2
C3 to C8 Aliphatic Saturated Aldehydes

Shannon D. Langford, Ph.D.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas

BACKGROUND

Spacecraft maximum allowable concentrations (SMACs) of C3 to C8 straight-chain, aliphatic aldehydes have been established and were documented in Volume 4 of Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (James 2000). These aldehydes, shown in Table 2-1 with their associated physical properties, can enter habitable compartments of spacecraft and contaminate breathing air by several routes, including incomplete oxidation of alcohols in the environmental control and life support system air revitalization subsystem, as a by-product of human metabolism, through materials off-gassing, and during food preparation. These aldehydes have been detected in the atmosphere of manned space vehicles in the past. The National Aeronautics and Space Administration (NASA) analyzed air samples from the crew cabin of the Russian Mir Space Station and found that C3 to C8 aldehyde concentrations peaked at approximately 0.1 milligram per cubic meter (mg/m3) (James 2000, unpublished NASA technical data from 1995).

NASA has reviewed most existing reports pertaining to aliphatic aldehyde toxicity in support of establishing the SMACs published in 2000. This report is intended to be a companion document to complement and update James (2000) on C3 to C8 saturated aliphatic aldehyde SMACs. This update summarizes the approach taken in developing the existing SMACs, identifies recent data that may affect existing SMAC values, and establishes and provides rationale for a new 1,000-day SMAC.

REVIEW OF EXISTING SMACs AND SUMMARY OF ORIGINAL APPROACH

The initial review in 2000 resulted in establishment of 1- and 24-h as well



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2 C3 to C8 Aliphatic Saturated Aldehydes Shannon D. Langford, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas BACKGROUND Spacecraft maximum allowable concentrations (SMACs) of C3 to C8 straight-chain, aliphatic aldehydes have been established and were documented in Volume 4 of Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (James 2000). These aldehydes, shown in Table 2-1 with their associated physical properties, can enter habitable compartments of spacecraft and contaminate breathing air by several routes, including incomplete oxidation of alcohols in the environmental control and life support system air revitalization subsystem, as a by-product of human metabolism, through materi- als off-gassing, and during food preparation. These aldehydes have been de- tected in the atmosphere of manned space vehicles in the past. The National Aeronautics and Space Administration (NASA) analyzed air samples from the crew cabin of the Russian Mir Space Station and found that C3 to C8 aldehyde concentrations peaked at approximately 0.1 milligram per cubic meter (mg/m3) (James 2000, unpublished NASA technical data from 1995). NASA has reviewed most existing reports pertaining to aliphatic aldehyde toxicity in support of establishing the SMACs published in 2000. This report is intended to be a companion document to complement and update James (2000) on C3 to C8 saturated aliphatic aldehyde SMACs. This update summarizes the approach taken in developing the existing SMACs, identifies recent data that may affect existing SMAC values, and establishes and provides rationale for a new 1,000-day SMAC. REVIEW OF EXISTING SMACs AND SUMMARY OF ORIGINAL APPROACH The initial review in 2000 resulted in establishment of 1- and 24-h as well 34

