Ann. occup. Hyg., Vol. 47, No. 4, pp. 297-304, 2003
© 2003 British Occupational Hygiene Society
Published by Oxford University Press
Sensory Irritation due to Methyl-2-cyanoacrylate, Ethyl-2-cyanoacrylate, Isopropyl-2-cyanoacrylate and 2-Methoxyethyl-2-cyanoacrylate in Mice
Department of Pollutants and Health, National Institute for Research and Safety, Avenue de Bourgogne, BP 27, 54501 Vand
uvre, France
Received 7 October 2002; in final form 22 January 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a period of 60 min of nasal exposure to methyl-2-cyanoacrylate, ethyl-2-cyanoacrylate, isopropyl-2-cyanoacrylate and 2-methoxyethyl-2-cyanoacrylate vapors using nose only exposure. Irritation of the upper respiratory tract caused a concentration-dependent decrease in the respiratory rate. The maximum effect occurred within the first 10 min of exposure and was followed by a drop-off in the response during the remainder of the exposure period. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each chemical. The results show that the four chemicals had similar irritant potencies. The RD50 values of methyl-2-cyanoacrylate, ethyl-2-cyanoacrylate, isopropyl-2-cyanoacrylate and 2-methoxyethyl-2-cyanoacrylate were 1.4, 0.7, 0.6 and 1.0 p.p.m. Tentative estimates of threshold limit values showed that 0.1 RD50 was closer to the values recommended by the American Conference of Governmental Industrial Hygienists for methyl- and ethyl-2-cyanoacrylate than 0.03 RD50. On the basis of a threshold limit value for short-term exposure limit (TLV STEL) equal to 0.1 RD50, the TLV STELs for the four cyanoacrylates should not exceed 0.1 or 0.2 p.p.m.
Keywords: cyanoacrylates; exposure limits; irritation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Alkyl-2-cyanoacrylates are used as solvent-free adhesives. They polymerize spontaneously at ambient temperature to form hard glassy resins that exhibit excellent adhesion to a wide variety of materials. Methyl- and ethyl-2-cyanoacrylate are the most commonly used in adhesive formulations. The base monomers are generally formulated with stabilizers such as hydroquinone and sulfonic acid and with thickeners including polymethylmethacrylate resin and silica. They have sharp, pungent odors and are lacrimators, even at very low concentrations. Whereas their possible sensitizing effects are still the subject of debate (Lee and London, 1985; London et al., 1986; Goodman et al., 2000; Paustenbach et al., 2001), these esters can be irritating to the nose and throat at low concentrations. To the best of our knowledge, few data from controlled human studies have been published. Furthermore, little information is available on levels of exposure in the workplace (Paustenbach et al., 2001). McGee et al. (1968) reported that nasal irritation occurred at
2–3 p.p.m. methyl-2-cyanoacrylate and ocular irritation at 4 p.p.m. Other studies have found irritating effects such as eye irritation, streaming eyes, irritated and runny nose and sore throat when workers were exposed to lower concentrations of 0.31–0.90 p.p.m. (Lee and London, 1985; London et al., 1986) and estimated that exposures at 0.2 mg/m3 (0.04 p.p.m.) would be well below the levels expected to cause health effects among non-sensitized individuals. Occupational exposure limits exist in several countries for methyl-2-cyanoacrylate and ethyl-2-cyanoacrylate. The American Conference of Governmental Industrial Hygienists estimated that the health surveillance and industrial hygiene data were not adequate to define a no-effect level for ethyl-2-cyanoacrylate. They did, however, recommend a threshold limit value (TLV) time-weighted average (TWA) for ethyl-2-cyanoacrylate and methyl-2-cyanoacrylate of 0.2 p.p.m. to reduce the incidence of irritation and possible respiratory sensitization (ACGIH, 2001). In the UK, the Working Group on the Assessment of Toxic Chemicals (WATCH) recently recommended a short-term exposure limit (STEL) of 0.3 p.p.m. for ethyl-2-cyanoacrylate (HSE, 2000). There is no common European occupational exposure level (OEL) at the present time. However, in most European countries the TWA and the STEL are 2 and 4 p.p.m., respectively.
