2

Chloroacetaldehyde
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Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1 This document was prepared by the AEGL Development Team composed of Peter Bos (RIVM, The Dutch National Institute of Public Health and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager Marinelle Payton (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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2 Chloroacetaldehyde1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Peter Bos (RIVM, The Dutch National Institute of Public Health and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager Marinelle Payton (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazard- ous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 48

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49 Chloroacetaldehyde effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Chloroacetaldehyde is a colorless, volatile liquid with an acrid, penetrating odor. It evaporates easily and dissolves in water. It is not flammable, but va- por/air mixtures may be explosive at temperatures above 88°C. Chloroacetalde- hyde can exist in combinations of four forms: monomer, monomer hydrate, dimer hydrate, and cyclic trimer. Commercial aqueous solution of chloroacetal- dehyde (45%) contains a 50:50 mixture of the monomer and dimer hydrates. Chloroacetaldehyde is predominantly used as a chemical intermediate in the manufacture of 2-aminothiazole and other compounds, in the control of algae, bacteria, and fungi in water, and in a spinning solution of poly β-alanine. The toxicity database on chloroacetaldehyde is poor. Apart from a brief statement indicating that a concentration of 10 ppm produced lacrimation and nasal irritation in humans, no information was available on human toxicity. Chloroacetaldehyde is known to be a strong corrosive agent. The predominant effect of chloroacetaldehyde in animals is direct, strong irritation of the eyes, nose, and lungs (resulting in pulmonary edema and death), and has a very steep concentration-response relationship. The best studies of these effects are by Dow Chemical Company (1952) and Arts (1987). The first study exposed mice, rats, and guinea pigs to chloroacetaldehyde at several concentrations and expo- sure duration, ranging from 400 ppm for 6 min to 10 ppm for 7 h. Rats, mice, and guinea pigs were also exposed repeatedly (eight exposures in 10 days) to

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50 Acute Exposure Guideline Levels chloroacetaldehyde at 5 ppm for 7 h (Dow Chemical Company 1952). In the second study, rats were exposed at concentrations of 44-2,643 ppm for 1 h (Arts 1987). Both studies focused on mortality and reported nonlethal effects in a gen- eral manner. In rats, the lowest concentration-time combinations that induced lethality ranged from 25 ppm for 7 h (19 of 20 rats died) to 400 ppm for 0.1 h (1 of 20 rats died). No deaths were reported at concentration-time combinations ranging from 10 ppm for 7 h to 100 ppm for 12 min. Lethality increased both with concentration and with duration. A 1-h LC50 (lethal concentration, 50% lethality) for rats was estimated to fall between 203 and 243 ppm. Guinea pigs were less sensitive to chloroacetaldehyde than rats. Nonlethal effects observed in these studies included ocular and nasal irri- tation. Irritation was slight after repeated exposure to chloroacetaldehyde at 5 ppm, and was more pronounced after single exposures at concentrations greater than 10 ppm. Pulmonary edema was found in some rats 2 weeks after being ex- posed to chloroacetaldehyde at 44 ppm for 1 h. Animals in this study also exhib- ited closed eyes and salivation. Pulmonary effects became more severe with increasing concentrations in some animals that died. Studies of the neurotoxicity of chloroacetaldehyde were not found; how- ever, indirect evidence from experiments with the anticancer drugs ifosfamide and cyclophosphamide (chloroacetaldehyde is a main metabolite of these drugs) suggests that it may have neurotoxic effects. In addition, chloroacetaldehyde was found to be mutagenic in several stains of Salmonella typhimurium, Asper- gillus nidulans, Streptomyces coelicolor, and Chinese hamster V79 cells. Little information was available on the carcinogenicity of chloroacetaldehyde. AEGL-1 values are based on nasal and ocular irritation observed in rats af- ter a single exposure to chloroacetaldehyde at concentrations of 10 ppm and higher. Slight irritation was also observed in rabbits, rats, and mice, but not guinea pigs, after repeated exposure to chloroacetaldehyde at 5 ppm (7 h/day) (Dow Chemical Company 1952). Irritation was reported to be related to both concentration and exposure duration. A concentration of 5 ppm was chosen as the point of departure for the AEGL-1 values. A modifying factor of 2 was ap- plied to reduce that concentration to a no-effect level. With the exception of the 10-min AEGL value, time scaling was performed using the equation Cn × t = k. The value of n was determined to be 1.2 based on mortality data. A total uncer- tainty factor of 10 (two factors of 3) was considered sufficient for toxicokinetic and toxicodynamic differences between species and for individual variability, and no relevant differences in kinetics were assumed (the effects are attributed to direct interaction of chloroacetaldehyde with the mucous membranes of the nose and eyes). The 10-min AEGL-1 was set equal to the 30-min value, because extrapolation from a 7-h exposure to a 10-min value had too much uncertainty. The report of lacrimation and nasal irritation in humans within a few minutes of exposure to chloroacetaldehyde at 10 ppm (Dow Chemical Company 1952) pro- vided supporting data to derive AEGL-1 values on the basis of the rat data. AEGL-2 values are based on impaired pulmonary function in rats. Data from a well-performed and adequately documented study in rats (Arts 1987)

