6

Ketene1

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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1This document was prepared by the AEGL Development Team composed of Peter Bos (RIVM, The Dutch National Institute of Public Health and the Environment), Lisa Ingerman (SRC, Inc.), Chemical Manager James Holler (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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6 Ketene1 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), Lisa Ingerman (SRC, Inc.), Chemical Manager James Holler (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 doc- ument 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). 267

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268 Acute Exposure Guideline Levels 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 susceptible 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 respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Ketene is a colorless gas with a sharp, penetrating odor that can be detect- ed at a concentration of 12 ppm but not at 1 ppm. It is an unstable, readily poly- merizing compound and cannot be stored in the gaseous state. Ketene reacts with water to form acetic acid, and the reaction is accelerated by the presence of alkali; it will acetylate amino groups, phenolic hydroxyl groups, and sulfhydryl groups in aqueous solution (Cameron and Neuberger 1937). It is soluble in ace- tone, benzene, ether, and chloroform wherein it can react with a variety of com- pounds, such as amines, alcohols, and acids. Ketene is used as an acetylating agent in chemical synthesis, especially in synthesis of acetic acid and acetate esters. Human data on the acute toxicity of ketene are not available. Neurotoxici- ty, developmental and reproductive toxicity, genotoxicity, and carcinogenicity have not been examined in humans. Five studies examined the toxicity of ketene in various animal species. These studies indicate that the inhalation route of exposure is of particular con- cern for ketene and that the chemical has similarities to phosgene in clinical ef- fects and mode of action. Ketene is a respiratory poison that can exhibit delayed toxicity to alveolar structures (mainly capillaries) to produce death by pulmo- nary edema. Ketene has been shown to acetylate free amino (and other function- al) groups of proteins in aqueous solution. Like phosgene, the pulmonary effects of inhalation exposure to ketene may be manifested in the absence of direct irri-

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Ketene 269 tation by ketene or its breakdown product, acetic acid. For all species tested, the toxicologic profile of ketene is similar. Ketene is lethal at high concentrations; at lower concentrations, minor irritation during exposure and central nervous sys- tem impairment have been observed. However, severe damage to the lungs (at the alveolar level) may manifest as long as 24 h after exposure. The central nervous system effects are likely due to cerebral anoxia secondary to alveolar damage. Toxicity is greatest in mice, followed by rats, guinea pigs, cats, and rabbits. Ketene appears to exhibit a steep concentration-response relationship. Data were insufficient for deriving AEGL-1 values for ketene. No human or animal data on AEGL-1 severity effects following exposure to ketene were available. No overt signs of toxicity were observed in mice exposed at 1 ppm for 7 h in a repeated-exposure study (Treon et al. 1949). Pulmonary damage was reported at the end of the exposure period; however, whether pulmonary damage would occur following a single exposure is unknown. Because of the uncertainty of whether the lowest concentration tested (1 ppm) would result in effects which exceeded the AEGL-1 definition, derivation of AEGL-1 values is not recom- mended for ketene. Although ketene reportedly has a distinct, penetrating floral odor (Health Council of the Netherlands 2001), neither an odor threshold nor a level of odor awareness are available. Thus, whether odor detection and minor irritation would provide adequate warning of ketene exposure is uncertain, espe- cially given the potential for sensitive subpopulations (asthmatics) and delayed severe pulmonary toxicity (including lethality) after ketene exposure. Data on AEGL-2 severity effects in humans and animals were not availa- ble. As discussed in consideration of AEGL-1 values, uncertainty is associated with using the lowest test concentration of 1 ppm in the repeated-exposure study in mice (Treon et al. 1949) to derive AEGL-2 values. Therefore, AEGL-2 values for ketene were based on a 3-fold reduction of AEGL-3 values. This approach is used to estimate a threshold for irreversible effects and is considered appropriate given the apparent steep concentration-response curve for ketene (lethality in mice was 0/10 at 1 ppm for 7 h; 7/10 at 23 ppm for 30 min; and 10/10 at 50 ppm for 50 min). AEGL-3 values are based on the mouse studies of Treon et al. (1949). A 50-min exposure to ketene at 50 ppm caused 100% mortality in mice. A 30-min exposure at 23 ppm was lethal to 7/10 mice, but a 2-h exposure at this concen- tration was 100% lethal. A 4.5-h exposure at 12 ppm (the next lower test con- centration) did not result in deaths, but 3/7 mice died during a 5.5-h exposure at the same concentration on the subsequent day of exposure. Because the time of death during the second exposure was not reported, whether the deaths were a delayed effect of the first exposure or caused by the second exposure is uncer- tain. In a second repeated-exposure study (Treon et al. 1949), no deaths occurred in mice after a single 7-h exposure at 1 ppm and 1/10 mice died 3 days after the tenth exposure. The concentration of 1 ppm was considered a threshold for le- thal effects caused by a single exposure to ketene and was chosen as the point of departure for calculating AEGL-3 values. A total uncertainty factor of 10 was used. Mice appeared to be the most susceptible species, so an interspecies factor