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35 C3 to C8 Aliphatic Saturated Aldehydes as 7-, 30-, and 180-day SMACs for the C3 to C8 straight-chain, aliphatic alde- hydes. Table 2-2 presents the SMACs NASA established for these compounds. Respiratory irritation potential threshold data from rats and mice indicate similar properties (sensory irritation) within this group of compounds and the closely related acetaldehydes (Sim and Pattle 1957; Steinhagen and Barrow 1984; Babiuk et al. 1985). Because the C3 to C8 aldehydes exhibited similar toxicities for this particular end point, the Committee on Spacecraft Exposure Guidelines chose to establish SMACs for these compounds as a group instead of setting a separate SMAC for each compound. The toxicological end points of concern identified previously include mucosal irritation, nasal-cavity injury, nausea and vomiting, and liver damage. SMACs for each exposure time were selected based on the most conservative acceptable concentration (AC) for each toxicological end point. Protection Against Mucosal Irritation An early study reported that exposure to propanal at 134 parts per million (ppm) for 30 min was mildly irritating to mucosal surfaces in humans (Sim and Pattle 1957). The same study found that exposure to 230 ppm butanal and 207 ppm isobutanal for 30 min was not irritating to human subjects. Human data were available only for the three aldehydes propanal, butanal, and isobutanal. However, animal data available at the time indicated the possibility that other aldehydes in the group may be two to three times more irritating than propanal (Salem and Cullumbine 1960; Abdo et al. 1998). Thus, ACs for the 1- and 24-h SMACs based on mucosal irritation were set at 50 ppm (Equation 1). TABLE 2-1 Physical Properties of C3 to C8 Straight-Chain Aliphatic Aldehydes Name Propanal Butanal Pentanal Hexanal Heptanal Octanal CH3(CH2)nCHO: n=1 n=2 n=3 n=4 n=5 n=6 CAS no.: 123-38-6 123-72-8 110-62-3 66-25-1 111-71-7 124-13-0 Molecular weight: 58.1 72.1 86.1 100.2 114.2 128.2 Boiling point (°C): 49 76 103 128 154 171 Melting point (°C): –81 –99 –92 –56 –45 N/A Vapor pressure 687 92 50 10 3 N/A (mmHg): (At °C): 45 20 25 20 25 N/A a Conversion factors 2.3 mg/m3 1 ppm = 2.9 3.5 4.1 4.6 5.2 3 1 mg/m = 0.422 ppm 0.340 0.284 0.245 0.215 0.191 a 1 ppm converted to mg/m3, and 1 mg/m3 converted to ppm. Abbreviations: CAS, Chemical Abstracts Service; N/A, not available; ppm, parts per million; mg/m3, milligrams per cubic meter.

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36 SMACs for Selected Airborne Contaminants TABLE 2-2 SMACs for C3 to C8 Aliphatic Saturated Aldehydes from James (2000) mg/m3 Duration Ppm Toxic End Point to Avoid 125-250a 1h 50 Mucosal irritation 24 h 50 125-250 Mucosal irritation 7d 6 15-30 Liver injury, mucosal irritation 30 d 1.5 4-8 Liver injury 180 d 1.5 4-8 Liver injury a Value depends on molecular weight of the aldehyde. Source: James 2000, P. 52. 134 ppm(LOAEL) reduced downward by a factor of 2 to 3 1- and 24-h AC(mucosal irritation) = 50 ppm (1) where LOAEL is lowest-observed-adverse-effect level. Although short-term ACs were established conservatively to protect against mucosal irritation, some risk of this toxicological end point is allowed. However, for exposure durations exceeding 24 h, mucosal irritation should be precluded. Therefore, the NASA 7-, 30-, and 180-d SMACs based on mucosal irritation were established by dividing the human-derived mildly irritating con- centration of 134 ppm for propanal (Sim and Pattle 1957) by 10, yielding an AC of 13 ppm (James 2000) (Equation 2). 7-, 30-, and 180-day AC(mucosal irritation) = 134 ppm (LOAEL) × 1/10 (LOAEL to NOAEL) = 13 ppm (2) Protection Against Nasal-Cavity Injury Long-term studies of isobutanal exposure in rats and mice were used to es- timate ACs protective for injury to the nasal cavity (squamous metaplasia and olfactory epithelial degeneration in the nose) (Abdo et al. 1998). In the first study of this report, an isobutanal vapor cumulative exposure time of 390 h (6 h/d, 5 d/wk for up to 13 wk) resulted in a no-observed-adverse-effect level (NOAEL) of 500 ppm in rats and mice. Similarly, 500 ppm was reported as the LOAEL in female rats. In the second study from this report, the cumulative ex- posure time to isobutanal vapor was 3,120 h (6 h/d, 5 d/wk for 2 y). NASA ACs protective of nasal-cavity injury based on the NOAEL and LOAEL values from Abdo et al. (1998) are shown in Equations 3, 4, 5: 7-day AC(nasal-cavity injury) = 500 ppm (NOAEL) × 1/10 (species factor) = 50 ppm (3) 30-day AC(nasal-cavity injury) = 500 ppm (NOAEL) × 1/10 (species factor) × 390 h/720 h (time extrapolation) = 27 ppm (4)

