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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19 (2015)

Chapter: 2 Diketene Acute Exposure Guideline Levels

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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Page 44
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
×
Page 45
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Page 46
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
×
Page 47
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
×
Page 48
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
×
Page 49
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
×
Page 50
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
×
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Page 54
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Page 55
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Page 58
Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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Suggested Citation:"2 Diketene Acute Exposure Guideline Levels." National Research Council. 2015. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19. Washington, DC: The National Academies Press. doi: 10.17226/21701.
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2 Diketene1 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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Ko- wetha Davidson (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Robert Benson (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 re- vised 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 devel- oped 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). 41

42 Acute Exposure Guideline Levels 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 respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Diketene is a non-hygroscopic, light-colored or colorless liquid that is polymerized on standing. It is flammable and has a moderate fire risk. Diketene has a pungent odor. It is an irritant, causing mild irritation of the eyes, nose, and throat after occupational exposure at 0.58 ppm for 1 min. Inhalation of diketene was not lethal to rats at 250 ppm for 1 h or to rabbits at 194 ppm for 10 min, but deaths occurred in rats exposed at 500 or 750 ppm for 1 h. Rats exposed to diketene at 250-750 ppm for 1 h showed signs of ocular and respiratory-tract irritation. Deaths occurred in mice exposed to diketene at 870 ppm for 10 min and in guinea pigs exposed at 194 ppm for 10 min. Pulmonary edema was found in the animals that died. The 1-h LC50 (lethal concentration, 50% lethality) val- ues for rats were 548 ppm for males, 689 ppm for females, and 612 ppm for both sexes combined. Data were insufficient for deriving AEGL-1 values for diketene. There- fore, AEGL-1 values are not recommended. Data were also insufficient for deriving AEGL-2 values for diketene. The standing operating procedures for deriving AEGL values specify that AEGL-2 values for chemicals with steep concentration-response curves may be estimated by dividing the AEGL-3 values by a factor of 3. The steepness of the lethality concentration-response curve for diketene indicates that a factor of 3 should be adequate for reducing the AEGL-3 values to a level consistent with the defini- tion of AEGL-2. AEGL-3 values were derived on the basis of an acute inhalation study in which rats were exposed to diketene at 250, 500, or 750 ppm for 1 h (Katz

Diketene 43 1987). The point-of-departure was the lethality BMCL05 (benchmark concentra- tion, 95% lower confidence limit with 5% response) of 181 ppm, which was calculated using a log-probit model. A total uncertainty factor of 30 was applied; a factor of 10 for interspecies differences and a factor of 3 for intraspecies varia- bility. Diketene is irritating and much of its toxicity is likely caused by a direct chemical effect on the tissue; that type of portal-of-entry effect is not expected to vary greatly among individuals. The intraspecies uncertainty factor of 3 is further supported by the similarity in mortality incidence and clinical signs be- tween male and female rats exposed to diketene (Katz 1987). A modifying fac- tor of 2 was also applied because of the limited database on diketene. Time scal- ing was performed using the equation Cn × t = k. Data on diketene were insufficient for determining an empirical value for the exponent n, so default values of n = 3 for extrapolating to shorter durations (10 and 30 min) and n = 1 for extrapolating to longer durations (4 and 8 h) were used. The AEGL values for diketene are presented in Table 2-1. 1. INTRODUCTION Diketene is a light-colored or colorless non-hygroscopic liquid that poly- merizes on standing (AIHA 2000; Lewis 2007). It is flammable and has a mod- erate fire risk. Diketene is used in the production of pigments and toners, pesti- cides, food preservatives, and pharmaceutical intermediates (HSDB 2003; Lewis 2007). The odor of diketene has been described as pungent (Lewis 2007). The chemical and physical properties of diketene are presented in Table 2-2. 2. HUMAN TOXICITY DATA 2.1. Human Lethality No data regarding exposure of humans to lethal concentrations of diketene were found. TABLE 2-1 AEGL Values for Diketene End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient data (nondisabling) AEGL-2 1.8 ppm 1.3 ppm 1.0 ppm 0.25 ppm 0.13 ppm One-third of the (disabling) (6.2 (4.5 (3.4 (0.86 (0.45 AEGL-3 values. mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 5.5ppm 3.8 ppm 3.0 ppm 0.75 ppm 0.38 ppm BMCL05 (lethal) (19 (13 (10 (2.6 (1.3 for lethality mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Katz 1987) a Not recommended. Absence of AEGL-1 values does not imply that exposures at concen- trations below the AEGL-2 values are without effect.