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51 Chloroacetaldehyde were chosen for the point of departure for the 1-h AEGL value. A 1-h exposure at 44 ppm (the lowest concentration tested) resulted in pulmonary edema in some animals that were killed at the end of a 2-week observation period. A modifying factor of 2 was applied to derive a no-effect level. A larger modifying factor was considered unnecessary because of the steep concentration-response curve of chloroacetaldehyde. Analogous to AEGL-1 values, a total uncertainty factor of 10 was used to derive the AEGL-2 values; a larger uncertainty factor would lead to unrealistically low values. AEGL-2 values for other time periods were derived by time scaling. For AEGL-3 values, two studies of the acute lethality of chloroacetalde- hyde (Dow Chemical Company 1952; Arts 1987) were considered. The mortal- ity data showed a steep concentration-response curve; mortality shifted from 0% to close to 100% when concentration or exposure duration was doubled. Mortal- ity data from the Arts (1987) study, in which rats were exposed to chloroacetal- dehyde at 44-2,643 ppm for 1 h, was modeled using EPA benchmark dose soft- ware (version 1.3.2) (EPA 2005). A benchmark concentration associated with a 5% response (BMC05) of 136 ppm was calculated, with a lower 95% confidence limit (BMCL05) of 99 ppm. Application of a total uncertainty factor of 10, on the same basis as it used in deriving AEGL-1 and AEGL-2 values results, in a 1-h AEGL value of 9.9 ppm. AEGL-3 values for the other time periods were derived by time scaling. The AEGL values for chloroacetaldehyde are presented in Table 2-1. TABLE 2-1 Summary of AEGL Values for Chloroacetaldehyde End Point (Reference) Classification 10 min 30 min 1h 4h 8h AEGL-1 2.3 ppm 2.3 ppm 1.3 ppm 0.40 ppm 0.22 ppm Ocular and (nondisabling) (7.4 (7.4 (4.2 (1.3 (0.71 nasal mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) irritation (Dow Chemical Company 1952) AEGL-2 9.8 ppm 3.9 ppm 2.2 ppm 0.69 ppm 0.39 ppm Pulmonary (disabling) (31 (13 (7.1 (2.2 (1.5 edema mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Arts 1987) AEGL-3 44 ppm 18 ppm 9.9 ppm 3.1 ppm 1.8 ppm Mortality, (lethal) (140 (57 (32 (10 (5.6 BMCL05 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Dow Chemical Company 1952; Arts 1987)

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52 Acute Exposure Guideline Levels 1. INTRODUCTION Chloroacetaldehyde is a colorless, volatile liquid with an acrid, penetrating odor. It evaporates easily and dissolves in water. Chloroacetaldehyde is not flammable, but vapor/air mixtures may be explosive at temperatures above 88°C (see Table 2-2). Chloroacetaldehyde can exist in combinations of four forms depending on how it was prepared: monomer, monomer hydrate, dimer hydrate, and cyclic trimer (Elmore et al. 1976). The monomer and dimer hydrates are formed in- stantly when the anhydrous monomer is added to water. The cyclic trimer is formed from the anhydrous monomer upon standing under dry conditions. The cyclic trimer is only slightly soluble in water, but the monomer and dimer hy- drates are formed when the cyclic trimer is heated in water. The anhydrous monomer is obtained by cracking the cyclic trimer. Commercial aqueous solution of chloroacetaldehyde (45%) contains a 50:50 mixture of the monomer and dimer hydrates (Elmore et al. 1976). The two hydrates are dehydrated and converted to the monomer under gas-liquid phase chromatography conditions. Chloroacetaldehyde is sufficiently stable to permit its direct collection on silica gel and subsequent storage in a freezer. TABLE 2-2 Chemical and Physical Properties for Chloroacetaldehyde Parameter Value Reference CAS registry no. 107-20-0 HSDB 2009 Synonyms Monochloroacetaldehyde; 2-chloro-1-ethanal Budavari et al. 1989 Chemical formula C2H3ClO Budavari et al. 1989 Molecular weight 78.50 Budavari et al. 1989 Physical state Liquid Budavari et al. 1989 Color Colorless HSDB 2009 Odor Acrid, penetrating Budavari et al. 1989 Melting point -16.3°C (40% aqueous solution) IPCS 2005 Boiling point 85-86°C (pure) Budavari et al. 1989 85-100°C IPCS 2005 90-100°C (40% aqueous solution) OSHA 1989 Vapor density (air = 1) 2.7 IPCS 2005 Liquid density 1.19 (40% aqueous solution) IPCS 2005 (water = 1) Solubility in water Yes Budavari et al. 1989 Vapor pressure 100 mm Hg at 45°C (40% aqueous solution) NIOSH 1991 110 mm Hg at 20°C HSDB 2009 Explosive Vapor/air mixtures may be explosive IPCS 2005 (40% aqueous solution) above 88°C 1 mg/m3 = 0.312 ppm Conversion factors NIOSH 2011 1 ppm = 3.21 mg/m3

