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3 Ammonia HÃ©ctor D. GarcÃa, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas Spacecraft maximum allowable concentrations (SMACs) for ammonia were published in Volume 1 of this series, Spacecraft Maximum Allowable Con- centrations for Selected Airborne Contaminants, for exposure durations of 1 h, 24 h, 7 d, 30 d, and 180 d (Wong 1994). In anticipation of longer-duration ex- ploration missions, this document establishes a SMAC for ammonia for an ex- tended exposure duration of 1,000 d and revisits the SMACs for 1 h, 24 h, 7 d, 30 d, and 180 d. OCCURRENCE AND USE Ammonia vapor (NH3) is found naturally in air at reported background concentrations of 0.001 to 0.005 ppm (ATSDR 2004), but typical concentrations of ammonia in urban and nonurban areas are on the order of 0.029 and 0.007 part per million (ppm), respectively (Ontario Ministry of the Environment 2001). Values of 5 to 20 ppm have been reported for the odor threshold of am- monia (ATSDR 2006; OSHA 2008). Ammonia, which is highly water soluble, is produced in humans and animals as a by-product of amino acid metabolism. It is required or produced by most living organisms (ATSDR 2004). Humans pro- duce an estimated 17 grams (g) of ammonia per day, of which about 4 g is pro- duced in the gut by intestinal bacteria (ATSDR 2004). Ammonia is produced in the environment by the breakdown of manure and dead plants and animals. It is used in fertilizer; in the manufacture of synthetic fibers, plastics, and explosives; and in household cleaning agents, floor waxes, and smelling salts. Anhydrous ammonia is used in large quantities in the U.S. Space Shuttle and in the Interna- tional Space Station (ISS) as a refrigerant (several hundred kilograms) in exter- nal coolant loops. Ammonia concentrations in the ISS atmosphere have been measured by the Russians and nominal concentrations are reported to range 48
Ammonia 49 from 1.0 to 1.5 ppm, but the Russians reported that they had little confidence in the values produced by the âGANKâ measurement system they were using. Measurements taken in recent months with a new measurement system (Draeger CMS) have indicated that ammonia concentrations were below the detection limit of 2 ppm for the new system. SUMMARY OF ORIGINAL APPROACH The SMACs for exposure durations of 1 h to 180 d were set by King-Lit Wong in 1994 (Table 3-1) and were based on mucosal irritation, which is the most sensitive toxic end point for exposures at low to moderate concentrations of ammonia. To establish the SMACs, Wong used data from subjects who were not inured to ammonia because, in adapted workers, mild inflammation (con- junctival erythema) was reported even in those who did not complain of discom- fort at exposures to 20 ppm (Vigliani and Zurlo 1955; Wong 1994). The 1- and 24-h SMACs were set at 30 and 20 ppm, respectively, to permit no more than slight mucosal irritation during emergency situations, whereas the SMACs for 7, 30, and 180 d were set at 10 ppm, the estimated maximum nonirritating concentration. The 1-h SMAC was based on a report (MacEwen et al. 1970) that expo- sure of volunteers to 30 ppm of ammonia for 10 min was not perceptible in three of five noninured subjects and was barely perceptible in the other two. Thus, a 1-h exposure to 30 ppm of ammonia is expected to produce no more than mild irritation, which is acceptable for emergency situations. For the 24-h SMAC, a lower concentration was desired so as to reduce the degree of discomfort that astronauts would have to endure during a longer emer- gency situation. A concentration of 20 ppm was selected, because it produced only eye and respiratory discomfort in workers (Vigliani and Zurlo 1955; Furgu- son et al. 1977). No data were available on the maximum concentration that would be non- irritating for longer-term exposures to ammonia. Therefore, the 7-, 30-, and 180- d SMACS were based on a comparison of dose-response data from occupational and laboratory studies in humans (Vigliani and Zurlo 1955; Verberk 1977; MacEwen et al. 1970). A lowest-observed-adverse-effect level (LOAEL) of 20 ppm was used to set the 24-h SMAC, but, rather than apply the traditional safety factor of 10 for extrapolation from the LOAEL to a no-observed-adverse-effect level (NOAEL), dose-response data from several studies in the literature were used to decrease the safety factor from 10 to 2. Verberk (1977) reported that, for 1-h exposures, a reduction in the ammonia concentration from 120 to 80 ppm decreased the reported degree of eye irritation from ânuisanceâ to between âjust perceptibleâ and âdistinctly perceptible,â whereas a reduction from 80 to 50 ppm decreased the irritation ratings from âjust perceptibleâ and âdistinctively notice- ableâ to âjust noticeable.â MacEwen et al. (1970) reported that, for 10-min ex-