Whenever possible, the setting of OELs for sensory irritants should be based on data recorded in humans. However, animal models have been developed to set guidelines for the prevention of sensory irritation in humans. The aim of the present study was to evaluate and compare the irritating power of four cyanoacrylates using a quantitative methodology initially developed to test the sensory irritation properties of airborne chemicals in mice. This method is based on observations showing that inhalation of irritants stimulates the trigeminal nerve endings in the nasal mucosa of mice, thereby causing a characteristic reflexively induced decrease in respiratory rate. This decrease in respiratory rate is related to concentration. The concentration responsible for a 50% decrease in the respiratory rate (RD50) is used to compare the irritant potencies of chemicals and to estimate acceptable levels of exposure (Kane et al., 1979, 1980; Alarie, 1981a,b; Nielsen and Bakbo, 1985; Schaper, 1993; Paustenbach, 2002). The test is only to be used to evaluate the sensory irritation power of chemicals. It is not predictive of the local damage to the respiratory tract a chemical could cause (Bos et al., 1992). It still remains appropriate as a first approach test when information on sensory irritation in humans is not available or of poor quality.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chemicals
Methyl-2-cyanoacrylate [137-05-3] (Loctite 493, 99.5% pure), ethyl-2-cyanoacrylate [7085-85-0] (Loctite 420, 99.5% pure) and 2-methoxyethyl-2-cyanoacrylate [27816-23-5] (Loctite 460, 96% pure) were supplied by Loctite France (Senlis, France). Isopropyl-2-cyanoacrylate [10586-17-1] (Delo-CA 2347, 99.9% pure) was purchased from Supratec (Bondoufle, France). Methoxyethyl-2-cyanoacrylate contained 4% polymethylmethacrylate as the thickener.
Animals
Male OF1 mice (IFFA Credo, Domaine des Oncins, Saint-Germain-sur-l’Arbresle, France), weighing 20–25 g, were housed for 7 days in polycarbonate cages (37.5 cm long x 21.6 cm wide x 14.7 cm high, each holding 10 mice), with hardwood chip bedding, under controlled environmental conditions before the study period. Room temperature (22°C), humidity (55 ± 5%) and light cycle (07:00–19:00 h) were controlled automatically. Filtered tap water (pore size 0.3 µm) and food (UAR-Alimentation, Villemoisson, Epinay-sur-Orge, France), sterilized with 
-rays, were available ad libitum except during exposure periods.
Generation, sampling and analysis of test atmospheres
Exposures were conducted in a 37 l glass and stainless steel inhalation chamber equipped with four plethysmographs (Fig. 1). To prevent leakage, the chamber was maintained at a negative pressure (3–6 mmH2O). Cyanoacrylate vapors were generated in a vapor generating chamber by allowing a clean dry air stream (5–20 l/min) to sweep a small vial filled with the test product. The output vapors were mixed with a second dry air stream (0–15 l/min) to obtain the required concentration before entry into the exposure chamber. In an extra set of exposures with ethyl-2-cyanoacrylate the diluting air stream was humidified so as to reach 50% relative humidity in the inhalation chamber. The cyanoacrylate concentration inside the exposure chamber was controlled by varying the flow rate of the two air streams, the surface area of the vials containing the cyanoacrylate and the temperature of the vial (20–40°C).
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The concentrations in the exposure chamber were checked according to the method described by Keen et al. (1998). Briefly, samples of the atmosphere were pumped through an impinger filled with acetonitrile plus 0.2% phosphoric acid. The impinger was introduced into the inhalation chamber only during the sampling periods, which lasted 10 min. Two samples were taken at the beginning and at the end of the exposure period. As each experiment was performed twice with four mice in each experiment (see Experimental design and conduct), there were four samplings carried out for each concentration studied. The samples were analyzed by high performance liquid chromatography (HPLC) using a 15 cm Interchrome® Nucleosil® reverse phase C18 column, 4.6 mm inner diameter, 3 µm film thickness, maintained at 0°C in an ice bath. The mobile phase (1 ml/min) consisted of 45% H2O, 55% acetonitrile (+ 0.2% phosphoric acid) for methyl-2-cynoacrylate and ethyl-2-cyanoacrylate and 55% H2O, 45% acetonitrile (+ 0.2% phosphoric acid) for isopropyl-2-cyanoacrylate and 2-methoxyethyl-2-cyanoacrylate. UV detection was used at 220 nm. For a 10 µl injection, this procedure provided a detection limit of 1.5 ng expressed as methyl-2-cyanoacrylate.
Experimental design and conduct
Breathing frequency was used as an index of upper respiratory tract irritation. Stimulation of the trigeminal nerves in the eyes and the upper respiratory tract causes sensory irritation. In mice, it causes an elongation of the period from the end of inspiration until the start of expiration. Thus, the sensory irritation pattern is characterized by a ‘break’ in respiration. Stimulation of the vagal nerves in the lungs may cause pulmonary irritation. In mice, pulmonary irritation may increase the time from the end of the expiration to the initiation of the following inspiration. The reflex pattern of pulmonary irritation is thus characterized by a ‘pause’ in respiration (Vijayaraghavan et al., 1993). The method to measure the respiratory rate in oronasally exposed mice has already been described in detail (ASTM, 1984; Gagnaire et al., 2002). Briefly, the mice were restrained in a body plethysmograph, while the head was enclosed in the inhalation chamber. The breathing frequency was monitored with a pressure transducer (Validyne DP 45) before and during the 60 min exposure period, and throughout the recovery period. For each concentration, the maximum decrease in respiratory rate occurring during the exposure period was recorded and the RD50 max calculated. The effects of 8–11 different exposure concentrations were tested for each chemical. Eight previously unexposed mice were used to test each concentration. Four mice were used at the same time. Each experiment was performed twice and the results were combined.