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270 Acute Exposure Guideline Levels of 3 was considered adequate to account for interspecies differences. An intra- species factor of 3 was used because the mode of action (acylation of functional groups on proteins and enzymes in the lung) is not expected to vary greatly among individuals. Human studies examining the toxicity of phosgene, which appears to have a mode of action similar to ketene, did not identify sensitive subpopulations and used an intraspecies uncertainty factor of 3 in the derivation of the AEGL-2 and AEGL-3 values (NRC 2002). AEGL-3 values were derived by time scaling according to the equation Cn × t = k, using default values of n = 3 to extrapolate from longer to shorter durations and n = 1 to extrapolate from shorter to longer durations. The 10-min AEGL-3 value was set equal to the 30- min value because of the uncertainty associated with extrapolating a 7-h point of departure to a 10-min AEGL value. The AEGL values for ketene are presented in Table 6-1. 1. INTRODUCTION Ketene is a colorless gas (Hasek 1981; Taylor 1950; HSDB 2005) with a sharp, penetrating odor (Health Council of the Netherlands 2001) that can be detected at 12 ppm but not at 1 ppm (Treon et al. 1949). It is an unstable, readily polymerizing compound (Hasek 1981; HSDB 2005), and cannot be stored in the gaseous state. Ketene reacts with water to form acetic acid, and the process is accelerated by the presence of alkali (Treon et al. 1949). It is soluble in acetone, benzene, ether, and chloroform (Cameron and Neuberger 1937). When in a solu- tion of inert solvents, ketene can react with a variety of compounds, such as amines, alcohols, and acids. Ketene reacts with water to form acetic acid and will acetylate amino groups, phenolic hydroxyl groups, and sulfhydryl groups in aqueous solution (Cameron and Neuberger 1937). Ketene polymerizes slowly at 0°C and more quickly at room temperature. Polymerization is catalyzed by pyri- dine, dust particles, and rubber (Cameron and Neuberger 1937). Ketene is manufactured by pyrolysis of acetic acid at 700-800°C under re- duced pressure (10-50 kPa or 0.1-0.5 atm) (Hasek1981). A phosphate ester is injected to provide an acidic catalyst. After removal of water and unconverted acetic acid, gaseous ketene is absorbed immediately in an appropriate reaction medium (e.g., acetic anhydride is prepared by passage into a mixture of acetic acid and anhydride). Very pure ketene is best obtained from pyrolysis of acetic anhydride. In the laboratory, ketene is prepared easily in a “ketene lamp”, in which acetone vapors are passed over an electrically-heated tungsten wire at about 700°C (Cameron and Neuberger 1937; Hasek1981). The major problem with this production is contamination of ketene with large amounts of methane pro- duced in equivalent amounts (Cameron and Neuberger 1937) and other gaseous byproducts. If the temperature is increased further, ketene decomposes into eth- ylene and carbon monoxide. A substantially better product is obtained by pyrol- ysis of diketene (the commercially available dimer of ketene) or acetic anhy-

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Ketene 271 dride, the latter material easily affords a ketene stream of better than 99% purity (Hasek 1981). Ketene is used as an acetylating agent in chemical synthesis, especially of acetic acid and acetate esters (Health Council of the Netherlands 2001). The chemical and physical properties of ketene are presented in Table 6-2. 2. HUMAN TOXICITY DATA No human data on ketene were found. TABLE 6-1 AEGL Values for Ketene End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient (nondisabling) data AEGL-2 0.08 ppm 0.08 ppm 0.063 ppm 0.040 ppm 0.029 ppm One third of (disabling) (0.14 (0.14 (0.11 (0.069 (0.050 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (NRC 2001) AEGL-3 0.24 ppm 0.24 ppm 0.19 ppm 0.12 ppm 0.088 ppm Nonlethal (lethal) (0.41 (0.41 (0.33 (0.21 (0.15 exposure of mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) mice, 1 ppm for 7 h (Treon et al. 1949) a Not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects. A penetrating odor was reported for ketene, but neither an odor threshold nor a level of odor awareness are available. Therefore, whether the distinct floral odor of ketene will be noticeable by individuals is unclear. TABLE 6-2 Chemical and Physical Properties for Ketene Parameter Value Reference Synonyms Ethenone; carbomethene HSDB 2005 CAS registry no. 463-51-4 HSDB 2005 Chemical formula C2H2O HSDB 2005 Molecular weight 42.04 HSDB 2005 Physical state Gas HSDB 2005 Color Colorless HSDB 2005 Odor Penetrating HSDB 2005 Melting point -150°C HSDB 2005 Boiling point -56°C HSDB 2005 Solubility Fairly soluble in acetone HSDB 2005 Vapor density (air = 1) 1.45 HSDB 2005 Vapor pressure 1.4 × 104 mm Hg at 25°C HSDB 2005 Conversion factors 1 mg/m3 = 0.582 ppm NIOSH 2011 1 ppm = 1.719 mg/m3