50 SMACs for Selected Airborne Contaminants TABLE 3-1 SMACs for Ammonia Vapors, 1994 Duration ppm mg/m3 Target Toxicity 1h 30 20 Irritation 24 h 20 14 Irritation 7d 10 7 Irritation 30 d 10 7 Irritation 180 d 10 7 Irritation Source: Wong 1994 posures, reducing the ammonia concentration from 50 to 30 ppm decreased the reported degree of irritation from âmoderateâ to âjust perceptible.â Because of the dose responses in these two studies, Wong concluded that a 50% reduction in the LOAEL of 20 ppm should yield a concentration that does not produce irritation or discomfort. Thus, the 7-, 30-, and 180-d SMACs were set at 10 ppm, assuming that, because of adaptation, a concentration that would be nonir- ritating for 7 d would remain nonirritating for longer exposures. Conversion factors of 0.69 milligram per cubic meter (mg/m3) per ppm or 1.44 ppm per mg/m3 were used. CHANGES IN FUNDAMENTAL APPROACHES RECOMMENDED BY THE NATIONAL RESEARCH COUNCIL The original SMACs for ammonia, set in 1994, were calculated using safety factors applied to a LOAEL. More recently, the National Research Coun- cil has recommended the use of a benchmark dose (BMD) analysis (preferred) or ten Bergeâs generalization (CN Ã T = K) of Haberâs rule when the data permit. NEW DATA SINCE 1994 A single case report (Brautbar et al. 2003) was found of a patient with long-term repetitive occupational exposure to ammonia at concentrations at or above odor recognition (0.043 to 53 ppm, with a geometric mean of 17 ppm) (Ontario Ministry of the Environment 2001) who developed interstitial lung disease. Little weight can be given to a single case report, because causation cannot reasonably be established. No other reports were found describing inter- stitial lung disease associated with ammonia exposures in humans or animals. Swedish researchers (Sundblad et al. 2004) reported the respiratory effects on 12 volunteers of controlled exposures (18 to 20 air changes per h) in a cham- ber (one to four persons per session) to sham or ammonia vapors at 5 and 25 ppm (randomly) on three occasions, with each 3-h session consisting of a total of 1.5 h of resting plus 1.5 h of exercising (50 watts on a bicycle ergometer), changing activity every 30 min. Exposures were separated by at least 1 wk. Par-
Ammonia 51 ticipants rated the perceived discomfort on a questionnaire with 10 symptom descriptions, each having a 0- to 100-mm visual analog scale (VAS) (0 = no symptoms, 100 = almost unbearable), immediately before, during (3, 28, 58, 88, 118, 148, and 178 min from the start of exposure), and after (270 min from the start of) the exposure. Bronchial responsiveness to methacholine, lung function, and exhaled nitric oxide (NO) were measured 1 wk before and 7 h after the start of exposures. Nasal lavage was performed and peripheral blood samples were drawn 0.5 h before and 7 h after the start of exposures. All 10 perceived discom- fort ratings increased significantly during the exposure to 25 ppm of ammonia compared with the control exposure. However, no differences were observed in lung function or bronchial responsiveness when the exposure to fresh air (sham) was compared with the exposure to 5 and 25 ppm of ammonia. Ammonia expo- sure did not cause detectable upper-airway inflammation and did not signifi- cantly affect the levels of exhaled NO, total cell or interleukin 8 concentration in nasal lavage fluid, or complement factor 3b in plasma. At 5 ppm, the authors reported statistically significant increases in eye discomfort, solvent smell, headache, dizziness, and a feeling of intoxication, but not for the other five sub- jective measures (nose discomfort, throat or airway discomfort, breathing diffi- culty, fatigue, and nausea). No odor adaptation was apparent at 25 ppm, but Sundblad reported a ten- dency toward adaptation at 5 ppm (Sundblad et al. 2004), a concentration that has been reported as the lower end of the range of odor thresholds for ammonia (ATSDR 2006; OSHA 2008). Examination of the responses for the individuals exposed to 5 ppm of ammonia reveals that, although 5 of 12 subjects reported decreasing irritation over time, 4 of 12 reported relatively constant irritation over the 3-h exposure and 3 of 12 reported increasing irritation that appeared to pla- teau after 