Statistical analysis
Differences in the respiratory rates before and during exposure to cyanoacrylates were analyzed statistically by Student’s t-test for paired data. The level of significance was set at P < 0.05. The concentration–response curves were analyzed by least squares linear regression and the RD50 values calculated with their 95% confidence intervals.
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RESULTS |
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Examples of the time–response relationships for the effect of the four 2-cyanoacrylates studied in mice are presented in Fig. 2. The four tested substances showed virtually the same time-dependent effect. The onset of the response was rapid. The maximum response was concentration dependent, as shown in Fig. 3. It was reached within the first 10 min of exposure and used to calculate the RD50 max (0–10 min) given in Table 1. At the highest exposure concentrations the maximum was reached within 5 min of exposure. In the remaining part of the exposure period, the respiratory rate gradually increased. This disappearance of the response is reflected in the increase in RD50 values over time, as can be seen in Table 1. After exposure, recovery was relatively slow and partial, particularly for the highest concentrations of methyl-2-cyanoacrylate and ethyl-2-cyanoacrylate. However, even with the highest concentrations tested the breathing pattern of the exposed mice did not show typical characteristics of pulmonary irritation, i.e. a characteristic pause present at the end of expiration. The respiratory rate in the highest exposed groups of mice was calculated 20 h after exposure to the three 2-cyanoacrylates that did not show a complete recovery 15 min after the end of the exposure, i.e. methyl-2-cyanoacrylate, ethyl-2-cyanoacrylate and isopropyl-2-cyanoacrylate. Full or nearly full recovery was seen 20 h after the exposure. The respiratory rate had returned to 92 (P = 0.29, NS), 89 (P = 0.11, NS) and 109% (P = 0.15, NS) of that before exposure, respectively.
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The exposures conducted with ethyl-2-cyanoacrylate at 50% relative humidity gave similar results: RD50 (0–10 min) = 0.70 p.p.m. (95% confidence interval 0.5–0.9), y = 13.96 ln(x) + 55.05, r = 0.98, n = 7. These values are to be compared with those in Table 1 for ethyl-2-cyanoacrylate where experiments were carried out with dry air: RD50 (0–10 min) = 0.70 p.p.m. (95% confidence interval 0.6–0.9), y = 12.10 ln(x) + 53.93, r = 0.95, n = 11.
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DISCUSSION |
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The results of this study show that the four cyanoacrylates studied possess strong sensory irritating properties. With the bioassay used in this study, no clear difference emerged in the biological potency of the four chemicals. From the RD50 max values calculated in our study, the relative potency of the four cyanoacrylates varied from 1 to 2.33, which represents a low ratio compared with the scale on which RD50 values are observed. This scale extends from 0.2 p.p.m. for toluene diisocyanate (Sangha and Alarie, 1979) to >77 000 p.p.m. for acetone (Kane et al., 1980), which represents a ratio of >385 000.
To the best of our knowledge, no RD50 has been published for any cyanoacrylate. The RD50 max values of 0.6–1.4 p.p.m. found for these chemicals put them among the strongest sensory irritants, including isocyanates (Sangha and Alarie, 1979; Sangha et al., 1981; Weyel et al., 1982; Weyel and Schaffer, 1985; Ferguson et al., 1986; Alarie et al., 1987), allylic compounds (Nielsen et al., 1984; Gagnaire et al., 1987, 1989), nitrogen trichloride (Gagnaire et al., 1994), acrolein (Steinhagen and Barrow, 1984; Kane and Alarie, 1977) and peroxyacetic acid (Gagnaire et al., 2002). This powerful irritant activity is not surprising, given the presence of an ester (e.g. COOC2H5) and nitrile (CN) group on one carbon atom of the unsaturated bond of the molecules (Alarie, 1973).
Previous studies with several chemicals have shown that the RD50 values can be used successfully to predict safe industrial exposures if sensory irritation is the most sensitive end-point (Schaper, 1993). In this case, the RD50 values could be used as a basis to determine TLVs to prevent any unpleasant sensations such as piquancy, stinging or itching. It has been predicted that humans exposed to a chemical at its RD50 would experience intolerable burning of the eyes, nose and throat. At 0.1 RD50 they would experience a slight discomfort likely to be tolerable (Barrow et al., 1977) and this should be the highest level permitted in industry. Based on this animal model, TLVs for sensory irritation by airborne chemicals have been proposed at between 0.01 and 0.1 RD50. Furthermore, 0.03 RD50 has also been recommended as a tentative TLV because of the low degree of sensory irritation observed and the strong correlation with TLVs for a wide range of chemicals (Schaper, 1993).