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272 Acute Exposure Guideline Levels 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Monkeys Treon et al. (1949) exposed (whole body) monkeys (one animal per concen- tration, sex and strain not specified) to ketene at nominal concentrations of 50, 200, 750, and 1,500 ppm for 10 min under static conditions. The desired atmos- phere was obtained by introducing a calculated volume of freshly generated ketene gas (purity: 98-99%) into the chamber. At the lowest concentration of 50 ppm, the exposed monkey survived without noteworthy signs of intoxication. At higher concentrations, all monkeys died within 7.67, 1.95, and 0.6 h after exposure, re- spectively (see Table 6-3). Symptoms of toxicity were similar at the various con- centrations, but the onset of symptoms was shorter with higher concentrations. The only sign of intoxication during exposure was coughing at 1,500 ppm. Toxici- ty was characterized by dyspnea (rapid and labored breathing) and cyanosis cul- minating in fatal edema of the lungs (nasal discharge, slightly sanguineous fluid expelled from the mouth). Death was preceded by evidence of irritation (probably anoxic) of the central nervous system, which included lethargy, weakness, laying down inside position, closed eyes, and convulsive movements of the head. The observed clinical effects were confirmed by evidence of gross and microscopic pathologic changes in the lungs (generalized alveolar edema and congestion, occa- sional cases of an emphysematous condition at the periphery of the lobes, and dis- tended alveolar spaces with fluid) and brain (meningeal and cerebral edema and congestion, accompanied by neuronal chromatolysis indicating the presence of cerebral anoxia). No significant changes in other organs were found. Treon et al. (1949) exposed one monkey (sex and strain not specified) to ketene at 23 ppm for 4 h on two consecutive days and one monkey received 14 exposures of 1 ppm for 7 h/day, 5 days/week, followed by another 55 exposures after a 9-day interval (see Table 6-4). At the start of each experiment, ketene (purity: 98-99%) was injected in the chamber from a syringe to obtain the de- sired concentration. Because no analytic method was available to measure such low concentrations, estimates were calculated from measurements of the rate at which ketene flowed from the reservoir into a measured air stream (nominal concentrations). During the first 4-h exposure period, the monkey exposed at 23 ppm showed adverse clinical effects, including irritation of the eyes, coughing, and lethargy, especially signs related to the lungs and brain. Clinical effects were more pronounced during the second 4-h exposure (some nasal discharge, irregular and labored respiration, more severe coughing, and frothy fluid from the mouth). It was unclear whether microscopic examinations were performed on the tissues of this animal, but it was reported that in general all test species, except guinea pigs, showed alveolar edema and acute pulmonary congestion after repeated exposure to ketene at concentrations above 12 ppm. The monkey recovered and survived. No clinical signs were observed in the monkey exposed repeatedly to ketene at 1 ppm.

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Ketene 273 TABLE 6-3 Acute Lethality Data from Studies of Animals Exposed to Static Concentrations of Ketene for 10 Minutes Concentration (ppm) Mortality Time of death (h) Monkeys (n = 1) 50 0/1 – 200 1/1 7.67 750 1/1 1.95 1,500 1/1 0.6 Cats (n = 1) 200 0/1 – 750 1/1 2.83a 1,250 1/1 58.7 1,500 1/1 17 Rabbits ( n = 1-2) 200 0/2 – 250 0/2 – 375 0/2 – 500 0/2 – 750 0/2 – 1,000 1/2 0.8 1,250 2/2 2.8 and 3.07 1,500 1/1 1.3 Guinea pigs (n = 2) 100 0/2 – 200 0/2 – 250 0/2 – 375 0/2 – 500 1/2 5.5 750 1/2 1.6 1,000 2/2 2.0 and 6.0 1,250 2/2 2.16 and 9.1 Rats (n = 2) 100 0/2 – 200 0/2 – 250 0/2 – 375 2/2 3.25 and 9.67 500 2/2 4.45 and 6.75 750 2/2 3.7 and 5.5 1,000 2/2 2.0 and 2.6 1,250 2/2 0.95 and 1.95 Mice (n = 10-20) 25 0/10 – 50 8/20 1.1-7.75 (6 mice); 16.2-16.4 (2 mice) 75 10/10 1.5-4.5 (7 mice); 12-22.5 (2 mice); 60 (1 mouse) 100 10/10 1.05-3.05 (9 mice); 7.5-16 (1 mouse) a The cat had an obstruction of the bowel. Source: Adapted from Treon et al. 1949.