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53 Chloroacetaldehyde No current information was found on the chemical production of chloroacetaldehyde. The amount of chloroacetaldehyde manufactured or im- ported in the United States in 1977 was reported to be 1-10 million pounds (EPA 1987). Chloroacetaldehyde is used primarily as a chemical intermediate (EPA 1987) in the manufacture of 2-aminothiazole and other compounds (ACGIH 1991). It is also used in the control of algae, bacteria, and fungi in water, and in a spinning solution of poly β-alanine (ACGIH 1991). Furthermore, it has its application in tree-trunk debarking operations and in analytical chemistry as a fluorescent label (McCann 1975). 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No case reports on human deaths from acute exposure to chloroacetalde- hyde were found. 2.2. Nonlethal Toxicity Case reports of nonlethal toxicity in humans were not found, nor were oc- cupational or epidemiologic studies available. A report of the Dow Chemical Company (1952) on acute mortality in experimental animals stated the follow- ing: “Every concentration employed including the lowest (10 ppm) produced lacrimation and nasal irritation in humans within a few minutes.” No additional details were provided. Several studies have investigated the toxicity of the antineoplastic agent ifosfamide which indicate a causative role for chloroacetaldehyde (the main me- tabolite of ifosfamide) in the development of nephrotoxicity (Loebstein et al. 1999; Skinner et al. 2000; Aleksa et al. 2001; Yaseen et al. 2008; Hanly et al. 2009). Additional information on ifosfamide-induced nephrotoxicity is reviewed in Section 4.2. 2.3. Neurotoxicity No reports on neurotoxicity induced by chloroacetaldehyde were found. Goren et al. (1986), however, suggested a causative role for chloroacetaldehyde (a main metabolite of the anticancer drug ifosfamide) in the development of neu- rotoxic side-effects of ifosfamide chemotherapy. Cerebellar dysfunction, sei- zures, and changes in mental status were reported in as many as 30% of patients on high-dose treatment with ifosfamide. Blood concentrations of chloroacetal- dehyde were 88 micromoles per liter (μmol/L) at 6 h and 109 μmol/L at 24 h in two patients with neurotoxic effects (somnolescence, urinary incontinence, and inappropriate behavior), compared with 45 μmol/L at 6 h and 22 μmol/L at 24 h

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54 Acute Exposure Guideline Levels in four patients without such effects. Rieger et al. (2004) conducted a retrospec- tive trial of 60 cancer patients receiving ifosfamide as part of multiple drug che- motherapy regimens to evaluate potential risk factors for ifosfamide-induced encephalopathy. Sixteen patients (26.6%) developed neurologic symptoms; the effects were not correlated with age, sex, hepatic function, or renal function. 2.4. Developmental and Reproductive Toxicity No studies on developmental or reproductive toxicity of chloroacetalde- hyde in humans were found. 2.5. Genotoxicity No studies on the genotoxicity of chloroacetaldehyde in humans or on human cells were found. 2.6. Carcinogenicity No carcinogenicity studies of chloroacetaldehyde in humans were found. 2.7. Summary of Human Data No information on chloroacetaldehyde toxicity in humans was available, other than a brief statement that chloroacetaldehyde at 10 ppm produced lacri- mation and nasal irritation in humans (Dow Chemical Company 1952). Studies with ifosfamide suggest a causative role for chloroacetaldehyde (a main metabo- lite of the drug) in neurologic and renal effects. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality A summary of the data on acute lethality in laboratory animals exposed to chloroacetaldehyde is presented in Table 2-3. 3.1.1. Guinea Pigs Guinea pigs (10 animals/group; sex and strain not specified) were exposed to chloroacetaldehyde at target concentrations of 25 (for 7 h), 50 (for 4 h), 100 (for 2 h), or 400 ppm (for 0.5 h). No details were provided on the purity the chloroacetaldehyde or the exposure conditions. Target concentrations were monitored during the experiment, but the method and measurements were not specified. It was not clear whether an unexposed control group was used. Mor- tality was observed only at 400 ppm; seven of 10 guinea pigs died (Dow Chemi- cal Company 1952).

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55 Chloroacetaldehyde 3.1.2. Rats Rats (19 or 20 animals/group; sex and strain not specified) were exposed to chloroacetaldehyde at target concentrations of 10 (for 7 h), 25 (for 7 h), 50 (for 1, 3.5, or 4 h), 100 (for 0.2 or 2 h), or 400 ppm (for 0.1, 0.25, or 0.5 h). No details were provided on the purity of the chloroacetaldehyde or the exposure conditions. Target concentrations were monitored during the experiment, but the method and measurements were not specified. It was not clear whether an unex- posed control group was used. Mortality was related to the concentration and exposure duration (see Table 2-3). No mortality was occurred at concentrations (and durations) of 10 ppm (for 7 h), 50 ppm (for 1 h), and 100 ppm (for 0. 2 h). One animal died at 400 ppm (0.1 h). Almost all of the rats died at 25 ppm (for 7 h), 50 ppm (for 3.5 h and 4 h), 100 ppm (for 2 h), and 400 ppm (for 0.25 and 0.5 h) (Dow Chemical Company 1952). TABLE 2-3 Acute Lethality in Animals Exposed to Chloroacetaldehyde Concentration Exposure Species (ppm) Duration Mortality Reference Guinea pig 25 7h 0/10 Dow Chemical (n = 10) Company 1952 50 4h 0/10 100 2h 0/10 400 0.5 h 7/10 Rat 10 7h 0/20 Dow Chemical (n = 19-20) Company 1952 25 7h 19/20 50 1h 0/20 3.5 h 20/20 4h 18/20 100 0.2 h 0/19 2h 20/20 400 0.1 h 1/20 0.25 h 20/20 0.5 h 19/20 Rat 44 1h 0/10 Arts 1987 (n = 10) 159 3/10 203 4/10 243 10/10 309 10/10 596 10/10 2,643 10/10 203-243 1h LC50