1 to 2 h of exposure. This result suggests that a significant proportion of the population may not show signs of âadaptingâ to the effects of ammonia before the end of a 3-h exposure to 5 ppm. NASAâs experience is that some newly arriving crew members note a âgym lockerâ smell when first entering the ISS, which might be due to the 1- to 1.5-ppm measured concentrations of am- monia, but is more likely due to some organic amines such as those that have been detected in humidity condensate. No measurements have been made, how- ever, of amine concentrations in the ISS atmosphere. In every case, the U.S. crew members have adapted to the smell, so that they no longer notice it after a short while. Belgian and French researchers measured histologic changes (by light and scanning electron microscopy) in tissues from the respiratory tracts of pigs (four or five pigs per group) exposed continuously for 6 d to ammonia at 5 (baseline âcontrolâ), 25, 50, or 100 ppm (Urbain et al. 1996). Quantitative histologic analysis of the nasal and tracheal mucosa revealed considerable âmucosal inju- riesâ (epithelial hyperplasia and increased numbers of neutrophils in the epithe- lial layer and in the lamina propria) compared with the 5-ppm âcontrols.â Except for the lamina propria, all these changes were significant at ammonia concentra- tions as low as 25 ppm in the turbinates but not in the trachea, although func-
52 SMACs for Selected Airborne Contaminants tional disturbances of the tracheal smooth muscle contractions were found at concentrations as low as 25 ppm (Urbain et al. 1996). Ammonia induced a dose- related increase in the efficacy (peak contraction strength) but not the potency (dose/response) of carbechol in measurements of contractile strength in vitro of strips of tracheal smooth muscle as indicated by hyperresponsiveness to acetyl- choline. Ammonia did not influence the response of isolated strips of tracheal smooth muscle to isoproterenol. A nonsignificant decrease was observed in the area of ciliated surface of the turbinate mucosa with increasing ammonia con- centration (Urbain et al. 1996). Because all effects were measured at only one exposure duration (6 d), no conclusions can be drawn from these results about the time course of the observed effects. In addition, this study could not achieve an exposure to 0 ppm of ammonia. The reported average âbackgroundâ concen- tration of 5 ppm of ammonia was achieved by washing out the pig manure from the chambers twice a day (99% of total particles were <5 micrometers at 0.40 Â± 0.05 mg/m3 with respirable concentrations of 0.05 Â± 0.01 mg/m3). The results of the human study of Sundblad et al. and the pig study of Ur- bain et al. are summarized in Table 3-2. NEW RISK ASSESSMENT APPROACHES Neither the data available when the original SMACs were set in 1994 nor the data currently available for ammonia toxicity are amenable to application of the ten Berge approach to data analysis. Use of the ten Berge equation (CN Ã T = K) requires chemical-specific information on the relationship between concen- tration, duration, and effects in order to determine the value of N for a given effect level. Such data are not available for ammonia. In a recent review (Shus- terman et al. 2006) of how well the published data on various sensory irritants follow Haberâs rule (a specific case of the ten Berge equation in which N = 1), Shusterman et al. noted that usable published studies of ammonia show a stronger effect of concentration than of time on the intensity of sensory irrita- tion. For ammonia, diminution of the time effect (plateauing) was apparent within the first 10 s of exposure. They concluded that âThe studies reviewed here for ammonia â¦ suggest that extrapolation of effects utilizing the formula- tion c Ã t = k (âHaberâs Lawâ) may overestimate risk of sensory irritation (if extrapolating from short to long durations) or underestimate risk (if extrapolat- ing from long to short durations).â A BMD analysis was performed on the raw data from the Sundblad study (obtained from the first author). The VAS scores at seven exposure durations ranging from 3 to 178 min for each subject for ammonia concentrations of 0, 5, and 25 ppm for each measured effect were entered into the BMDS version 1.4.1 software of the U.S. Environmental Protection Agency (EPA) using the poly- nomial model for continuous data with nonhomogeneous variance. Results ob- tained using the linear and power models for continuous data were almost iden- tical to the results obtained from the polynomial model.