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37 C3 to C8 Aliphatic Saturated Aldehydes 180-day AC(nasal-cavity injury) = 500 ppm (LOAEL) × 1/3 (LOAEL to NOAEL) × 1/10 (species factor) × 3,120 h/4,320 h (time extrapolation) = 12 ppm (5) Protection Against Liver Injury ACs protective against possible liver injury from accumulation of organic acids from aldehyde metabolism were conservatively set at 6.4 ppm (7-d AC) and 1.5 ppm (30- and 180-d AC) (James 2000). The choice of liver injury as a presumptive toxicological end point was based on the observation of vacuoles within hepatocytes of rats exposed six times to 1,300 ppm propanal for 6 h each exposure (Gage 1970). To derive the ACs, NASA used, as a point of departure, the 90-ppm exposure level reported by Gage (20 exposures of 6 h each) to yield no observable liver changes (cumulative exposure of 120 h). It was assumed that harmful metabolites would not accumulate in liver cells below a threshold expo- sure concentration. Extrapolations to adjust for exposure duration based on ap- plication of Haber’s rule would correct the AC to a level below this threshold concentration. The resulting NASA ACs protective for liver injury are shown in Equations 6 and 7: 7-day AC(liver injury) = 90 ppm (NOAEL) × 1/10 (species factor) × 120 h/168 h (time extrapolation) = 6.4 ppm (6) 30- and 180-d AC(liver injury) = 90 ppm (NOAEL) × 1/10 (species factor) × 120 h/720 h (time extrapolation) = 1.5 ppm (7) As reviewed previously, the toxicities of the C3 to C8 aliphatic saturated aldehydes appear to be similar (James 2000). Upon review of the AC established for each toxicological end point, group SMACs were established for toxic ef- fects by selecting the acceptable concentration for the most active compound for that end point. Table 2-3 presents the individual ACs for each toxicological end point of concern. SUMMARY OF NEW RELEVANT DATA FROM LITERATURE No toxicity studies (including those examining relevant routes of pulmo- nary exposure) since 2000 with a bearing on C3 to C8 aliphatic saturated alde- hydes SMACs were located during this assessment. ADDITIONAL CONSIDERATION OF NONTOXIC ODOR THRESHOLD The group of C3 to C8 aliphatic saturated aldehydes have different odors, described as agreeably fruity to choking and suffocating (Furia and Bellanca 1975; Furia 1980; U.S. Coast Guard 1985; NFPA 1986; NIOSH 1994). The re-