In the present study, the response to exposure to the four cyanoacrylates dropped off during the course of exposure, thus indicating desensitization. This point poses a problem when it comes to setting OELs because the proposal of setting TLVs at 0.03 RD50 for irritants has been made without taking into account possible differences in the time–response curves. It would therefore appear that the RD50 calculated between 40 and 60 min of exposure [RD50 (40–60 min)] is between 2.7 (methyl-2-cyanoacrylate) and 7.2 (2-methoxyethyl-2-cyanoacrylate) times that calculated during the first 10 min of exposure (RD50 max). This desensitization has already been observed in mice and rats with other chemicals, such as aldehydes (Kane and Alarie, 1977; Chang et al., 1981; Cassee et al., 1996; Nielsen et al., 1999), alkylbenzenes (Nielsen and Alarie, 1982), amines (Gagnaire et al., 1993), alcohols (Kristiansen et al., 1986, 1988; Hansen and Nielsen, 1994; Nielsen et al., 1996) and acetone (Kane et al., 1980). The significance of the desensitization observed in animal models and its consequences regarding the establishment of an OEL are not yet well understood. To deal with this problem, more studies should be carried out, both on animals and humans, with chemicals with desensitizing properties. In the present study, the use of 0.03 RD50 max to establish the OELs might be too strict. Thus, OEL values calculated on this basis would lie between 0.02 and 0.04 p.p.m., which seems far below the presumed thresholds for irritation in humans.
Irritation symptoms have been associated with methyl-2-cyanoacrylate and methyl-2-cyanoacrylate levels ranging from 0.3 to 3 p.p.m. (McGee et al., 1968; Lenzi et al., 1974; Lee and London, 1985; London et al., 1986). Although these studies suffer from a number of limitations (self-reporting questionnaires, lack of detail provided on the total duration of exposures, non-specific colorimetric techniques to measure concentrations of pollutants and presence of other pollutants), the ACGIH and HSE have used these data to suggest OELs. The only human volunteer study with methyl-2-cyanoacrylate indicated that no sensory irritant responses in either the eyes or respiratory tract occurred with short-term exposures to 1 p.p.m. in 14 volunteers (McGee et al., 1968). ACGIH recommended a TLV TWA of 0.2 p.p.m. to reduce the incidence of irritation. The HSE, considering that sensory irritation is the key toxicological property of concern for methyl- and ethyl-2-cyanoacrylate, estimated that a STEL was sufficient. This stance is based on the argument that for substances for which sensory irritation is the only health effect of concern, adequate control could be achieved with a STEL with no need for an additional 8 h TWA exposure limit. They recommended a STEL of 0.3 p.p.m., which should be adequate to control against immediate sensory irritation effects. In that case, the use of 0.1 RD50 max might be more appropriate to establish a TLV STEL. The values of 0.1–0.2 RD50 max have been proposed as a basis for setting STELs (Kane et al., 1979). It can be seen from Table 2 that calculating a tentative standard TLV STEL on the basis of 0.1 RD50 max gives values of 0.1 p.p.m.
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In the light of the experimental results obtained in this study, the OELs recommended in most European countries for methyl- and ethyl-2-cyanoacrylate (2 p.p.m. for TWA and 4 p.p.m. for STEL) seem too high. Thus, the values recommended by ACGIH (0.2 p.p.m. for TWA) or by WATCH (0.3 p.p.m. for STEL) seem more appropriate. No value has been established for isopropyl- and 2-methoxyethyl-2-cyanoacrylate. On the basis of a TLV set at 0.1 RD50 max, no serious irritation is expected at 0.1 p.p.m. for isopropyl- and 2-methoxyethyl-2-cyanoacrylate. This concentration is easily attainable provided local exhaust ventilation devices are in place (London et al., 1986; HSE, 2000; Paustenbach, 2002).
In conclusion: (i) the four cyanoacrylates studied present a similar and powerful irritant power; (ii) the OELs for methyl- and ethyl-2-cyanoacrylate currently in force in most European countries seem too high and should be reduced to 0.1–0.2 p.p.m.; (iii) the OELs for isopropyl- and 2-methoxyethyl-cyanoacrylate should be of the same order.
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FOOTNOTES |
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* Author to whom correspondence should be addressed. Tel: +33-0383-50-20-33; e-mail: gagnaire@inrs.fr
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