Ammonia 53 TABLE 3-2 Human and Pig Responses to Ammonia Vapors [NH3], Reference Species Time ppm Effects Sundblad et Human 3 hour exposure, 0 None al. 2004 3 separate occasions Sundblad et Human 3 hour exposure, 5 Significant odor, very minor al. 2004 3 separate occasions (âhardly at allâ) discomfort Sundblad et Human 3 hour exposure, 25 Significant increase in mild al. 2004 3 separate occasions discomfort Urbain et al. Pig 24 h/d, 6 d 5a Baseline âcontrolâ 1996 Urbain et al. Pig 24 h/d, 6 d 25 Epithelial hyperplasia and 1996 increase in neutrophils in nasal turbinates a An atmospheric concentration of 5 ppm of ammonia was the mean background concen- tration for the âcontrolâ pigs. It was achieved by twice daily washing out the manure from the floor under the grating of the pig exposure chambers. No ammonia vapors were added to achieve this concentration. Figure 3-1 presents an example of the dose-response curve for eye irrita- tion output by the BMDS computer program. Benchmark response values of 2.26, 5.6, and 2.48 standard deviations for eye irritation, solvent smell, and headache, respectively, were selected to correspond to a score of 6 (âhardly at allâ) on the VAS used in the Sundblad study. The average VAS score (average for all participants at multiple exposure time points) for each symptom was cal- culated for each exposure concentration (see Table 3-3). For each ammonia con- centration, the VAS scores obtained at 3, 28, 58, 88, 118, 148, and 178 minutes from the beginning of an exposure were averaged for each symptom rated by each participant. The average for all participants of their average score for each symptom was used in calculating BMDs. For the purposes of establishing SMACs, VAS scores of â¤6 are considered to be nonadverse and acceptable ef- fects. The calculated BMD and BMDL (lower confidence limit on BMD) values for the symptoms (eye discomfort, solvent smell, headache) that showed signifi- cant increases over background and whose average VAS scores at the highest tested concentration (25ppm) were >6.0 are shown in Table 3-4. The SMACs determined as described in the Rationale section below are listed in Table 3-5 RATIONALE FOR A 1,000-D SMAC AND REVISED 7-, 30-, AND 180-D SMACS Acceptable concentrations (ACs) were determined following the guide- lines of the National Research Councilâs committee on Spacecraft Exposure Guidelines (NRC 2000).
54 SMACs for Selected Airborne Contaminants FIGURE 3-1 BMDS graphic representation of results for data on eye irritation. Source: Calculated from raw data provided by B.M. Sundblad. TABLE 3-3 VAS Severity Score Averages for Exposures of 3 to 178 min Average VAS Scores Symptom 0 ppm 5 ppm 25 ppm Eye irritation 1.5 5.1 18 Nose discomfort 4.9 8.6 25 Throat discomfort 5.6 8.1 20 Breathing difficulty 2.5 2.5 14 Solvent smell 0.73 39 66 Headache 1.6 3.2 9 Fatigue 6.6 8 16 Nausea 1.2 1.7 3.7 Dizziness 1 2.4 5.8 Feeling of intoxication 0.86 2.6 5.6 Source: Calculated from raw data provided by B.M. Sundblad. TABLE 3-4 Results from BMD Analysis of Sundblad et al. 2004 Data Symptom BMD, ppm BMDL, ppm Eye discomfort: burning, irritated, or running eyes 6 3 Solvent smell 1 0.5 Headache 15 8 Source: Calculated from raw data provided by B.M. Sundblad using the continuous, polynomial model of the BMD software distributed by EPA.
Ammonia 55 TABLE 3-5 SMACs for Ammonia Vapors, 2008 SMAC Duration ppm mg/m3 Target Toxicity 1h 30 20 Eye irritation 24 h 20 14 Eye irritation 7d 3 2 Eye irritation 30 d 3 2 Eye irritation 180 d 3 2 Eye irritation 1,000 d 3 2 Eye irritation The original SMACs for 1- and 24-h exposure durations will not be changed by the new data. These short-term SMACs are set to allow minor ef- fects to crew members who are working to clean up a release of ammonia. Two major studies of the toxicity of ammonia vapors have been published since the original SMACs for ammonia were established in 1996. The Sundblad et al. study in human volunteers was well done but was limited to exposures durations of â¤3 h. The study of Urbain et al. in pigs was also well done but was limited to a single exposure duration of 6 d and did not include an exposure to 0 ppm of ammonia. Because human data are preferable to animal data for setting human exposure limits, the data of Sundblad et al. rather than Urbain et al.âs pig data are used to calculate ACs. Although generally test data for a 3-h exposure would not be used to set exposure limits for chronic exposures, in the case of ammonia such an extrapolation is justified because ammonia at low concentra- tions is not known to produce any adverse effects that increase in severity or are cumulative with prolonged exposures. Sundblad et al. reported that 5 of the 10 measured effects (see Table 3-6) significantly increased at 5 ppm of ammonia compared with controls: eye dis- comfort and irritation, solvent smell, headache, dizziness, and a feeling of in- toxication. Nevertheless, statistical significance does not imply that low-severity effects should be considered adverse. For the case of âsolvent smellâ, although some subjects in the Sundblad study rated the severity of odor as âquiteâ even after 278 min of exposure to 5 ppm of ammonia, NASAâs experience has shown that, although some ISS crew members have reported an odor like ammonia (âlocker room smellâ) upon first entry, in all cases, they quickly adapted so that they no longer noticed the odor. Note also that the âlocker room smellâ is pre- sumed to be partly due to ammonia, but other organic amine compounds have been detected (but not quantitated) in ISS air samples that could account for some or all of the reported smell upon first entry into ISS. Nevertheless, based on NASAâs experience showing adaptation to low ambient concentrations of ammonia and organic amines, long-term SMACs will not be set to protect against smell.