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38 SMACs for Selected Airborne Contaminants ported odor threshold for one aldehyde in this group, pentanal (the only member of the group for which an odor threshold value is available), is 0.028 ppm (Amoore and Hautala 1983). Table 2-4 summarizes reported odor characteristics for the C3 to C8 aliphatic saturated aldehydes. Odor thresholds—the lowest concentration of a chemical in the air that people can smell—are imprecise measurements. Humans exhibit a wide sensi- tivity to odors, which can be further affected by factors such as illness. Because odor threshold detection can vary, the concentrations are often reported as ranges. Odor threshold values are not absolute points but rather an average of the sampled populations’ response. In addition, “fruity,” “choking,” and “suffo- cating” are descriptions of smells individuals have reported. In the case of many chemicals, continued exposure to a chemical odor can also affect detection of the odor. Olfactory adaptation is a very common phenomenon that results from continued exposure to an odor and is characterized by a reduction or loss in smell sensitivity to a particular chemical (Pryor et al. 1970). The lowest concentration of a chemical causing acute stinging, burning sensations, or tear generation in the nose and eyes is reported as the irritation threshold value. These values are distinctly different from odor thresholds and usually require higher ambient chemical concentrations to elicit an irritation response compared with detection of odor (Amoore and Hautala 1983). Acetal- dehyde, although not included in the group of C3 to C8 aldehydes, exhibits hu- man irritancy similar to that of pentanal and propanal. As with propanal, human subjects exposed for 30 min to 134 ppm acetaldehyde reportedly experienced slight irritation (Sim and Pattle 1957). Acetaldehyde has a pungent suffocating odor with an odor threshold of 0.05 ppm and a threshold limit value of 25 ppm, very similar to values for propanal and pentanal (Amoore and Hautala 1983; EPA 1987; ACGIH 1999). Amoore and Hautala (1983) reported an irritation threshold of 2,200 ppm for the nose and an ocular level of 11,000 ppm for acet- TABLE 2-3 Acceptable Concentrations for Identified Toxicological End Points, 2000 Uncertainty Factors Acceptable Concentration (ppm) Space End Point Species flight NOAEL Time 1h 24 h 7d 30 d 180 d Mucosal 2-3 1 1 1 50 50 — — — Irritation 10 1 1 1 — — 13 13 13 Nasal-cavity 1 HR 10 1 — — 50 27 — injury 3 HR 10 1 — — — — 12 Liver injury 1 HRthreshold 10 1 — — 6 1.5 1.5 SMACsa 50 50 6 1.5 1.5 a SMACs for each exposure time are selected based on the most conservative AC for each toxicological end point. Abbreviation: HR, Haber’s rule.

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39 C3 to C8 Aliphatic Saturated Aldehydes TABLE 2-4 Selected Odor Characteristics of C3 to C8 Aliphatic Saturated Aldehydes Compound Odor Odor Threshold Reference Propanal Suffocating, fruity, Not available Furia and Bellanca 1975; similar to acetaldehyde, Furia 1980; USCG 1985; pungent, unpleasant, NFPA 1986 choking Butanal Pungent, aldehyde Not available Lewis 1997 Pentanal Powerful, acrid, 0.028 ppm Amoore and Hautala pungent, strong 1983; NIOSH 1994 Hexanal Fruity, strong green Not available Furia and Bellanca 1975; grass, sharp aldehyde Furia 1980; Lewis 1997 Heptanal Fatty pungent, Not available Furia 1980; Budavari 1989 penetrating fruity Octanal Sharp fatty, fruity Not available Furia and Bellanca 1975 Abbreviations: NFPA, National Fire Protection Association; NIOSH, National Institute for Occupational Safety and Health; USCG, U.S. Coast Guard. aldehyde—approximately 44,000 times higher (nose) than the odor threshold value for this compound. Amoore and Hautala (1983) classified both acetalde- hyde and pentanal as “Class A” substances, which can serve as bellwether indi- cators because their odor threshold values are much lower than their threshold limit values. The low odor threshold of pentanal (and, by inference, the other C3 to C8 aldehydes) could serve as a means to alert spacecraft crew to the presence of a substance at levels far lower than would be expected to cause toxicological ef- fects. Granted, crew could experience smell aversion as a result of exposure to noxious chemical smells. Although such aversion could impede crew perform- ance, it should not be categorized as a toxic effect. Therefore, odor threshold values are not used here as a toxicological end point. The odor threshold for pentanal (0.028 ppm) is several times higher than the lowest SMAC values for the C3 to C8 aldehydes (about 143 times higher). Therefore, it is understood that the SMAC levels, which are designed to protect against adverse health effects, will not necessarily prevent spacecraft crew from experiencing smell aversion due to noxious odors. REVISION OF EXISTING SMACs AND ESTABLISHMENT OF 1,000-DAY SMAC After review of the studies considered in setting the original SMACs in 2000, the Committee on Spacecraft Exposure Guidelines decided to revise all the ACs for the C3 to C8 aldehydes.