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274 TABLE 6-4 Acute Lethality Data from Studies of Animals Exposed to Dynamic Concentrations of Ketene for 10 Minutes Intended Exposure Concentration (ppm) (time/day) (day) Mortality Time of Death Monkeys (n = 1) 23 4h 2 0/1 – 1 7h 14 0/1a – 1 7h 55 0/1a – Cats (n = 1-2) 23 4h 2 0/1 – 23 6.5 h 2 0/1 – 12 4.5-6 hb 15 1/1 After fifth exposure 1 7h 14 0/2 – 1 7h 55 0/2 – Rabbits (n = 4-5) 50 50 min 1 0/4 – 53 100 min 1 3/4 1.87-3.57 h (2 rabbits), 135.5 h (1 rabbit) 23 4h 2 4/4 1.5-8 d after second exposure 23 6.5 h 2 2/4 24 min after first exposure and during second exposure 12 4.5-6 hb 15 4/4 During or after fifth exposure (3 rabbits); during ninth exposure (1) 1 7h 14 0/4 – 1 7h 55 3/5 During ninth exposure (1 rabbit); after twenty-third exposure (1 rabbit); after thirty-ninth exposure (1 rabbit) Guinea pigs (n = 2) 50 50 min 1 0/2 – 53 100 min 1 2/2 4.04 and 4.32 h 23 120 min 1 0/2 –

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Guinea pigs (n = 2) 23 4h 2 2/2 Less than 7.3 h after first exposure 1 7h 14 0/2 – 1 7h 55 0/2 – Rats ( n = 2) 50 50 min 1 0/2 – 53 100 min 1 2/2 1.37 and 3.04 h 23 4h 2 0/2 – 23 6.5 h 2 2/2 0 and 55 min after first exposure b 12 4.5-6 h 15 1/2 After sixth exposure 1 7h 14 0/2 – 1 7h 55 0/2 – Mice (n = 7-10) 50 50 min 1 10/10 0-94 min (7 mice); 5.25-8.25 h (3 mice) 53 100 min 1 10/10 0-92 min 23 30 min 1 7/10 1.05-4.2 h (5 mice); 7 h (1 mouse), 16 h ( 1 mouse) 23 120 min 1 10/10 1.85-6.85 h 23 4h 2 10/10 During first exposure (3 mice); less than 7 h after first exposure (7 mice) 12 4.5-6 hb 15 4/7 During second exposure (3 mice); during seventh exposure (1 mouse) 1 7h 14 1/10 3 days after tenth exposure 1 7h 55 1/10 1 day after forty-ninth exposure a The same monkey was exposed in both of these experiments, with a 9-day interval between them. b Animals were exposed for 4.5 h on the first day, 5.5 h on the second day, and 6 h on each of 13 other days for 5 days per week. Source: Adapted from Treon et al. 1949. 275

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276 Acute Exposure Guideline Levels 3.1.2. Cats Wooster et al. (1947) exposed groups of 1-2 cats (sex and strain not speci- fied) to ketene vapor (purity not specified). The amount of ketene generated per minute was determined at the beginning and the end of exposure by titration method to calculate the mean ketene concentration during exposure. Cats were exposed (whole body) for 10 min to mean concentrations of 233 ppm (0.40 g/m3; n = 1), 367 ppm (0.63 g/m3; n = 2), 623 ppm (1.07 g/m3; n = 2), and 815 ppm (1.40 g/m3; n = 1); the observation period was 15 days. Cats showed no signs of irritation during exposure, but salivated profusely. Mortality rates of 0/1, 1/2, 2/2, and 1/1, respectively, were found (see Table 6-5). Cats died within 12 h. Deaths were preceded by convulsive seizures, during which animals gasped for breath. Necropsy revealed trachea and bronchi containing foam and hyperemic lungs con- taining lobules filled with edema fluid. Microscopically, the perivascular connec- tive tissue of the bronchial and bronchiolar vessels was very edematous, as were many alveoli. No changes in the epithelium of the airways or other organs were found. Toxicity was reported in a general way for several species and without ref- erence to exposure concentrations. Treon et al. (1949) exposed four cats (one animal per concentration, sex and strain not specified) to ketene (purity: 98-99%) at initial nominal concentrations of 200, 750, 1,250, and 1,500 ppm for 10 min under static conditions. The lowest concentration that caused death was 750 ppm, although it was noticed that the cat had an obstruction of the bowel. Times of death are presented in Table 6-3. Cats displayed signs of illness only after a latency period much longer than that ob- served for any of the other species tested. Referring to all species tested, general toxicity of ketene was reported to be characterized by dyspnea and cyanosis cul- minating in fatal edema of the lungs. Death was preceded by evidence of irritation (probably anoxic) of the central nervous system. The lowest concentration that induced edema and congestion of the pulmonary alveoli was 750 ppm. Treon et al. (1949) exposed cats (one or two cats per concentration, sex and strain not specified) to ketene at nominal concentrations ranging from 1 to 23 ppm for a various number of exposures (see Section 3.1.1 for technical details and Ta- ble 6-4 for information on exposure conditions). No mortality was seen in cats exposed at 1 ppm for up to 55 days or in cats exposed for two successive days at 23 ppm (4- or 6.5-h exposures). The only cat that died had received five exposures at 12 ppm for 4.5-6 h. Cats exposed to ketene at 12 or 23 ppm for several hours on successive days exhibited sneezing, coughing, salivation, slight nasal discharge, slight irritation of the eyelids, and labored respiration. Convulsions preceded death in the case of the cat exposed at 12 ppm. 3.1.3. Rabbits and Guinea Pigs Cameron and Neuberger (1937) studied the noxious properties of ketene in guinea pigs (number, sex, and strain not specified). Ketene was prepared accord