44 Acute Exposure Guideline Levels TABLE 2-2 Chemical and Physical Properties of Diketene Parameter Value Reference Synonyms 3-Butenoic acid, 3-hydroxy-, beta-lacone; HSDB 2003 ethenone, dimer; ketene, dimer; 4-methylene- 2-oxetanone; vinylaceto-beta-lactone CAS registry no. 674-82-8 HSDB 2003 Chemical formula C4H4O2 HSDB 2003 Molecular weight 84.08 HSDB 2003 Physical state Light-colored or colorless liquid AIHA 2000; Lewis 2007 Melting point -6.5°C HSDB 2003 Boiling point 127.4°C HSDB 2003 Density/Specific gravity 1.096 (20/20°C) Lewis 2007 (water = 1) 1.0897 HSDB 2003 Vapor density (air = 1) 2.9 HSDB 2003 Solubility Soluble in common organic solvents; soluble Lewis 2007 in water Vapor pressure 10 mm Hg at 24.3°C AIHA 2000 1.07 kPa at 20°C HSDB 2003 Flash point (tagged closed cup) 34°C AIHA 2000 Autoignition temperature 310°C AIHA 2000 Conversion factors 1 mg/m3 = 0.29 ppm; AIHA 2000 1 ppm = 3.44 mg/m3 2.2. Nonlethal Toxicity Occupational exposure to diketene at a concentration of 2 mg/m3 (0.58 ppm) for 1 min caused mild irritation of the conjunctiva and mucosa of the nose and throat (Danishevskii 1948,1951; Feldman 1967). 2.3. Summary No studies were found on human exposure to lethal concentrations of diketene. A concentration of 0.58 ppm caused mild ocular, nasal, and throat irri- tation. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rat Groups of five male and five female CRL:CD®(SD)BR rats were exposed to diketene at concentrations of 0, 250, 500, or 750 ppm for 1 h and observed for 14 days after exposure (Katz 1987). The analytic concentrations were 271 ± 2.4, 466 ± 13.7, and 778 ± 16.9 ppm, respectively. The rats were exposed in a 420-L

Diketene 45 stainless steel and glass chamber with 10-13 air changes per hour. The chamber atmosphere was analyzed four or five times using an infrared analyzer; the nom- inal concentration was calculated on the basis of the amount of diketene used and the air flow rate. All rats were subjected to gross examination, but no tissues were collected for microscopic examination. Mortality and clinical signs are summarized in Table 2-3. The mortality rate was 0/10, 3/10, and 7/10 rats (sexes combined) in the 250-, 500-, and 750- ppm groups, respectively. All deaths occurred within 48 h after exposure, except for one male rat exposed at 750 ppm that died on day 6. The LC50 values were 548 ppm for male rats, 689 ppm for female rats, and 612 ppm for both sexes combined. LC10 values calculated by the investigators were 346 ppm for males, 410 ppm for females, and 370 ppm for both sexes combined. All rats exposed to diketene exhibited excessive tearing (lacrimation) during exposure and for a few hours after exposure. Porphyrin discharge from the nose was observed in male and female rats for up to 48 h after exposure at 500 and 750 ppm. Effects on the respiratory tract consisted of gasping in all rats at all concentrations and wheez- ing in one or two rats per group. Rales were observed in one male rat in each exposure group and one female in the 500-ppm group, but the effect might not have been due to diketene, because no increase in the incidence of rales occurred with a 15-fold increase in the exposure concentration. No gross lesions were found in any rats exposed to diketene. 3.1.2. Mice Wooster et al. (1947) exposed groups of 4, 30, and 20 mice to diketene at concentrations of 194, 580, or 870 ppm, respectively, for 10 min. Diketene was prepared at a known concentration in acetone and sprayed into the chamber from a glass atomizer; the concentration of diketene in inhaled air was 0.67 mg/L (194 ppm). The animals were observed for up to 15 days after exposure. No additional details on the experimental protocol were provided. One mouse died TABLE 2-3 Mortality and Clinical Signs in Rats Exposed to Diketene Exposure Concentration 0 250 500 750 0 250 500 750 Parameter No. males No. females No. exposed 0 5 5 5 0 5 5 5 Mortality 0 0 2 4 0 0 1 3 Excessive tearing 0 5 5 5 0 5 5 5 Porphyrin discharge 0 0 2 2 0 0 2 3 Gasping 0 5 5 5 0 5 5 5 Rales 0 1 1 1 0 0 1 0 Wheezing 0 1 0 0 0 0 1 2 Poor condition 0 0 0 4 0 0 0 1 Source: Katz 1987.