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40 SMACs for Selected Airborne Contaminants The uncertainty factor of 2 to 3 originally applied to the acute 1- and 24-h SMAC in 2000 will be revised to a factor of 3. A factor of 3 is considered the most conservative for this group of aldehydes and reflects animal data suggest- ing that some members of this group of compounds are two to three times more irritating than the base compound—propanal (Salem and Cullumbine 1960; Abdo et al. 1998). The 1- and 24-h ACs remain based on the point of departure of 134 ppm (mildly irritating to mucosal surfaces after 30 min of exposure in humans) (Sim and Pattle 1957). Therefore, the revised 1- and 24-h C3 to C8 aldehyde SMACs based on mucosal irritation are set at 45 ppm (Equation 8). 1- and 24-h AC(mucosal irritation) = 134 ppm (LOAEL) × 1/3 (safety factor) = 45 ppm (8) The 2006 Committee revisited the original rationale used in setting the 7- through 180-d SMACs in 2000. In 2000, the long-term SMACs were predicated on protecting against liver pathology, which was based on acute (5-d) exposure data from rats (Gage 1970). The study reported by Gage used discontinuous exposures to propanal. The 2000 SMACs then used a factor to correct for con- tinuous versus discontinuous exposure conditions. No additional factors were applied to account for differences in the duration of exposure (5 d to 7, 30, or 180 d) based on the assumption that a threshold dose, below which no liver pa- thology would occur, had been established. However, upon reevaluation, the acute exposure protocol and the now questioned relationship between cellular vacuoles and liver pathology eliminated use of the NOAEL reported by Gage as a point of departure for the longer-term SMACs. The Committee chose instead to select the study of Abdo et al. (1998). This study design more closely corre- sponds to exposure durations bounded by the longer-term SMACs (7 through 1,000 d). In addition, the end point (squamous metaplasia of respiratory epithe- lium) was believed to be more toxicologically appropriate and defensible. Abdo et al. used exposure of rats and mice to select concentrations of iso- butanal vapor for 6 h/d, 5 d/wk, for up to 13 wk or 2 y. The 13-wk study re- vealed a NOAEL of 500 ppm in both rats and mice, whereas the 2-y study re- vealed a LOAEL of 500 ppm in female rats. The LOAEL of 500 ppm reported for female rats exposed for 2 y was selected as the point of departure for the 7- through 1,000-day SMACs. A factor of 10 was applied to extrapolate from a LOAEL to a NOAEL. A correction factor of 3 was applied to account for inter- species differences in response. Finally, a factor of 3 was applied, as was the case for the new 1- and 24-h ACs (discussed previously), to reflect animal data suggesting differences in irritating potential for these aldehydes (Salem and Cul- lumbine 1960; Abdo et al. 1998). The revised 7-, 30-, and 180-d and the new 1,000-d SMACs based on nasal-cavity injury are set at 5 ppm (Equation 9). 7- through 1,000-d AC(nasal-cavity injury) = 500 ppm (LOAEL) × 1/10 (LOAEL to NOAEL) × 1/3 (species factor) × 1/3 (safety factor) = 5 ppm (9)