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Ketene 277 TABLE 6-5 Acute Lethality Data from Studies of Animals Exposed to Ketene for 10 Minutes Concentration (ppm) Mortality Time of Death or Observation Period Cats (n = 1-2) 233 0/1 15 d 367 1/2 8-12 h 623 2/2 26 min and 8-12 h 815 1/1 135 min Rabbits (n = 2) 652 0/2 10 d Guinea pigs (n = 2-4) 367 2/4 8-12 h 3/4 3d 623 4/4 8-12 h 652 2/2 8-12 h Rats (n = 4) 122 0/4 10 d 250 4/4 150 min 774 4/4 135 min Mice (n = 20-24) 70 9/20 115 min 20/20 240 min 122 16/20 180 min 18/20 3d 192 20/20 115 min 349 11/20 55 min 20/20 80 min 815 24/24 60 min Source: Adapted from Wooster et al. 1947. ing to the method of Herriott (1934.) Methane was produced in equivalent amounts using this method, but the authors stated that methane could be ignored because very high concentrations were known to be without effect on white mice. In some experiments (not further specified) ketene was passed through ice-cold liquid paraffin to remove acetone. The exposure chamber was an 18-L glass vessel containing a fan and perforated for some inlets and outlets (glass tubes). The use of rubber was minimized to prevent polymerization of ketene. The system ensured that ketene entered within 30 seconds after commencing the experiment and allowed the concentration to be measured during exposure. A titration method was used, but no details about when the measurements were taken or how many were made were provided. Guinea pigs were exposed (whole body) for 5 min to ketene at 200-300 ppm (whether these were actual or nominal

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298 Acute Exposure Guideline Levels TABLE 6-12 Standards and Guidelines for Ketene Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NR NR NR NR NR AEGL-2 0.08 ppm 0.08 ppm 0.063 ppm 0.040 ppm 0.029 ppm (0.14 mg/m3) (0.14 mg/m3) (0.11 mg/m3) (0.069 mg/m3) 0.050 mg/m3) AEGL-3 0.24 ppm 0.24 ppm 0.19 ppm 0.12 ppm 0.088 ppm (0.41 mg/m3) (0.41 mg/m3) (0.33 mg/m3) (0.21 mg/m3) (0.15 mg/m3) IDLH – 5 ppm – – – (NIOSH)a (9 mg/m3) TLV-TWA – – – – 0.5 ppm (ACGIH)b (0.86 mg/m3) PEL-TWA – – – – 0.5 ppm (OSHA)c (0.9 mg/m3) REL-TWA – – – – 0.5 ppm (NIOSH)d (0.9 mg/m3) TLV-STEL 1.5 ppm – – – – (ACGIH)e (2.6 mg/m3) (15 mins) REL-STEL 1.5 ppm – – – – (NIOSH)f (3 mg/m3) (15 mins) MAC – – – – 0.5 ppm (The Netherlands)g (0.9 mg/m3) a IDLH (immediately dangerous to life or health, National Institute for Occupational Safe- ty and Health [NIOSH 1994]) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects. b TLV-TWA (threshold limit value - time-weighted average, American Conference of Governmental Industrial Hygienists [ACGIH 2012]) is the time-weighted average con- centration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. c PEL-TWA (permissible exposure limit - time-weighted average, Occupational Safety and Health Administration [(29 CFR 1910.1000) [2006]) is defined analogous to the ACGIH TLV-TWA, but is for exposures of no more than 8 h/day, 40 h/week. d REL-TWA (recommended exposure limit - time-weighted average, National Institute for Occupational Safety and Health [NIOSH 2011]) is defined analogous to the ACGIH TLV-TWA. e TLV-STEL (threshold limit value-short-term exposure limit, American Conference of Governmental Industrial Hygienists [ACGIH 2012]) is defined as a 15-min TWA expo- sure which should not be exceeded at any time during the workday even if the 8-h TWA is within the TLV-TWA. Exposures above the TLV-TWA and up to the STEL should not be longer than 15 min and should not occur more than four times per day. There should be at least 60 min between successive exposures in this range. f REL-STEL (recommended exposure limit – short-term exposure limit, National Institute for Occupational Safety and Health [NIOSH 2011) is defined analogous to the ACGIH TLV-STEL.