46 Acute Exposure Guideline Levels after exposure at 870 ppm, but no deaths occurred in mice exposed at 580 or 194 ppm. No specific clinical signs or pathologic findings were described. The in- vestigators noted that the findings in the animals that died were similar to those described for animals (particularly the cat) exposed to ketene. Microscopically, animals that died after ketene exposure had proteinaceous edematous fluid in the alveoli of the lungs and in the perivascular connective tissue of the bronchial and bronchiolar vessels. After describing the microscopic lesions in animals that died after ketene exposure, Wooster et al. (1947) stated that “the findings in the few animals dying after diketene poisoning were similar.” That suggests that the mice that died after exposure to diketene had alveolar and bronchial edema (pulmonary edema). 3.1.3. Other Species All three guinea pigs died after exposure to diketene at 194 ppm under the same conditions as described for mice (see Section 3.1.2) (Wooster et al. 1947). No clinical signs or pathologic effects were described. From the investigators’ description that the findings in the dead animals were similar to those of animals that died from ketene exposure, it was implied that the guinea pigs also had pulmonary edema. 3.2. Nonlethal Toxicity Wooster et al. (1947) exposed four rats and three rabbits to diketene at 0.67 mg/L (194 ppm) for 10 min under the same conditions as described for mice (see Section 3.1.2). All of the animals survived to the end of the study. No clinical signs or pathologic lesions were described. 3.3. Other End Points of Toxicity No data were found on the neurotoxicity, developmental toxicity, repro- ductive toxicity, genetic toxicity, or carcinogenicity of inhaled diketene in ex- perimental animals. 3.4. Summary Table 2-4 summarizes the lethal effects of acute inhalation exposure to diketene in several species. The LC50 for a 1-h exposure of rats to diketene ranged from 548 to 689 ppm. Rats died after exposure to diketene at concentrations 500 or 750 ppm for 1 h, guinea pigs died after exposure at 194 ppm for 10 min, and mice died after exposure at 870 ppm for 10 min. No deaths occurred in rats and rabbits after exposure to diketene at 194 ppm for 10 min. Ocular and respiratory- tract irritation were observed in rats exposed at lethal and nonlethal concentrations

Diketene 47 of diketene greater than 250 ppm. The primary findings in mice and guinea pigs exposed to diketene were the same as those found in the cat that died after expo- sure to ketene (alveolar and bronchial edema or pulmonary edema). 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition No data on the uptake, metabolism, disposition, or excretion of inhaled diketene were found. 4.2. Mechanism of Toxicity Diketene is an irritant (Lewis 2007). Wooster et al. (1947) noted that the pathologic changes caused by ketene were similar to those of phosgene. 4.3. Structure-Activity Relationships Diketene is the dimeric form of ketene, and is similar to but less toxic than ketene. At high temperatures (510-603K), diketene undergoes thermal decom- position to form ketene, cyclobuta-1,3-dione, and cyclobuta-1,2-dione (Bui et al. 2007). Wooster et al. (1947) exposed rats, cats, guinea pigs, and rabbits to ke- tene for 10 min and observed the survivors for up to 15 days. Ketene exposure caused severe damage to the respiratory tract (pulmonary edema), but the patho- logic effects were described only for cats. The lowest concentrations associated TABLE 2-4 Summary of Acute Lethality Data from Studies of Laboratory Animals Exposed to Diketene by Inhalation Exposure Effect Species (sex) Concentration Time (% lethality) Reference Rat 194 10 min 0% Wooster et al. 1947 Rat (females) 689 1h LC50 Katz 1987 Rat (males and females) 612 1h LC50 Katz 1987 Rat (males) 548 1h LC50 Katz 1987 Rat (females) 410 1h LC10 Katz 1987 Rat (males and females) 370 1h LC10 Katz 1987 Rat (males) 346 1h LC10 Katz 1987 Mouse 870 10 min 5% Wooster et al. 1947 Mouse 194-580 10 min 0% Wooster et al. 1947 Guinea pig 194 10 min 100%a Wooster et al. 1947 Rabbit 194 10 min 0% Wooster et al. 1947 a Only three animals exposed.