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41 C3 to C8 Aliphatic Saturated Aldehydes The 2008 SMACs for C3 to C8 aliphatic saturated aldehydes are presented in Table 2-5. DIFFERENCES BETWEEN ORIGINAL AND CURRENT APPROACH OF THE NATIONAL RESEARCH COUNCIL COMMITTEE ON TOXICOLOGY The National Research Council (NRC) Committee on Toxicology, as well as other regulatory bodies, is primarily interested in using benchmark dose mod- eling (BMD) to interpret toxicological data, as BMD modeling is favored over traditional threshold dose (NOAEL, LOAEL) methods, since it allows for greater use of the available data. The NRC recommends that BMD methods be used when sufficient and appropriate dose-response data are available (NRC 2000). However, the NOAEL/LOAEL-based method is recommended by the NRC in the absence of sufficient data or when special considerations are war- ranted. The original SMACs for C3 to C8 straight-chain, aliphatic aldehydes were established based on a LOAEL/NOAEL and uncertainty factor method. BMD methodology was applied to data from the long-term SMAC (7- through 1,000- d) study of Abdo et al. (1998). The BMD analysis is summarized below. Background for BMD Analysis of Long-Term Exposure Data Isobutyraldehyde was administered to male and female F344/N rats and to B6C3F1 mice by inhalation (6 h/d, 5 d/wk) for up to 13 wk or 2 y (Abdo et al. 1998). These results were used to the calculate benchmark concentration (BMC) for various toxic effects. Uncertainty factors were applied to the lower 95% con- fidence limit of the benchmark concentration (BMCL) to arrive at maximum allowable concentrations. These values are compared with the proposed current SMACs. TABLE 2-5 SMACs for C3 to C8 Aliphatic Saturated Aldehydes, 2008 mg/m3 Duration ppm Toxic End Point to Avoid 1h 45 113 Mucosal irritation 24 h 45 113 Mucosal irritation 7d 5 11.8 Nasal-cavity injury 30 d 5 11.8 Nasal-cavity injury 180 d 5 11.8 Nasal-cavity injury 1,000 d 5 11.8 Nasal-cavity injury Note: A representative average odor threshold concentration for the C3 to C8 aliphatic saturated aldehydes is 0.028 ppm (pentanal) (Amoore and Hautala 1983). Some alde- hydes in this group exhibit strong noxious odors detectable by humans at levels well be- low SMAC levels for these compounds.

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42 SMACs for Selected Airborne Contaminants 13-Week Exposures Reported by Abdo et al. 1998 Ten animals per group were exposed to 0, 500, 1,000, 2,000, 4,000, and 8,000 ppm of isobutyraldehyde. All rats died at 8,000 ppm and three male and six female rats died at 4,000 ppm. All mice died at 8,000 ppm, and all except one mouse, a male, died at 4,000 ppm. Body weight gains were reduced at 4,000 ppm in both sexes of rats and at 1,000 ppm in both sexes of mice. Several end points could not be ascertained at 8,000 ppm. Hence, data from the 8,000-ppm group were not used for estimating low-dose BMCs. Incidence rates for the most sensitive end point for each sex of rats and mice are listed in Table 2-6. Because the multistage model can describe a wide variety of dose- response shapes, it was used to estimate the dose-response relationships. BMCs and BMCLs associated with an excess risk of 10% (BMC10 and BMCL10) are listed in Table 2-6. Using the BMCL10 as a point of departure for establishing a maximum allowable concentration is generally more conservative (stringent) than using the NOAEL. Consistent with the calculation of SMACs, an uncertainty factor of 10 was used for interspecies extrapolation; no uncertainty factor was used for intraspe- cies variability or a potential risk at the point of departure (NOAEL or BMCL). Further, adjustment for the duration of exposure used Haber’s rule, which as- sumes equal toxic effects for equal cumulative exposures. Hence, experimental exposures of 6 h/d for 5 d/wk are assumed to be equivalent to continuous expo- sures of (6/24) × (5 / 7) = 0.18 times the exposure administered over the (13 × 7) = 91 d. The most sensitive end point, lowest BMCL10 = 340 ppm, occurred for se- rous exudate in male mice (Table 2-6). This results in a 30-d SMAC of 30-d SMAC = 340 (BMCL10) × 1/10 (interspecies) × [6 / 24 × 5/7] (discontin. to contin.) × 91/30 (time extrapolation) = 18.4 ppm and a 180-d SMAC of 180-d SMAC= 340 (BMCL10) × 1/10 (interspecies) × [6/24 × 5/7] (discontin. to contin.) × 91/180 (time extrapolation) = 3.1 ppm These results are complementary to the proposed SMAC of 5 ppm, which is based on a LOAEL/NOAEL method. Further, average severity scores were examined by using a polynomial model with the dose-response data procedure for continuous data in the EPA Benchmark Dose Software program. The most sensitive end point for severity was for olfactory epithelium degeneration in male rats. The benchmark response corresponding to an average severity grade of 1 (minimal effect) produced a BMCL of 1,110 ppm, which exceeds the minimum BMCL of 340 ppm obtained for the incidences of effects.