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56 Acute Exposure Guideline Levels 3.2. Nonlethal Toxicity SPF-reared Borr:WISW rats (five animals/sex/group) were exposed (whole body; individually housed) for 1 h to mean concentrations of chloroacet- aldehyde (45.4% (w/w) at 44, 159, 203, 243, 309, 596, or 2,643 ppm (0.14, 0.51, 0.65, 0.78, 0.99, 1.91, or 8.47 g/m3, respectively). Concentrations of chloroacet- aldehyde were continuously monitored during exposure. No unexposed control animals were used. Relative humidity was high (51-91%) during exposure, due, in part, to the large amount of water in the test material. The animals were ob- served for up to 2 weeks. Mortality rates of 0% (44 ppm), 30% (159 ppm), 40% (203 ppm), and 100% (≥243 ppm) were found (see Table 2-3). Deaths were ob- served during exposure (at the two highest concentrations) or within several hours or 1-2 days after exposure. A 1-h LC50 value of 203-243 ppm was esti- mated. Because of the steep concentration-effect curve and natural variability between groups, it was not possible to determine an LC50 value for chloroacetal- dehyde with 95% confidence intervals. The LC50 value was estimated to be closer to 203 ppm, because a considerable decrease in body weight that would probably have lead to death was observed in some animals exposed at 159 and 203 (Arts 1987). A summary of the nonlethal effects of chloroacetaldehyde in laboratory animals is presented in Table 2-4. 3.2.1. Guinea Pigs and Rabbits In the acute inhalation experiment with guinea pigs describe earlier (see Section 3.1.1.), ocular and nasal irritation was found very early during exposure at all concentrations tested (25-400 ppm) (Dow Chemical Company 1952). The degree of irritation was related to concentration. Labored breathing was also observed at the higher concentrations, and slight drowsiness was apparent at some concentrations (not specified). In a repeated-exposure study by Dow Chemical Company (1952), groups of five male guinea pigs and one female rabbit (strains not specified) were ex- posed to chloroacetaldehyde at 0 or 5 ppm for 7 h/day, 5 days/week, for a total of eight exposures in 10 days. No details were provided on the purity of chloroacetaldehyde, actual or nominal concentrations, or exposure conditions. Slight ocular irritation was observed in the rabbit, but it was unclear from the report whether nasal irritation was also present. No irritating effects were re- ported in the guinea pigs. No effect on growth, organ weights, and gross pathol- ogy were found in either species. 3.2.2. Rats Rats (19 or 20 animals/group; sex and strain not specified) were exposed to chloroacetaldehyde at target concentrations of 10 (for 7 h), 25 (for 7 h), 50 (for 1, 3.5, or 4 h), 100 (for 0.2 or 2 h), or 400 ppm (0.1, 0.25, or 0.5 h). No

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57 Chloroacetaldehyde details were provided on the purity of the chloroacetaldehyde or the exposure conditions. Target concentrations were monitored during the experiment, but the method and measurements were not specified. It was not clear whether an unex- posed control group was used. Ocular and nasal irritation was observed very early during exposure at all concentrations. Degree of irritation was related to concentration and duration of exposure. Labored breathing was also observed at the higher concentrations, and slight drowsiness was apparent at some concen- trations (not specified) (Dow Chemical Company 1952). Groups of five male and five female rats (strain not specified) were ex- posed to chloroacetaldehyde at 0 or 5 ppm for 7 h/day, 5 days/week, for a total of eight exposures in 10 days. No details were provided on the purity of chloroacetaldehyde, actual or nominal concentrations, or exposure conditions. Exposed rats exhibited slight nasal irritation and very slight ocular irritation. Growth of the male rats was slightly depressed, while the growth of the female rats was comparable to that of the control animals. No effects on organ weight or gross pathology were found (Dow Chemical Company 1952). SPF-reared Borr:WISW rats (five animals/sex/group) were exposed (whole body; individually housed) for 1 h to mean concentrations of chloroacet- aldehyde (45.4% (w/w) at 44, 159, 203, 243, 309, 596, or 2,643 ppm (0.14, 0.51, 0.65, 0.78, 0.99, 1.91, or 8.47 g/m3, respectively). Concentrations of chloroacet- aldehyde were continuously monitored during exposure. No unexposed control animals were used. Relative humidity was high (51-91%) during exposure, due, in part, to the large amount of water in the test material. The animals were ob- served for up to 2 weeks. Descriptions of the observations were generally re- ported and did not always specify the number of animals affected or the expo- sure concentrations. Rats were restless and showed signs of discomfort (closed eyes, salivation, and, at the higher concentrations, wet nares, nasal discharge, and wet and soiled heads and breasts). At the highest concentration of 2,643 ppm, all rats exhibited labored respiration, accompanied by dyspnea and mouth breathing. Mortality was observed at all concentration, except the lowest of 44 ppm (see Table 2-3). Many of the rats that died had bloodstains around the nose and mouth. Rats exposed at the highest concentrations that did not die immedi- ately were reported to have breathed “wheezingly”. Two rats exposed at 596 ppm became blind. No chloroacetaldehyde-induced effects on body weight we found, although two animals in the 159- and 203-ppm groups lost a considerable amount of weight. Animals that died during exposure or within the first 2 days of observation had pulmonary edema, which was accompanied in some cases by atelectasis and in most cases by hydrothorax. The investigators suggested that the latter finding could be explained by induced hypertension, although no in- formation was provided to support that conclusion. Pulmonary edema was also observed in some animals exposed at the three lowest concentrations. The inves- tigators concluded that the pulmonary effects suggested an impairment of pul- monary function. The stomachs and intestines were often filled with air because of mouth breathing, and an occasional thrombus was detected in the heart area (Arts 1987).