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Ketene 299 g MAC (maximaal aanvaaarde concentratie [maximum accepted concentration], SDU Uitgevers [under the auspices of the Ministry of Social Affairs and Employment], Dutch Expert Committee for Occupational Standards, The Netherlands (MSZW 2004) is de- fined analogous to the ACGIH TLV-TWA. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2012. Ketene (CAS Reg. No. 463-51-4). 2012 TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substance and Physical Agents. Ameri- can Conference of Governmental Industrial Hygienists, Cincinnati, OH. Cameron, G.R., and A. Neuberger. 1937. Ketene as a noxious gas. J. Pathol. Bacteriol. 45(3):658-660. Hasek, R.H. 1981. Ketenes and related substances. Pp. 874-893 in Kirk-Othmer Encyclo- pedia of Chemical Technology, 3rd Ed., Vol. 13, J.I. Kroschwitz, and M. Howe- Grant, eds. New York: Wiley. Health Council of the Netherlands. 2001. Ketene (CAS Reg. No. 463-51-4). Health-based Reassessment of Administrative Occupational Exposure Limits. No. 2000/15OSH/ 024. Health Council of the Netherlands, The Hague [online]. Available: http:// www.gezondheidsraad.eu/sites/default/files/00@15024OSH.PDF [accessed Jan. 9, 2014]. Herriott, R.M. 1934. A convenient ketene generator. J. Gen. Physiol. 18:69-70 (as cited in Cameron and Neuberger 1937). HSDB (Hazardous Substances Data Bank). 2005. Ketene (CAS Reg. No. 463-51-4). TOXNET Specialized Information Services, U.S. National Library of Medicine, Be- thesda, MD [online]. Available: http://toxnet.nlm.nih.gov/ [accessed Jan. 9, 2014]. Jensen, K.A., I. Kirk, G. Kølmark, and M. Westergaard. 1951. Chemically induced muta- tions in Neurospora. Cold Spring Harb. Symp. Quant. Biol. 16:245-261. Mendenhall, R.M., and H.E. Stokinger. 1959. Tolerance and cross-tolerance development to atmospheric pollutants ketene and ozone. J. Appl. Physiol. 14(6):923-926. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Keteen. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook. net/lasrookNL/maclijst2004.htm [accessed Jan. 3, 2014]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Ketene. U.S. Department of Health and Human Services, Centers for Disease Control and Pre- vention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/idlh/463514.html [accessed Jan. 10, 2014]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: Ketene. U.S. Department of Health and Human Ser- vices, Centers for Disease Control and Prevention, National Institute for Occupa- tional Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc.gov/ niosh/npg/npgd0367.html [accessed Jan. 10, 2014]. NRC (National Research Council). 1993. Guidelines for Developing Community Emergen- cy Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.

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300 Acute Exposure Guideline Levels 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). 2002. Phosgene. Pp. 13-70 in Acute Exposure Guide- line Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: National Academies Press. Potts, A.M., F.P. Simon, and R.W. Gerard. 1949. The mechanism of phosgene and di- phosgene. Arch. Biochem. 24(2):327-337. Rapoport, I.A. 1947. Derivatives of carbamic acid and mutations [in Russian]. Biull. Eksp. Biol. Med. 23(3):198-201. Sciuto, A.M. 2005. Inhalation toxicology of an irritant gas: Historical perspectives, cur- rent research, and case studies of phosgene exposure. Pp. 457-482 in Inhalation Toxicology, 2nd Ed., H. Salem, and S.A. Katz, eds. Boca Raton, FL: CRC Press. Taylor, H. 1950. Non-metallic toxicological hazards: Some of the newer compounds in industry. Br. Med. Bull. 7(1-2):15-18. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. Treon, J.F., H.E. Sigmon, K.V. Kitzmiller, F.F. Heyroth, W.J. Younker, and J. Cholak. 1949. Physiologic response of animals exposed to air-borne ketene. J. Ind. Hyg. Toxicol. 31(4):209-219. Wooster, H.A., C.C. Lushbauch, and C.E. Redemann. 1947. The inhalation toxicity of ketene and ketene dimer. J. Ind. Hyg. Toxicol. 29(1):56-57.