56 TABLE 3-6 Time-Averaged Scores for Each Subject and Measured Effect Eye Irritation Solvent Smell Headache Average Score (3 to 178 min) Average Score (3 to 178 min) Average Score (3 to 178 min) Subject 0 ppm 5 ppm 25 ppm 0 ppm 5 ppm 25 ppm 0 ppm 5 ppm 25 ppm 2 0 0.9 10.4 0 55 49 0.14 0 3.9 3 1.5 19.6 20.4 1.5 23 71 2.5 2.6 2.4 4 4 7.3 38.4 3.1 4 48 3 4.4 11 5 6.9 7.6 23.1 0 64 76 5.9 4.1 20 6 0.4 5.4 43.7 0.43 67 82 0.29 1.7 8.1 8 1.7 1.9 20.4 1.1 23 79 1.1 0.86 2.3 9 1.4 1.9 5.0 0.57 49 67 3.6 4.6 9.1 10 0 0.0 14.8 0 36 72 0 5.1 20 11 0 1.0 13.1 0 26 51 0.14 0.43 1 12 0.1 3.1 17.3 0 19 79 0 2.1 23 13 2.1 9.1 8.4 2 74 34 2 10 3.4 14 0 3.4 5.6 0 27 82 0.14 2.9 3.9 Average 1.51 5.1 18.38 0.73 38.9 65.83 1.57 3.23 9.008 Standard deviation 2.09 5.44 12.13 1.01 22.3 16.16 1.88 2.72 7.855 Each score in the table is the average of the scores reported by an individual subject at exposure durations of 3, 28, 58, 88, 118, 148, and 178 min. Source: Sundblad et al. 2004.
Ammonia 57 Although Sundblad et al. reported that the scores at 5 ppm for symptoms eye irritation, solvent smell, headache, dizziness, and feeling of intoxication (refer to Table 3-3) are statistically significant, NASA does not consider the severity scores for dizziness and feeling of intoxication (â¤6 or âhardly at allâ) to be adverse. Because mild, transient effects in astronauts are acceptable for expo- sure durations of 1 and 24 h, no factor will be applied to protect sensitive indi- viduals when calculating ACs for 1 and 24 h. The chronic (12.2-year, occupa- tional) NOAEL of 9.2 ppm time-weighted average (TWA) reported by Holness et al. (1989) and described below supports the conclusion that chronic exposure to low concentrations of ammonia does not produce cumulative injury to the respiratory tract. Thus, a lack of adverse effects observed during a 3-h exposure should remain a lack of adverse effects for all longer durations for both sensory irritation and injury to the respiratory tract. Because workers have been reported to adapt to both the smell and the eye irritant effects of ammonia vapors in the workplace, the use of a score of âhardly at allâ as a nonadverse effect is consid- ered conservative. ACs were calculated for eye irritation and headache by set- ting them equal to the BMDL values (see Table 3-4) for those symptoms. Table 3-7 presents exposure limits for ammonia vapors set by other or- ganizations, while Table 3-8 presents ACs and SMACs developed in this docu- ment. OTHER STANDARDS FOR AMMONIA IN AIR Holness et al. (1989) investigated production workers exposed to ammonia in a soda ash facility. No statistical difference in the prevalence of reporting symptoms (eye, skin, and respiratory symptoms) between exposed and control groups was found for TWA ammonia exposures to 9.2 and 0.3 ppm, respec- tively, for 8.4 h/d, 5 d/wk (Holness et al. 1989; Ontario Ministry of the Envi- ronment 2001), although workers reported that exposure at the plant had aggra- vated specific problems including coughing, wheezing, nasal complaints, eye irritation, throat discomfort, and skin problems. Based on the lack of subjective symptoms and changes in spirometry, the EPA established a TWA NOAEL of 9.2 ppm (6.4 mg/m3). An uncertainty factor of 10 was applied to protect sensi- tive individuals and an additional factor of 3 was applied for deficiencies in the database, including the lack of chronic exposure data, the proximity of the LOAEL to the NOAEL, and the lack of reproductive and developmental studies. RfC values are meant to be protective of the entire population, including the elderly, children, and unusually sensitive individuals. SPACEFLIGHT EFFECTS None of the reported adverse effects of ammonia exposures are known to be affected by spaceflight other than transient nausea (spaceflight motion sick- ness) that lasts no more than 2 to 3 d.