48 Acute Exposure Guideline Levels with mortality were 35 ppm for the mouse, 125 ppm for the rat, 183 ppm for the cat and guinea pig, and 325 ppm for the rabbit. In contrast, no deaths were ob- served in mice exposed to diketene at 194-580 ppm for 10 min, and 100% mor- tality occurred in rabbits exposed to diketene at 194 ppm for 10 min (Wooster et al. 1947). 4.4. Species Variability According to Wooster et al. (1947), guinea pigs died after exposure to diketene at 194 ppm for 10 min, but mice, rats, and rabbits survived a 10-min exposure at 194 ppm. Thus, the guinea pig appears to be more sensitive than other species to diketene. 4.5. Susceptible Populations No data are available on populations that might be susceptible to diketene. 4.6. Concentration-Exposure Duration Relationship Lethality data from the study by Katz (1987) was used to create Figure 2-1, which shows a steep concentration-response curve. See Section 3.1.1. for a de- scription of the study. 100 90 80 70 60 50 40 30 20 10 0 -10 0 100 200 300 400 500 600 700 800 FIGURE 2-1 Concentration-response relationship between diketene and lethality in rats.

Diketene 49 4.7. Concurrent Exposure Issues No concurrent exposure issues for diketene were found. 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 Humans occupationally exposed to diketene at 0.58 ppm for 1 min experi- enced mild irritation of the eyes, nose, and throat (Danishevskii 1948, 1951). 5.2. Animal Data Relevant to AEGL-1 No animal data relevant to deriving AEGL-1 values for diketene were found. 5.3. Derivation of AEGL-1 Values No AEGL-1 values were derived for diketene. The only data available for deriving AEGL-1 values are from a study in which workers exposed to diketene at 0.58 ppm were reported to experience mild irritation of the eyes, nose, and throat. That information is from a secondary source and could not be verified, so the data are considered insufficient for deriving AEGL-1 values. Absence of AEGL-1 values does not imply that exposures at concentrations below the AEGL-2 values are without adverse effects. 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data relevant to deriving AEGL-2 values for diketene were found. 6.2. Animal Data Relevant to AEGL-2 Lacrimation and gasping were observed in rats exposed to diketene at 250 ppm for 1 h, and none of the animals died (Katz 1987). No deaths occurred among groups of mice exposed to diketene at 194-580 ppm for 10 min (Wooster et al. 1947). 6.3. Derivation of AEGL-2 Values The experimental data from animal studies were not appropriate for deriv- ing AEGL-2 values for diketene. Although rats exposed at 250 ppm for 1 h

50 Acute Exposure Guideline Levels showed clinical signs indicative of ocular and respiratory-tract irritation and no deaths occurred (Katz 1987), the BMCL05 for lethality (used as the point-of- departure for deriving AEGL-3 values) was lower than the highest concentration causing no lethality in rats. Therefore, the rat study should not be used to derive AEGL-2 values. The standing operating procedures for deriving AEGL values specify that AEGL-2 values for chemicals with steep concentration-response curves may be estimated by dividing the AEGL-3 values by 3 (NRC 2001). Be- cause diketene is judged to have a steep concentration-response relationship for lethality, that approach was used to determine AEGL-2 values for diketene. The AEGL-2 values for diketene are presented in Table 2-5. 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data relevant to deriving AEGL-3 values for diketene were found. 7.2. Animal Data Relevant to AEGL-3 In an acute inhalation study using rats exposed to diketene vapor (250, 500, and 750 ppm) for 1 h (Katz 1987), deaths occurred at the two highest con- centrations. The exposure conditions and results of the study were well docu- mented. Wooster et al. (1947) reported that one of 20 mice died after exposure to diketene at 870 ppm for 10 min and all three guinea pigs exposed to diketene at 194 ppm for 10 min died. These data show that the guinea pig is the more sensitive species to diketene. 7.3. Derivation of AEGL-3 Values The AEGL-3 values were derived on the basis of the mortality study of rats exposed to diketene at 250, 500, or 750 ppm for 1 h (Katz 1987). A BMCL05 of 181 ppm was calculated using the log-probit model in EPA’s Benchmark Dose Software (v. 1.3.2), and an LC01 (lethality threshold, 1% lethality) of 276 ppm was calculated by probit regression analysis. The BMCL05 of 181 ppm was used as point-of-departure for deriving AEGL-3 values. A total uncertainty fac- tor of 30 was applied; a factor of 10 for interspecies differences and a factor of 3 for intraspecies variability. The factor of 3 was applied because diketene is TABLE 2-5 AEGL-2 Values for Diketene 10 min 30 min 1h 4h 8h 1.8 ppm 1.3 ppm 1.0 ppm 0.25 ppm 0.13 ppm (6.2 mg/m3) (4.5 mg/m3) (3.4 mg/m3) (0.86 mg/m3) (0.45 mg/m3)