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Ketene 301 APPENDIX A DERIVATION OF AEGL VALUES FOR KETENE Derivation of AEGL-1 Values Due to the uncertainty of whether the lowest concentration of ketene tested of 1 ppm (Treon et al. 1949) would result in effects that exceed the definition of AEGL-1 effects, derivation of AEGL-1 values is not recommended for ketene. Ab- sence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. Derivation of AEGL-2 Values Toxicity end point: 3-fold reduction of AEGL-3 values 10-min AEGL-2: 0.24 ppm ÷ 3 = 0.080 ppm (0.14 mg/m3) 30-min AEGL-2: 0.24 ppm ÷ 3 = 0.080 ppm (0.14 mg/m3) 1-h AEGL-2: 0.19 ppm ÷ 3 = 0.063 ppm (0.11 mg/m3) 4-h AEGL-2: 0.12 ppm ÷ 3 = 0.040 ppm (0.069 mg/m3) 8-h AEGL-2: 0.088 ppm ÷ 3 = 0.029 ppm (0.050 mg/m3) Derivation of AEGL-3 for Ketene Key study: Treon, J.F., H.E. Sigmon, K.V. Kitzmiller, F.F. Heyroth, W.J. Younker, and J. Cholak. 1949. Physiologic response of animals exposed to air-borne ketene. J. Ind. Hyg. Toxicol. 31(4):209-219. Toxicity end point: No mortality in mice exposed to ketene at 1 ppm for 7 h. Time scaling: Cn × t = k (default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations); time scaling not performed for the 10-min AEGL-3 value, because of the uncertainty in extrapolating a 7-h point of departure to a 10-min value.

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302 Acute Exposure Guideline Levels Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Calculations: (1 ppm)3 × 7 h = 7 ppm-h (1 ppm)1 × 7 h = 7 ppm-h 10-min AEGL-3: 0.24 ppm (0.41 mg/m3) (equal to 30-min value) 30-min AEGL-3: C3 × 0.5 h = 7 ppm-h C = 2.4 ppm 2.4 ppm ÷ 10 = 0.24 ppm (0.41 mg/m3) 1-h AEGL-3: C3 × 1 hr = 7 ppm-h C = 1.9 ppm 1.9 ppm ÷ 10 = 0.19 ppm (0.33 mg/m3) 4-h AEGL-3: C3 × 4 h = 7 ppm-h C = 1.2 ppm 1.2 ppm ÷ 10 = 0.12 ppm (0.21 mg/m3) 8-h AEGL-3: C × 8 h = 7 ppm-h C = 0.875 ppm 0.875 ÷ 10 = 0.088 ppm (0.15 mg/m3)

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Ketene 303 APPENDIX B ACUTE GUIDELINE LEVELS FOR KETENE Derivation Summary AEGL-1 VALUES AELG-1 values for ketene are not recommended because of insufficient da- ta. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.08 ppm 0.08 ppm 0.063 ppm 0.040 ppm 0.029 ppm (0.14 mg/m3) (0.14 mg/m3) (0.11 mg/m3) (0.069 mg/m3) (0.050 mg/m3) Data adequacy: Data consistent with the definition of AEGL-2 values were not available. The AEGL-2 values for ketene were based on a 3-fold reduction of the AEGL-3 values. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 0.24 ppm 0.24 ppm 0.19 ppm 0.12 ppm 0.088 ppm (0.41 mg/m3) (0.41 mg/m3) (0.33 mg/m3) (0.21 mg/m3) (0.15 mg/m3) Key reference: Treon, J.F., H.E. Sigmon, K.V. Kitzmiller, F.F. Heyroth, W.J. Younker, and J. Cholak. 1949. Physiologic response of animals exposed to airborne ketene. J. Ind. Hyg. Toxicol. 31(4): 209-219. Test species/Strain/Number: Mouse, strain and sex not specified, 10/ group Exposure route/Concentrations/Durations: Inhalation, 1 ppm for 7 h/day for 14 days End point/Concentration/Rationale: No deaths were observed after the first day of exposure; 1/10 mice died 3 days after the tenth exposure. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, mouse is the most susceptible animal species for ketene Intraspecies: 3, mode of action (acylation of functional groups on proteins and enzymes in the lung) is not expected to vary greatly among individuals. Human studies examining the toxicity of phosgene, which appears to have a mode of action similar to ketene, did not identify sensitive subpopulations. An intraspecies uncertainty factor of 3 was used to derive AEGL-2 and AEGL-3 values for phosgene (NRC 2002). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable (Continued)

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304 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Time scaling: Cn × t = k (default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations). Time scaling was not performed for the 10-min AEGL-3 value, because of the uncertainty in extrapolating a 7-h point of departure to a 10-min value. The 10-min AEGL-3 value of 0.24 ppm is supported by the study of Treon et al. (1949), which reported no deaths in mice (0/10) after exposure to ketene at 25 ppm for 10 min. Data adequacy: The database on ketene is poor. Only four studies were available on the acute toxicity of ketene in laboratory animals; these studies are old and sometimes lack sufficient details. No human data on ketene were available. Although Treon et al. (1949) reported only nominal concentrations of ketene, the results of the study are generally in agreement with other studies. Therefore, the study by Treon et al. (1949) provides an appropriate point of departure for deriving AEGL-3 values because it used ketene of high purity (98-99%), involved dynamic exposure conditions, involved longer exposure durations (up to 7 h), and tested a wide concentration range of ketene.