58 SMACs for Selected Airborne Contaminants TABLE 3-7 Air Standards for Ammonia Set by Other Organizations Organization, Standard Value Reference ACGIH ACGIH 2001 TLV TWA 25 ppm (17 mg/m3) ACGIH 2001 STEL 35 ppm (27 mg/m3) OSHA 29 CFR 1910.1000 PEL TWA 50 ppm (35 mg/m3) NIOSH NIOSH 2005 REL TWA 25 ppm (17 mg/m3) NIOSH 2005 REL STEL 35 ppm (27 mg/m3) NIOSH 1996 IDLH 300 ppm EPA EPA 1991 RfCa 0.144 ppm (0.1 mg/m3) EPA 1991 NOAEL TWA 9.2 ppm (6.4 mg/m3) EPA 1991 NOAEL ADJ 3.3 ppm (2.3 mg/m3) EPA 1991 LOAEL HEC 2.8 ppm (1.9 mg/m3) a RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The basis for this calculation is explained in the EPA (1991) reference cited in Table 3-7. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; ADJ, adjusted; EPA, U.S. Environmental Protection Agency; HEC, human equivalent concentration; IDLH, immediately dangerous to life or health; LOAEL, lowest-observed- adverse-effect-level; NOAEL, no-observed-adverse-effect level; NIOSH, National Insti- tute for Occupational Safety and Health; OSHA, Occupational Safety and Health Ad- ministration; PEL, permissible exposure limit; REL, recommended exposure limit; RfC, reference concentration; STEL, short-term exposure limit; TLV, threshold limit value; TWA, time-weighted average. RECOMMENDATIONS FOR ADDITIONAL RESEARCH An extension of the study by Sundblad et al. (with a larger number of sub- jects and for continuous exposure durations of â¥24 h at ammonia concentrations between 5 and 25 ppm) is needed to test the assumption that ammonia concen- trations that are NOAELs at short exposure durations remain NOAELs at longer exposure durations. Because mucosal injury has been reported to occur without subjective complaints of irritation, the study should incorporate objective meas- ures of mucosal injury.
TABLE 3-8 ACs for Ammonia Uncertainty Factors Acceptable Concentrations, ppm Space Effect Exposure Data Species and Reference NOAEL Species Time flight 1h 24 h 7d 30 d 180 d 1,000 d Eye 30 ppm, Human LOAEL 1 1 1 30 NC NC NC NC NC irritation 10 min (MacEwen et al. 1970) Eye 20 ppm, Human LOAEL 1 1 1 NC 20 NC NC NC NC irritation occupational (Fergeson et al. 1977) (Vigliani and Zurlo 1955) Eye 20 ppm, Human 2 1 1 1 NC NC 10 10 10 10 irritation occupational (Fergeson et al. 1977) (Vigliani and Zurlo 1955) Eye 0, 5, 25 ppm, Human BMDL 1 1 1 NSa NSa 3 3 3 3 irritation 3h (Sundblad et al. 2004) Headache 0, 5, 25 ppm, Human BMDL 1 1 1 NSa NSa 8 8 8 8 3h (Sundblad et al. 2004) SMAC 30 20 3 3 3 3 a AC values for 1 and 24 h were previously set by King Lit Wong in 1994 and were not changed because these short-term limits, unlike the limits for exposures of >1 d, are set to allow minor adverse effects, thereby permitting the crew to attempt to clean up or contain minor releases if they can do so within about 24 h. Abbreviations: NC, not calculated; NS, not set in this document. 59
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