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43 C3 to C8 Aliphatic Saturated Aldehydes TABLE 2-6 Incidence of Effects in the Most Sensitive End Point in Each Sex of Rats and Mice (10 Animals per Dose Group) and Estimates of BMC10 and BMCL10 for 13-wk Exposures Exposure (ppm) BMC BMCL Species/Sex End Point (ppm) (ppm) 0 500 1,000 2,000 4,000 Rat (male) 0 0 0 10 10 880 680 Olfactory epithelium degeneration Rat (female) 2 6 2 0 10 2,030 1,000 Suppurative inflammation Mice (male) 0 2 0 4 10 1,000 340 Serous exudate Mice (female) 0 0 0 3 10 1,480 1,020 Serous exudate Two-Year Exposures Reported by Abdo et al. 1998 Initially, 50 animals per group were exposed to 0, 500, 1,000, and 2,000 ppm of isobutyraldehyde. Incidence rates for the most sensitive end point for each sex of rats and mice are listed in Table 2-7. Because the multistage model can describe a wide variety of dose-response shapes, it was used to estimate the dose-response relationships. BMCs and BMCLs associated with an excess risk of 5% (BMC5 and BMCL5) are listed in Table 2-7. With 50 animals per group, at least 5 animals (10%) with an effect are required to achieve a statistically sig- nificant increase (P ≤ 0.05) above a background of 0 of 50 animals with the ef- fect. However, using the BMCL5 rather than the BMCL10 as a point of departure for establishing a maximum allowable concentration is generally more conserva- tive (stringent) than using the NOAEL. Consistent with the calculation of SMACs, an uncertainty factor of 10 was used for interspecies extrapolation; no uncertainty factor was used for intraspe- cies variability or a potential risk at the point of departure (NOAEL or BMCL). Further, adjustment for the duration of exposure used Haber’s rule, which as- sumes equal toxic effects for equal cumulative exposures. Hence, experimental exposures of 6 h/d for 5 d/wk are adjusted by the factor (6/24) × (5/7) for equivalency to continuous exposure. The most sensitive end point (lowest BMCL5 = 150 ppm) occurred for respiratory epithelium squamous metaplasia in female rats (Table 2-7). Pre- sumably, a 2-y lifetime exposure in rodents would be adequate to provide pro- tection for a 1,000-d exposure to humans. The resulting 1,000-d SMAC is 1,000-d SMAC = 150 (BMCL5) × 1/10 (interspecies) × [6/24 × 5/7] (discontin. to contin.) = 2.7 ppm

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44 SMACs for Selected Airborne Contaminants TABLE 2-7 Incidence of Effects and Estimates of BMC5 and BMCL5 for 2-y Exposures Exposure (ppm) BMC BMCL Species/Sex End Point (ppm) (ppm) 0 500 1,000 2,000 Respiratory epithelium squamous metaplasia 1/50a Rat (male) 1/49 10/49 44/50 590 450 Rat (female) 1/49 11/50 9/49 44/50 270 150 Olfactory epithelium degeneration Mice (male) 0/50 0/50 11/50 45/50 580 480 Mice (female) 1/50 1/50 27/50 49/50 440 320 a Observed/total. These results again are indistinguishable from (within a factor of 2) the proposed SMAC of 5 ppm, which is based on a LOAEL/NOAEL method. Further, average severity scores were examined by using a polynomial model with the dose-response data procedure for continuous data in the EPA Benchmark Dose Software program. The most sensitive end point for severity was for olfactory epithelium degeneration in female mice. The benchmark re- sponse corresponding to an average severity grade of 1 (minimal effect) pro- duced a BMCL of 1,420 ppm, which exceeds the minimum BMCL of 150 ppm obtained for the incidences of effects. Therefore, the lower BMCL value (for incidence rather than severity) will be used to develop a proposed SMAC. Summary of Conclusions from BMD Analyses Results from the 13-wk exposures to isobutyraldehyde were used to calcu- late 30- and 180-d SMACs. The most sensitive end point was the incidence of serous exudate in male mice, leading to 30- and 180-d SMACs of 18.4 and 3.1 ppm, respectively. The most sensitive end point from the 2-y exposures was the incidence of respiratory epithelium squamous metaplasia in female rats produc- ing a 1,000-d SMAC of 2.7 ppm. The proposed 7- to 1,000-d SMAC of 5 ppm, derived via application of a LOAEL/NOAEL method should provide protection for the effects observed in the study by Abdo et al. (1998). COMPARISON WITH OTHER AIR-QUALITY LIMITS Exposure guidelines for a limited subset of C3 to C8 aliphatic saturated aldehydes exist with various public health and occupational health entities as well as with industry and government advisory bodies. Table 2-8 lists of some of these guidelines and regulatory standards for comparison with the current and proposed NASA SMACs.

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45 C3 to C8 Aliphatic Saturated Aldehydes TABLE 2-8 Selected Inhalation Exposure Levels for Selected C3 to C8 Aliphatic Saturated Aldehydes Organization/ Compound Reference Exposure Guideline Exposure Level Propanal ACGIH 2004 TLV (8 h TWA) 20 ppm Pentanal ACGIH 2005 TLV (8 h TWA) 50 ppm Pentanal NIOSH 2005 REL (10 h TWA) 50 ppm Butanal AIHA 2003 WEEL (8 h TWA) 25 ppm NASAa C3 to C8 aliphatic SMAC (1 h and 24 h) 45 ppm aldehydes a Only 1- and 24-h SMACs are listed here for comparison with similar exposure duration guidelines from other organizations. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AIHA, American Industrial Hygiene Association; NIOSH, National Institute for Occupa- tional Safety and Health; REL, recommended exposure limit; TLV, threshold limit value; TWA, time-weighted average; WEEL, workplace environmental exposure level. The current NASA 1- and 24-h SMACs are very similar to exposure levels from other organizations at comparable exposure durations. Exposure limits and guidelines for pentanal (for which values are available for comparison) have remained stable for several years. No guidelines are available for long-term ex- posure durations to compare with the 7-, 30-, 180-, and 1,000-d SMACs. RECOMMENDATIONS FOR ADDITIONAL RESEARCH Shortcomings in the toxicity database pertaining to C3 to C8 aliphatic saturated aldehydes persist. Lack of data on the effects of acute (humans) and chronic (humans and animals) exposures as well as lack of data elucidating the nonlethal exposure effects to animals confounds attempts to establish exposure guidelines. Recommendations for additional research pertaining to toxicity of this group of aldehydes are unchanged from those proposed by James (2000). Increasing the number of exposure concentrations used as well as expanding the end point measurements examined for all aldehydes in this group would be most beneficial. The long-term exposure guidelines established here are designed to protect against nasal epithelial squamous metaplasia. Long-term pulmonary studies would be beneficial in confirming and extending the work of Gage (1970) and validating the protective assumptions made in establishing our in- termediate and long-term SMACs. REFERENCES Abdo, K.M., J.K. Haseman, and A. Nyska. 1998. Isobutyraldehyde administered by inha- lation (whole body exposure) for up to 13 weeks or 2 years was a respiratory tract

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