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Ketene 305 APPENDIX C CATEGORY PLOT FOR KETENE FIGURE C-1 Category plot of toxicity data and AEGL values for ketene.

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306 TABLE C-1 Data Used in Category Plot for Ketene Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-2 0.08 10 AEGL AEGL-2 0.08 30 AEGL AEGL-2 0.063 60 AEGL AEGL-2 0.040 240 AEGL AEGL-2 0.029 480 AEGL AEGL-3 0.24 10 AEGL AEGL-3 0.24 30 AEGL AEGL-3 0.19 60 AEGL AEGL-3 0.12 240 AEGL AEGL-3 0.088 480 AEGL Treon et al. 1949 Mouse 1 75 10 3 Mortality (10/10) Treon et al. 1949 Mouse 1 23 30 SL Mortality (7/10) Treon et al. 1949 Rabbit 1 50 50 0 Treon et al. 1949 Rat 1 50 50 0 Treon et al. 1949 Guinea pig 1 50 50 1 Treon et al. 1949 Mouse 1 50 50 3 Mortality (10/10) Treon et al. 1949 Guinea pig 1 53 100 3 Mortality (2/2) Treon et al. 1949 Rat 1 53 100 3 Mortality (2/2) Treon et al. 1949 Mouse 1 53 100 3 Mortality (10/10) Treon et al. 1949 Rabbit 1 53 100 SL Mortality (3/4) Treon et al. 1949 Guinea pig 1 23 120 2 Treon et al. 1949 Mouse 1 23 120 3 Mortality (10/10) Treon et al. 1949 Cat 1 23 240 1

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Treon et al. 1949 Monkey 1 23 240 2 Adverse clinical effects, ocular irritation, coughing, lethargy Treon et al. 1949 Guinea pig 1 23 240 3 Mortality (2/2) Treon et al. 1949 Mouse 1 23 240 3 Mortality (10/10) Treon et al. 1949 Rabbit 1 15 270 1 Treon et al. 1949 Mouse 1 15 270 2 Treon et al. 1949 Rat 1 15 270 2 Treon et al. 1949 Cat 1 23 390 1 Treon et al. 1949 Rat 1 23 390 3 Mortality (2/2) Treon et al. 1949 Rabbit 1 23 390 SL Mortality (1/4) Treon et al. 1949 Cat 1 1 420 0 Treon et al. 1949 Cat 1 1 420 0 Treon et al. 1949 Monkey 1 1 420 0 Treon et al. 1949 Mouse 1 23 30 SL Mortality (7/10) Treon et al. 1949 Rabbit 1 50 50 0 Treon et al. 1949 Rat 1 50 50 0 Treon et al. 1949 Guinea pig 1 50 50 1 Treon et al. 1949 Mouse 1 50 50 3 Mortality (10/10) Treon et al. 1949 Guinea pig 1 53 100 3 Mortality (2/2) Treon et al. 1949 Rat 1 53 100 3 Mortality (2/2) Treon et al. 1949 Mouse 1 53 100 3 Mortality (10/10) Treon et al. 1949 Rabbit 1 53 100 SL Mortality (3/4) Treon et al. 1949 Guinea pig 1 23 120 2 Treon et al. 1949 Mouse 1 23 120 3 Mortality (10/10) Treon et al. 1949 Cat 1 23 240 1 (Continued) 307

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308 TABLE C-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Treon et al. 1949 Monkey 1 23 240 2 Adverse clinical effects, ocular irritation, coughing, lethargy Treon et al. 1949 Guinea pig 1 23 240 3 Mortality (2/2) Treon et al. 1949 Mouse 1 23 240 3 Mortality (10/10) Treon et al. 1949 Rabbit 1 15 270 1 Treon et al. 1949 Mouse 1 15 270 2 Treon et al. 1949 Rat 1 15 270 2 Treon et al. 1949 Cat 1 23 390 1 Treon et al. 1949 Rat 1 23 390 3 Mortality (2/2) Treon et al. 1949 Rabbit 1 23 390 SL Mortality (1/4) Treon et al. 1949 Cat 1 1 420 0 Treon et al. 1949 Cat 1 1 420 0 Treon et al. 1949 Monkey 1 1 420 0 For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal