed of 3 layers, out of which only one constitutes a polymer barrier to permeation. The thickness of this membrane alone may in fact be smaller than the thickness of the other tested materials (0.10-0.21 mm).

Furthermore, of importance is the composition of the docetaxel preparation, which contains some ethyl alcohol (in contrast to the other 2 solutions). Due to this, we conducted an additional test investigating the resistance of material D to ethyl alcohol permeation and found that in this case the breakthrough time was only 65 min. Thus, it may be expected that the content of ethyl alcohol in the amount of 25.1% (weight to weight ratio--w/w) in the commercially available docetaxel preparation (and also in the tested solution) facilitated the diffusion of the cytostatic through the material structure.

Indeed, according to the dissolution-diffusion model of permeation of chemical substances through polymer barrier materials, the presence of more readily permeable components may boost the penetration of other components [24, 25]. In this case, the permeation of both components (docetaxel and ethyl alcohol) may proceed at a much higher rate than for each component separately. Furthermore, this may be linked to the solubility of the chemical solution--tested material system, as the number of liquid substances that may permeate through the polymer is limited. Therefore, it has been observed that increased permeation of one component of a mixture may be accompanied by lower permeation of another component [26].

In addition, the cumulative quantity of the permeated cytostatic was determined for the docetaxel-material D system. The results show that docetaxel solution started to penetrate through 2 samples of the layered material (D1 and D2) after 120 min (Figure 4), while the third sample of this material (D3) was not penetrated until 240 min of exposure to the cytostatic). Due to the fact that the collection medium was analyzed at intervals, it was not possible to precisely determine normalized breakthrough time. The data shows that upon sampling at 240 min and 360 min the cumulative quantity of the permeated cytostatic was between 4.5-7.8 [micro]g x [cm.sup.-2], exceeding the breakthrough amount defined in the standard (2.5 [micro]g x [cm.sup.-2]). Given the above, under conditions of exposure to docetaxel, the safe use time for material D should be that during which permeation was not detected for all 3 samples, which is 120 min. The results of the conducted tests show a slow permeation rate of the selected cytostatics through the tested materials as, except for 1 case, the maximum permissible volume of permeate (2.5 [micro]g x [cm.sup.-2]) was not reached throughout the long experimental time (8 h). Such a long test time reflected a rigorous scenario according to the questionnaire survey in which medical or pharmaceutical personnel was exposed to cytostatics for several hours at a time. The obtained results indicate very good barrier properties of the tested materials as the breakthrough times (> 480 min) correspond to high performance levels. Similar results were reported by Klein et al. [27], who studied the permeation of cytostatics (bleomycin, dacarbazine, daunorubicin, etoposide, etoposide phosphate, ifosfamide, idarubicin, irinotecan, mitomycin, mitoxantrone, oxaliplatin, teniposide, topotecan, and vinorelbine) through natural rubber latex and chloroprene rubber using HPLC with a ultraviolet-visible (UV-VIS) detector. For most cytostatics, the mean permeation rate obtained by Klein et al. was lower than 0.2 nmolxmin-1xcm-2 or permeation was not observed at all (at the adopted limit of detection (LOD) level and sensitivity of the apparatus). Permeation below the threshold value indicated that breakthrough time was longer than the duration of the experiment (3 h). A much higher permeation rate (10-fold increase) was only found for carmustine, which was attributed by Klein et al. to the fact that the chemical compound was characterized by small, partially lyophilic particles, as it was previously noted by other researchers [28, 29].

Moreover, Klein et al. reported that permeation rate was determined by glove thickness [27], which was not corroborated by the presented study. While the thickness of polymer materials in the form of smooth membranes differed by approx. a factor of 2 (0.10-0.21 mm), that did not lead to differences in the detected amounts of permeated cytostatics.

CONCLUSIONS

Most of the materials tested in the presented study, and in particular those made of natural rubber latex (code A), acrylonitrile-butadiene rubber (code B), and chloroprene rubber (code C), provide good protection against permeation of solutions of all selected cytostatics (docetaxel, 5-fluorouracil, and doxorubicin). Indeed, no cytostatic breakthrough was observed throughout the experiment despite its long duration (480 min), which indicates very high barrier properties of the materials.

Lower barrier properties were exhibited by the layered clothing material composed of a non-woven PES, a PP membrane, and a non-woven PP (code D), in particular with respect to one cytostatic (docetaxel). The results showed that docetaxel solution permeated through the layered material at a faster rate than through the other materials, which were smooth membranes sampled from protective gloves. Breakthrough time for material D was established at 120 min. It was found that the content of ethyl alcohol in the commercially available docetaxel preparation (and in the test solution) facilitated cytostatic diffusion through the sample of the layered material, compromising its barrier properties. The tests have demonstrated that cytostatics may faster permeate through clothing materials, which often combine non-wovens and polymer films, than through the smooth membranes of glove materials. This may be due to the structure of material B, which facilitates wetting and cytostatic penetration. Therefore, personnel exposed to cytostatics should pay greater attention to the possibility of accidental contamination with those substances because they may affect not only gloves, but also other PPE products, which are under lower scrutiny than gloves. Naturally, individuals working with cytostatics stress that it is their hands which are at greatest risk of contamination, but it must be kept in mind that those substances may also contaminate other parts of the body.

https://doi.org/10.13075/ijomeh.1896.01140

REFERENCES

[1.] Walusiak-Skorupa J, Wugrowska-Koski E, Palczynski C. [Cytostatics: Occupational hazards, Health consequences, Prevention, Expert opinions]. 3rd ed. Lodz: Instytut Medycyny Pracy; 2009. Polish.

[2.] Szmyd K, Haus O. [Cancers among medical personnel exposed to anticancer agents]. Med Pr. 2011;62(1):17-21. Polish.

[3.] Centers for Disease Control and Prevention. NIOSH Alert: Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. Cincinnati: National Institute for Occupational Safety and Health; 2004.

[4.] De Werk NA, Wadden RA, Chlou WL. Exposure of hospital workers to airborne antineoplastic agents. Am J Hosp Pharm. 1983;40(4):597-601.

[5.] Gac P, Pawlas K. [Hazards entailed by occupational exposure to cytostatic preparations]. Bezp Pr Nauk Prakt. 2010;9: 18-21. Polish.

[6.] Meijster T, Fransman W, Veldhof R, Kromhout H. Exposure to antineoplastic drugs outside the hospital environment. Ann Occup Hyg. 2006;50(7):657-64, https://doi.org/10.1093/ annhyg/mel023.

[7.] Nygren O, Lundgren C. Determination of platinum in workroom air and in blood and urine from nursing staff attending patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health. 1997;70(3):209-14.

[8.] Chu WC, Hon CY, Danyluk Q, Chua PP, Astrakianakis G. Pilot assessment of the antineoplastic drug contamination levels in British Columbian hospitals pre-and post-cleaning. J Oncol Pharm Pract. 2012;18(1):46-51, https://doi.org/10.1177/1078155211402106.

[9.] Sabatini L, Barbieri A, Lodi V Violante FS. Biological monitoring of occupational exposure to antineoplastic drugs in hospital settings. Med Lav. 2012;103(5):394-401.

[10.] Ziegler E, Mason HJ, Baxter PJ. Occupational exposure to cytotoxic drugs in two UK oncology wards. Occup Environ Med. 2002;59(9):608-12, https://doi.org/10.1136/oem.59.9.608.

[11.] [Regulation of the Minister of Health and Social Security of 19 June 1996 on occupational safety and health during the preparation, administration, and storage of cytostatic medications in health care facilities. J Laws 1996, No. 80, item 376]. Polish.

[12.] [Regulation of the Minister of Health and Social Security of 31 August 2000 amending the regulation on occupational safety and health during the preparation, administration, and storage of cytostatic medications in health care facilities. J Laws 2000, No. 79, item 897]. Polish.

[13.] Walusiak J, Wugrowska-Koski E. [Handling of cytostatic medications]. Pr Zdrow. 2008;3:38-40. Polish.

[14.] El-Helaly M, Abdel-Elah K, Haussein A, Shalaby H. Paternal occupational exposures and the risk of congenital malformations--A case-control study. Int J Occup Med Environ Health. 2011;24(2):218-27, https://doi.org/10.2478/s13382-011-0019-x.

[15.] Krzeminska S, Posniak M, Szewczynska M. [Use of personal protective equipment under occupational exposure to cytostatics]. Med Pr. 2016;67(4):499-508, https://doi.org/10.13075/mp.5893.00323. Polish.

[16.] EN ISO 5084:1996. Textiles. Determination of thickness of textiles and textile products. Geneva: International Organization for Standardization; 1996.

[17.] PN-EN 12127:1997. [Textiles. Flat textile products. Determination of mass per unit area using small samples]. Warszawa: Polish Committee for Standardization; 1997. Polish.

[18.] EN 863:1995. Protective clothing. Mechanical properties. Test method: Puncture resistance. European Commission; 1996.

[19.] EN 388:2003. Protective gloves against mechanical risks. European Commission; 2003.

[20.] EN ISO 6529:2001. Protective clothing. Protection against chemicals. Determination of resistance of protective clothing materials to permeation by liquids and gases. Geneva: International Organization for Standardization; 2001.

[21.] Szewczynska M, Krzeminska S, Posniak M. The resistance of gloves and protective clothing materials to permeation of cytostatic solutions. Proceeding of the 16th World Textile Conference Autex; 2016 Jun 8-10; Ljubljana, Slovenia. Ljubljana: University of Ljubljana; 2016.

[22.] EN 14605+A1:2009. Protective clothing against liquid chemicals. Performance requirements for clothing with liquid-tight (Type 3) or spray-tight (Type 4) connections, including items providing protection to parts of the body only (Types PB [3] and PB [4]). Brussels: European Commission; 2009.

[23.] PN-EN 374-1:2003. [Protective gloves against chemicals and micro-organisms. Terminology and performance requirements]. Warszawa: Polish Committee for Standardization; 2003. Polish.

[24.] Vahdat N, Sullivan VDJ. Estimation of permeation of chemicals through elastomeric materials. J Appl Polym Sci. 2001;79(7):1265-72, https://doi.org/10.1002/1097-4628(20010214)79:7<1265::AID-APP140>3.0.CO;2-H.

[25.] Krzeminska S. Determination of organic solvents mixtures permeating through butyl rubber membranes by means of gas chromatography. Polish J Appl Chem. 2007;51(1-2):49-53.

[26.] Krzeminska S. [Resistance of membranes made of butyl rubber vulcanizates to permeation of mixtures of organic solvents]. Polimery. 2005;50(11-12):868-72. Polish.

[27.] Klein M, Lambov N, Samev N, Carstens G. Permeation of cytotoxic formulations through swatches from selected medical gloves. Am J Health Syst Pharm. 2003;60(10):1006-11.

[28.] Thomas PH, Fenton-May V Protection offered by various gloves to carmustine exposure. Pharm J. 1987;238:775-7.

[29.] Connor TH, Laidlaw JL, Theiss JC. Permeability of latex and polyvinyl chloride gloves to carmustine. Am J Hosp Pharm. 1984;41(4):676-9.

SYLWIA KRZEMINSKA (1), MALGORZATA POSNIAK (2), and MALGORZATA SZEWCZYNSKA (2)

(1) Central Institute for Labour Protection--National Research Institute, Lodz, Poland Department of Personal Equipment

(2) Central Institute for Labour Protection--National Research Institute, Warszawa, Poland Department of Chemical, Biological and Aerosol Hazards

Funding: the publication was based on the results of Phase III of the National Program "Safety and working conditions improvement," funded in the years 2014-2016 in the area of tasks related to services for the State by the Ministry of Labour and Social Policy. The Program coordinator was Central Institute for Labour Protection--National Research Institute. Task 3.Z.17 "Evaluation of barrier materials for clothing and gloves to protect against cytostatics in the solutions form." Program managers: Sylwia Krzeminska, Ph.D. Eng., and Malgorzata Szewczynska, Ph.D.

Received: September 29, 2016. Accepted: August 17, 2017.

Corresponding author: M. Szewczynska, Central Institute for Labour Protection--National Research Institute, Department of Chemical, Biological and Aerosol Hazards, Czerniakowska 16, 00-701 Warszawa, Poland (e-mail: mapol@ciop.pl), and S. Krzeminska, Central Institute for Labour Protection--National Research Institute, Department of Personal Equipment, Wierzbowa 48, 90-133 Lodz, Poland (e-mail: sykrz@ciop.lodz.pl).

Caption: Fig. 1. Permeation cell for testing the resistance of materials to permeation of cytostatic solutions

Caption: Fig. 2. Doxorubicin and 5-fluorouracil breakthrough time for the tested materials

Caption: Fig. 3. Docetaxel breakthrough time for the tested materials

Caption: Fig. 4. Cumulative amount of cytostatic (docetaxel) permeated through the material D over time

Caption: Photo 1. Permeation cell with a peristaltic pump used in testing material resistance to cytostatic permeation
Table 1. Physical properties of the studied materials

Parameter                             Material

                             A                      B

Thickness [mm]        0.21 [+ or -] 0.01     0.10 [+ or -] 0.00
  (M [+ or -] SD)
Surface density     191.80 [+ or -] 9.10   100.80 [+ or -] 2.20
  [g/[m.sup.2]]
  (M [+ or -] SD)
Puncture              6.95 [+ or -] 0.37    11.30 [+ or -] 1.20
  resistance [n]
  (M [+ or -] SD)
Abrasion             48.00 [+ or -] 3.00    20.00 [+ or -] 0.00
  resistance
  [cycles]
  (M [+ or -] SD)

Parameter                               Material

                              C                         D

Thickness [mm]          0.17 [+ or -] 0.01      0.32 [+ or -] 0.02
  (M [+ or -] SD)
Surface density       214.90 [+ or -] 4.00     83.80 [+ or -] 0.90
  [g/[m.sup.2]]
  (M [+ or -] SD)
Puncture               14.07 [+ or -] 2.09      6.62 [+ or -] 0.90
  resistance [n]
  (M [+ or -] SD)
Abrasion            8 000.00 [+ or -] 0.00   1250.00 [+ or -] 290.00
  resistance
  [cycles]
  (M [+ or -] SD)

M--mean; SD--standard deviation.

A--natural rubber latex; B--acrylonitrile-butadiene rubber;
C-chloroprene rubber; D--layered clothing material composed of a
non-woven polyester (PES), a polypropylene (PP) film, and a
non-woven PP.

Table 2. Parameters of chromatographic analysis of the studied
cytostatics

Parameter                  Cytostatic

                          fluorouracil

Mobile phase        0.05 M disodium phosphate
                    ([Na.sub.2]HP[O.sub.4]) :
                    acetonitrile (ACN) (v/v
                    65:35) with the addition
                      of 0.5 ml x [l.sup.-1]
                  triethylamine (TEA) pH = 3.7
                      (orthophosphoric acid)

Phase flow                    0.65
  [ml x
  [min.sup.-1]]
Injection                     20.00
  volume
  [[micro]l]
Detector                     266.00
  wavelength
  [nm]

Parameter                    Cytostatic

                             doxorubicin

Mobile phase         0.05 M disodium phosphate
                     ([Na.sub.2]HP[O.sub.4]) :
                        acetonitrile (ACN)
                       (v/v 65:35) with the
                       addition of 0.5 ml x
                  [l.sup.-1] triethylamine (TEA)
                  pH = 3.7 (orthophosphoric acid)

Phase flow                     0.65
  [ml x
  [min.sup.-1]]
Injection                       20
  volume
  [[micro]l]
Detector                      266.00
  wavelength
  [nm]

Parameter                Cytostatic

                          docetaxel

Mobile phase         acetonitrile (ACN):
                   0.01 M ammonium acetate
                  (C[H.sub.3]COON[H.sub.4])
                     (v/v 45:55) pH = 4.5
                    (orthophosphoric acid)

Phase flow                  1.50
  [ml x
  [min.sup.-1]]
Injection                   20.00
  volume
  [[micro]l]
Detector                   230.00
  wavelength
  [nm]

v/v--volume/volume.

Table 3. Validation parameters for chromatographic analysis
of the studied cytostatics

Parameter            Fluorouracil   Doxorubicin    Docetaxel

Concentration         0.03-16.00    0.09-50.00    0.20-200.00
  [[micro]gx[ml.
  sup.-1]] (range)
Limit of detection      0.0007        0.0005        0.0065
  [[micro]gx[ml.
  sup.-1]]
Limit of                0.0021        0.0015        0.0195
  quantification
  [[micro]gx
  [ml.sup.-1]]
Correlation             0.9998        0.9976        0.9993
  coefficient
Overall                 1.1900        1.8900        1.8700
  measurement
  precision
Total uncertainty       3.3800        4.7810        4.7600
  of the
  method [%]
Expanded                6.7700        9.5620        9.5200
  uncertainty [%]
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Title Annotation:ORIGINAL PAPER
Author:Krzeminska, Sylwia; Posniak, Malgorzata; Szewczynska, Malgorzata
Publication:International Journal of Occupational Medicine and Environmental Health
Article Type:Report
Date:May 1, 2018
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