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58 Acute Exposure Guideline Levels 3.2.3. Mice Groups of five female mice (strain not specified) were exposed to chloroacetaldehyde at 0 or 5 ppm for 7 h/day, 5 days/week for a total of eight exposures in 10 days. No details were provided on the purity of the chloroacet- aldehyde, actual or nominal concentrations, or the exposure conditions. Mice exhibited slight nasal irritation. No effects on growth, organ weights, or gross pathology were found. TABLE 2-4 Nonlethal Toxicity in Animals Exposed to Chloroacetaldehyde Concentration Species (ppm) Exposure Duration Effects Reference Guinea pig 25 7h Concentration-related ocular and Dow (n = 10) 50 4h nasal irritation; labored breathing Chemical 100 2h at the higher concentrations; slight Company 400 0.5 h drowsiness (concentrations not 1952 specified) Guinea pig 5 7 h/d, 5 d/wk, No effects reported Dow (n = 5) 8 exposures Chemical in 10 d Company 1952 Rabbit 5 7 h/d, 5 d/wk, Slight ocular irritation Dow (n = 1) 8 exposures Chemical in 10 d Company 1952 Rat 10 7h Concentration- and duration-related Dow (n = 19 or 20) 25 7h ocular and nasal irritation; labored Chemical 50 1, 3.5, 4 h breathing at higher concentrations; Company 100 0.2, 2 h slight drowsiness (concentrations 1952 400 0.1, 0.25, 0.5 h not specified) Rat (n = 10) 5 7 h/d, 5 d/wk, Slight nasal irritation, very slight Dow 8 exposures ocular irritation Chemical in 10 d Company 1952 Rat (n = 10) 44 1h At all concentrations, closed eyes, Arts 1987 159 salivation, and decreased pulmonary 203 function (e.g., pulmonary edema 243 [with some atelectasis and 309 hydrothorax], labored breathing). 596 At higher concentrations, wet 2,643 nares, nasal discharge, wet and soiled heads and breasts. Mouse (n = 5) 5 7 h/d, 5 d/wk, Slight nasal irritation Dow 8 exposures Chemical in 10 d Company 1952

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71 Chloroacetaldehyde Arts, J.H.E. 1987. Acute (One-Hour) Inhalation Toxicity Study of Chloroacetaldehyde in Rats. Report No. V 87.094/261236. Organization for Applied Scientific Research (TNO), Zeist, The Netherlands [online]. Available: http://yosemite.epa.gov/oppts/ epatscat8.nsf/by+Service/731D9542E140E7DC85256F2600655CA2/$File/888700 00029.pdf [accessed Feb. 10, 2012]. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Pro- file for Vinyl Chloride. U.S. Department of Public Health, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. September 1997. Bartsch, H., C. Malaveille, A. Barbin, H. Bresil, L. Tomatis, and R. Montesano. 1976. Mutagenicity and metabolism of vinyl chloride and related compounds. Environ. Health Perspect. 17:193-198. Budavari, S., M.J. O’Neil, A. Smith, and P.H. Heckelman, eds. 1989. Chloroacetalde- hyde. P. 326 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11 Ed. Rahway, NJ: Merck. Daniel, F.B., A.B. DeAngelo, J.A. Stober, G.R. Olson, and N.P. Page. 1992. Hepatocar- cinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fundam. Appl. Toxicol. 19(2):159-168. Dow Chemical Company. 1952. Toxicity of Chloroacetaldehyde, Document No. 8EHQ- 0392-2833A. U.S. Environmental Protection Agency, Washington, DC. EPA Document No. 88920001475. Microfiche No. OTS0536151. Dubourg, L., C. Michoudet, P. Cochat, and G. Baverel. 2001. Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. J. Am. Soc. Nephrol. 12(8):1615-1623. Dubourg, L., P. Tanière, P. Cochat, G. Baverel, and C. Michoudet. 2002. Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules. Pediatr. Nephrol. 17(2):97-103. EC/JRC (European Commission Joint Research Centre). 2012. Chloroacetaldehyde. EINECS No. 203-472-8. European Inventory of Existing Commercial Chemical Substances. European Commission, Joint Research Centre, Institute for Health and Consumer Protection [online]. Available: http://esis.jrc.ec.europa.eu/ [accessed Feb. 9, 2012]. Elmore, J.D., J.L. Wong, A.D. Laumbach, and U.N. Streips. 1976. Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacetaldehyde monomer hydrate. Biochim. Biophys. Acta 442(3):405-419. EPA (U.S. Environmental Protection Agency). 1987. Section 8(e) Submission and Status Report on Chloroacetone and Chloroacetaldehyde. Document No. 8EHQ-0387- 0660. Office of Toxic Substances, U.S. Environmental Protection Agency: Wash- ington, DC. April 22, 1987. EPA (U.S. Environmental Protection Agency). 2005. Benchmark Dose Software, Version 1.3.2. National Center for Environmental Assessment, Office of Research and De- velopment, U.S. Environmental Protection Agency, Washington, DC. Goldschmidt, B.M. 1984. Role of aldehydes in carcinogenesis. J. Environ. Sci. Health C 2(2):231-249. Goren, M.P., R.K. Wright, C.B. Pratt, and F.E. Pell. 1986. Dechloroethylation of ifos- famide and neurotoxicity. Lancet 2(8517):1219-1220. Hanly, L., N. Chen, M. Rieder, and G. Koren. 2009. Ifosfamide nephrotoxicity in chil- dren: A mechanistic base for pharmacological prevention. Expert Opin. Drug Saf. 8(2):155-168. HSDB (Hazardous Substances Data Bank). 2009. Chloroacetaldehyde (CASRN 107- 20-0). TOXNET, Specialized Information Services, U.S. National Library of

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72 Acute Exposure Guideline Levels Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?HSDB. [accessed Feb. 9, 2012]. IPCS (International Programme on Chemical Safety). 2005. Chloroacetaldehyde (40% solu- tion). International Chemical Safety Card IPCS 0706. International Programme on Chemical Safety, Commission of the European Communities [online]. Available: http://www.inchem.org/documents/icsc/icsc/eics0706.htm [accessed Feb. 9, 2012]. Joqueviel, C., M. Malet-Martino, and R. Martino. 1997. A 13C NMR study of 2-13C - chloroacetaldehyde, a metabolite of ifosfamide and cyclophosphamide, in the iso- lated perfused rabbit heart model. Initial observations on its cardiotoxicity and car- diac metabolism. Cell. Mol. Biol. 43(5):773-782. Lawrence, W.H., E.O. Dillingham, J.E. Turner, and J. Autian. 1972. Toxicity profile of chloroacetaldehyde. J. Pharm. Sci. 61(1):19-25. Loebstein, R., G. Atanackovic, R. Bishai, J. Wolpin, S. Khattak, G. Hashemi, M. Gobrial, S. Baruchel, S. Ito, and G. Koren. 1999. Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J. Clin. Pharmacol. 39(5):454-461. Manzano, R.G., K.A. Wright, and P.R. Twentyman. 1996. Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance- associated protein (MRP). Clin. Cancer Res. 2(8):1321-1326. McCann, J., V. Simmon, D. Streitwieser, and B.N. Ames. 1975. Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophos- phamide. Proc. Natl. Acad. Sci. USA 72(8):3190-3193. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Chlooraceetaldehyde. Den Haag: SDU Uitgevers [online]. Available: http:// www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Feb. 9, 2012]. NIOSH (National Institute for Occupational Safety and Health). 1991. Occupational Health Guidelines for Chemical Hazards: Chloroacetaldehyde. DHHS (NIOSH) 81-123. Centers for Disease Control and Prevention, National Institute for Occupa- tional Safety and Health, Atlanta, GA [online]. Available: http://www.cdc.gov/ niosh/docs/81-123/ [accessed Feb. 9, 2012]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Chloroacetal- dehyde. U.S. Department of Health and Human Services, Centers for Disease Con- trol and Prevention, National Institute for Occupational Safety and Health, Cincin- nati, OH [online]. Available: http://www.cdc.gov/niosh/idlh/107200.html[accessed Feb. 9, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: Chloroacetaldehyde. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http:// www.cdc.gov/niosh/npg/npgd0118.html [accessed Feb. 09, 2012]. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2012. Vinyl Chloride in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 11. Washington, DC: National Academies Press.

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73 Chloroacetaldehyde OSHA (Occupational Safety and Health Administration). 1989. Chloroacetaldehyde. Sampling and Analytical Methods: Method No. 76. Occupational Safety & Health Administration, Washington, DC [online]. Available: http://www.osha.gov/dts/sl tc/methods/organic/org076/org076.htm [accessed Feb. 9, 2012]. Rieger, C., M. Fiegl, J. Tischer, H. Ostermann, and X. Schiel. 2004. Incidence and sever- ity of ifosfamide-induced encephalopathy. Anticancer Drugs 15(4):347-350. Sharpe, A.L., and D.E. Carter. 1993. Substrate specificity of rat liver aldehyde dehydro- genase with chloroacetaldehydes. J. Biochem. Toxicol. 8(3):155-160. Skinner, R., S.J. Cotterill, and M.C. Stevens. 2000. Risk factors for nephrotoxicity after ifosfamide treatment in children: A UKCCSG Late Effects Group study. Br. J. Cancer 82(10):1636-1645. Sood, C., and P.J. O'Brien. 1993. Molecular mechanisms of chloroacetaldehyde-induced cytotoxicity in isolated rat hepatocytes. Biochem. Pharmacol. 46(9):1621-1626. Sood, C., and P.J. O'Brien. 1994. Chloroacetaldehyde-induced hepatocyte cytotoxicity. Mechanisms for cytoprotection. Biochem. Pharmacol. 48(5):1025-1032. Van Duuren, B.L., B.M. Goldschmidt, G. Loewengart, A.C. Smith, S. Melchionne, I. Seldman, and D. Roth. 1979. Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice. J. Natl. Cancer Inst. 63(6):1433-1439. Visarius, T.M., J.W. Stucki, and B.H. Lauterburg. 1999. Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats. J. Pharmacol. Exp. Ther. 289(2):820-824. Yaseen, Z., C. Michoudet, G. Baverel, and L. Dubourg. 2008. Mechanisms of the ifos- famide-induced inhibition of endocytosis in the rat proximal kidney tubule. Arch. Toxicol. 82(9):607-614.

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74 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR CHLOROACETALDEHYDE Derivation of AEGL-1 Values Key study: Dow Chemical Company. 1952. Toxicity of Chloroacetaldehyde. Document No. 8EHQ-0392- 28338. EPA Document No. 88920001475. Microfiche No. OTS0536151. Toxicity end point: 5 ppm for 7 h, lowest-observed-adverse-effect level for nasal and ocular irritation. The point of departure was 2.5 ppm after a modifying factor of 2 was applied (see below). Cn × t = k; n = 1.2 based on lethality data Time scaling: k = (2.5 ppm)1.2 × 420 min = 1,261 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Total uncertainty factor of 10 Modifying factor: A modifying factor of 2 was applied to reduce the lowest-observed-adverse-effect level to a no-effect level. Calculations: 10-min AEGL-1: Set equal to the 30-min AEGL of 2.3 ppm (= 7.4 mg/m3) C1.2 × 30 min = 1,261 ppm-min 30-min AEGL-1: C = 22.5 ppm 22.5 ÷ 10 = 2.3 ppm (rounded) (= 7.4 mg/m3) C1.2 × 60 min = 1,261 ppm-min 1-h AEGL-1: C = 12.7 ppm 12.7 ÷ 10 = 1.3 ppm (rounded) (= 4.2 mg/m3) C1.2 × 240 min = 1,261 ppm-min 4-h AEGL-1: C = 4.0 ppm 4.0 ÷ 10 = 0.40 ppm (rounded) (= 1.3 mg/m3) C1.2 × 480 min = 1,261 ppm-min 8-h AEGL-1: C = 2.2 ppm 2.2 ÷ 10 = 0.22 ppm (rounded) (= 0.71 mg/m3)

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75 Chloroacetaldehyde Derivation of AEGL-2 Values Key study: Arts, J.H.E. 1987. Acute (One-Hour) Inhalation Toxicity Study of Chloroacetaldehyde in Rats. Report No. V 87.094/261236. Organization for Applied Scientific Research (TNO), Zeist, The Netherlands [online]. Available: http://yosemite. epa.gov/oppts/epatscat8.nsf/by+Service/731D954 2E140E7DC85256F2600655CA2/$File/88870000 029.pdf [accessed Feb. 10, 2012]. Toxicity end point: 44 ppm for 1 h, lowest-observed-adverse-effect level for impaired pulmonary function. The point of departure was 22 ppm after a modifying factor of 2 was applied (see below). Cn × t = k; n = 1.2 based on lethality data Time scaling: k = (22 ppm)1.2 × 60 min = 2,449 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Total uncertainty factor of 10 Modifying factor: A modifying factor of 2 was applied to reduce the lowest-observed-adverse-effect level, because the pulmonary effects were more severe than those that define AEGL-2 values. Calculations: C1.2 × 10 min = 2,449 ppm-min 10-min AEGL-2: C = 97.9 ppm 97.9 ÷ 10 = 9.8 ppm (rounded) (= 31 mg/m3) C1.2 × 30 min = 2,449 ppm-min 30-min AEGL-2: C = 39.2 ppm 39.2 ÷ 10 = 3.9 ppm (rounded) (= 13 mg/m3) 22 ppm ÷ 10 = 2.2 ppm (= 7.1 mg/m3) 1-h AEGL-2: C1.2 × 240 min = 2,449 ppm-min 4-h AEGL-2: C = 6.9 ppm 6.9 ÷10 = 0.69 ppm (= 2.2 mg/m3) C1.2 × 480 min = 2,449 ppm-min 8-h AEGL-2: C = 3.9 ppm 3.9 ÷10 = 0.39 ppm (= 1.5 mg/m3)

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76 Acute Exposure Guideline Levels Derivation of AEGL-3 Values Key studies: Arts, J.H.E. 1987. Acute (One-Hour) Inhalation Toxicity Study of Chloroacetaldehyde in Rats. Report No. V 87.094/261236. Organization for Applied Scientific Research (TNO), Zeist, The Netherlands [online]. Available: http://yosemite. epa.gov/oppts/epatscat8.nsf/by+Service/731D954 2E140E7DC85256F2600655CA2/$File/88870000 029.pdf [accessed Feb. 10, 2012]. Dow Chemical Company. 1952. Toxicity of Chloroacetaldehyde. Document No. 8EHQ-0392- 28338. EPA Document No. 88920001475. Microfiche No. OTS0536151. Toxicity end point: Lethality in rats exposed for 1 h. The 1-h BMC05 is 136 ppm, with a lower 95% confidence limit of 99 ppm (the point of departure). Cn × t = k; n = 1.2 based on lethality data Time scaling: k = (99 ppm)1.2 × 60 min = 14,891 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Total uncertainty factor of 10 Calculations: C1.2 × 10 min = 14,891 ppm-min 10-min AEGL-3: C = 441 ppm 441 ÷ 10 = 44 ppm (rounded) (= 140 mg/m3) C1.2 × 30 min = 14,891 ppm-min 30-min AEGL-3: C = 176 ppm 176 ÷ 10 = 18 ppm (rounded) (= 57 mg/m3) 99 ppm ÷ 10 = 9.9 ppm (= 32 mg/m3) 1-h AEGL-3: C1.2 × 240 min = 14,891 ppm-min 4-h AEGL-3: C = 31 ppm 31 ÷ 10 = 3.1 ppm (= 10 mg/m3) C1.2 × 480 min = 14,891 ppm-min 8-h AEGL-3: C = 18 ppm 18 ÷ 10 = 1.8 ppm (= 5.6 mg/m3)

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77 Chloroacetaldehyde APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLOROACETALDEHYDE Derivation Summary for Chloroacetaldehyde AEGL-1 VALUES 10 min 30 min 1h 4h 8h 2.3 ppm 2.3 ppm 1.3 ppm 0.40 ppm 0.22 ppm (7.4 mg/m3) (7.4 mg/m3) (4.2 mg/m3) (1.3 mg/m3) (0.71 mg/m3) Key reference: Dow Chemical Company. 1952. Toxicity of Chloroacetaldehyde. Document No. 8EHQ-0392-28338. EPA Document No. 88920001475. Microfiche No. OTS0536151. Test species/Strain/Number: Guinea pigs (strain not specified): 5 Rabbit (strain not specified): 1 Rats (strain not specified): 10 Mice (strain not specified): 5 Exposure route/Concentrations/Durations: Inhalation, chloroacetaldehyde at 0 or 5 ppm for 7 h/d, 5 d/wk for a total of eight exposures in 10 d. Effects at 5 ppm: Guinea pigs: no effects Rabbit: slight ocular irritation Rats: slight nasal irritation, very slight ocular irritation Mice: slight nasal irritation End point/Concentration/Rationale: Rabbit, rats, and mice had slight nasal and ocular irritation after 7 h of exposure at 5 ppm (lowest-observed-adverse-effect level). Uncertainty factors/Rationale: Total uncertainty factor: 10 was considered sufficient for toxicokinetic and toxicodynamic differences between species and individual variability. The effects were attributed to direct interaction of chloroacetaldehyde and, therefore, no relevant differences in kinetics between species and between humans were assumed. Interspecies: 3 Intraspecies: 3 Modifying factor: A modifying factor of 2 was applied to reduce 5 ppm to a no-effect level of 2.5 ppm. Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; n = 1.2 based on lethality data (Continued)

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78 Acute Exposure Guideline Levels AEGL-1 VALUES Continued 10 min 30 min 1h 4h 8h 2.3 ppm 2.3 ppm 1.3 ppm 0.40 ppm 0.22 ppm (7.4 mg/m3) (7.4 mg/m3) (4.2 mg/m3) (1.3 mg/m3) (0.71 mg/m3) Data adequacy: No human data were available. Lacrimation and nasal irritation reported in humans within a few minutes of exposure to chloroacetaldehyde at 10 ppm (Dow Chemical Company 1952) provides supporting data for deriving AEGL-1 values on the basis of rat data. No adequate animal data identifying a no-effect level for ocular and nasal irritation were available. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 9.8 ppm 3.9 ppm 2.2 ppm 0.69 ppm 0.39 ppm (31 mg/m3) (13 mg/m3) (7.1 mg/m3) (2.2 mg/m3) (1.5 mg/m3) Key reference: Arts, J.H.E. 1987. Acute (One-Hour) Inhalation Toxicity Study of Chloroacetaldehyde in Rats. Report No. V 87.094/261236. Organization for Applied Scientific Research (TNO), Zeist, The Netherlands. Test species/Strain/Number: SPF-reared Borr:WISW rats (5 animals/sex/group) Exposure route/Concentrations/Durations: Inhalation, mean actual concentrations of chloroacetaldehyde at 44, 159, 203, 243, 309, 596, and 2,643 ppm for 1 h. Effects: 44 ppm: closed eyes, salivation; pulmonary edema (still presented 2 weeks after exposure) 159 ppm: 3/10 deaths 203 ppm: 4/10 deaths 243 ppm: 100% mortality 309 ppm: 100% mortality 596 ppm: 100% mortality 2,643 ppm: 100% mortality End point/Concentration/Rationale: Pulmonary edema at 44 ppm, the lowest concentration tested. Uncertainty factors/Rationale: Total uncertainty factor: 10 was considered sufficient for toxicokinetic and toxicodynamic differences between species and individual variability. The effects were attributed to direct interaction of chloroacetaldehyde and, therefore, no relevant differences in kinetics between species and between humans were assumed. Interspecies: 3 Intraspecies: 3 Modifying factor: A modifying factor of 2 was applied because of an incomplete database (a no-effect level was not identified). A factor of 2 was considered sufficient because of the steep concentration-response curve. (Continued)

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79 Chloroacetaldehyde AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 9.8 ppm 3.9 ppm 2.2 ppm 0.69 ppm 0.39 ppm (31 mg/m3) (13 mg/m3) (7.1 mg/m3) (2.2 mg/m3) (1.5 mg/m3) Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; n = 1.2 based on lethality data Data adequacy: No human data were available. A no-effect level for effects defined by the AEGL-2 could not be determined. However, because of the steep concentration-response curve and the additional animal data, the uncertainties in the AEGL-2 values probably not very large. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 44 ppm 18 ppm 9.9 ppm 3.1 ppm 1.8 ppm (140 mg/m3) (57 mg/m3) (32 mg/m3) (10 mg/m3) (5.6 mg/m3) Key references: (1) Dow Chemical Company. 1952. Toxicity of Chloroacetaldehyde. Document No. 8EHQ-0392-28338. EPA Document No. 88920001475. Microfiche No. OTS0536151. (2) Arts, J.H.E. 1987. Acute (One-Hour) Inhalation Toxicity Study of Chloroacetaldehyde in Rats. Report No. V 87.094/261236. Organization for Applied Scientific Research (TNO), Zeist, The Netherlands. Test species/Strain/Number: SPF-reared Borr: WISW rats (5 animals/sex/group) Exposure Route/Concentrations/Durations: Inhalation, mean actual concentrations of 44, 159, 203, 243, 309, 596, and 2,643 ppm for 1 h Effects: 44 ppm: 0/10 deaths 159 ppm: 3/10 deaths 203 ppm: 4/10 deaths 243 ppm: 100% mortality 309 ppm: 100% mortality 596 ppm: 100% mortality 2,643 ppm: 100% mortality End point/Concentration/Rationale: A BMCL05 of 99 ppm for 1 h was calculated using EPA benchmark dose software (EPA 2005). Uncertainty factors/Rationale: Total uncertainty factor: 10 was considered sufficient for toxicokinetic and toxicodynamic differences between species and individual variability. The effects were attributed to direct interaction of chloroacetaldehyde and, therefore, no relevant differences in kinetics between species and between humans were assumed. Interspecies: 3 Intraspecies: 3 (Continued)

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80 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 44 ppm 18 ppm 9.9 ppm 3.1 ppm 1.8 ppm (140 mg/m3) (57 mg/m3) (32 mg/m3) (10 mg/m3) (5.6 mg/m3) Modifying factor: Not applied Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; n = 1.2 based on lethality data Data adequacy: Sufficient for deriving AEGL-3 values.

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81 Chloroacetaldehyde APPENDIX C CATEGORY GRAPH OF TOXICITY DATA AND AEGL VALUES FOR CHLOROACETALDEHYDE Chloroacetaldehyde Toxicity 1000 100 Human - No effect Human Discomfort Human - Disabling Animal - No effect ppm 10 Animal - Discomfort Animal Disabling Animal - Some Lethality Animal - Lethal 1 AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category graph of toxicity data and AEGLs values for chloroacetaldehyde.