Diketene 51 irritating and much of its toxicity is likely caused by a direct chemical effect on the tissue. That type of portal-of-entry effect is not expected to vary greatly among individuals. A factor of 3 is further supported by the fact that mortality incidences and clinical signs were similar between male and female rats exposed to diketene (Katz 1987). A modifying factor of 2 was also applied because of the limited database on diketene. Time scaling was performed using the equation Cn × t = k. The data on diketene were inadequate to determine an empirical value for the exponent n, so default values of n = 3 when extrapolating to shorter dura- tions (10 and 30 min) and n = 1 when extrapolating to longer durations (4 and 8 h) were used. The AEGL-3 values for diketene are presented in Table 2-6. 8. SUMMARY OF AEGLS 8.1. AEGL Values and Toxicity End Points The AEGL values for diketene are presented in Table 2-7. AEGL-1 values are not recommended because of insufficient data. AEGL-2 values were estimated by reducing the AEGL-3 values by a factor of 3. AEGL-3 values were derived from the BMCL05 for lethality calculated from an acute inhalation study in rats. 8.2. Other Standards and Guidelines The Russian occupational exposure limit for diketene is 1 mg/m3 (0.29 ppm) (RTECS 2006). The AEGL-2 and AEGL-3 values for 1-h exposures are similar to the emergency response planning guidelines (ERPG-2 and ERPG-3) of the American Industrial Hygiene Association (AIHA 2000) (Table 2-8). No other standards or guidelines for diketene were found. TABLE 2-6 AEGL-3 Values for Diketene 10 min 30 min 1h 4h 8h 5.5 ppm 3.8 ppm 3.0 ppm 0.75 ppm 0.38 ppm (19 mg/m3) (13 mg/m3) (10 mg/m3) (2.6 mg/m3) (1.3 mg/m3) TABLE 2-7 AEGL Values for Diketene Classification 10 min 30 min 1h 4h 8h AEGL-1 NRa NRa NRa NRa NRa (nondisabling) AEGL-2 1.8 ppm 1.3 ppm 1.0 ppm 0.25 ppm 0.13 ppm (disabling) (6.2 mg/m3) (4.5 mg/m3) (3.4 mg/m3) (0.86 mg/m3) (0.45 mg/m3) AEGL-3 5.5 ppm 3.8 ppm 3.0 ppm 0.75 ppm 0.38 ppm (lethal) (19 mg/m3) (13 mg/m3) (10 mg/m3) (2.6 mg/m3) (1.3 mg/m3) a Not recommended. Absence of AEGL-1 values does not imply that exposures at concen- trations below the AEGL-2 values are without effect.

52 Acute Exposure Guideline Levels TABLE 2-8 Standards and Guidelines for Diketene Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NR NR NR NR NR AEGL-2 1.8 ppm 1.3 ppm 1.0 ppm 0.25 ppm 0.13 ppm AEGL-3 5.5ppm 3.8 ppm 3.0 ppm 0.75 ppm 0.38 ppm ERPG-1 (AIHA)a – – 1 ppm – – ERPG-2 (AIHA) – – 5 ppm – – ERPG-3 (AIHA) – – 20 ppm – – a ERPG (emergency response planning guideline, American Industrial Hygiene Associa- tion) (AIHA 2000). The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor. The ERPG-1 for diketene is based on the threshold-limit value for ketene. The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversi- ble or other serious health effects or symptoms that could impair an individual’s ability to take protective action. The ERPG-2 for diketene is based on clinical signs from a 1-h rat lethality study. The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life- threatening health effects. The ERPG-3 is based on 1-h lethality data (LC50 of 612 ppm) in the rat. 8.3. Data Adequacy and Research Needs Additional animal studies with exposure durations relevant to the AEGL durations other than 1 h and with at least one species other than rat are needed to better characterize the acute inhalation toxicity of diketene. The diketene con- centrations tested should encompass the entire spectrum of AEGL end points, ranging from 90-100% lethality to no lethality and no-effect-levels for clinical signs and pathologic findings. 9. REFERENCES AIHA (American Industrial Hygiene Association). 2000. Emergency Response Planning Guidelines: Diketene. Fairfax, VA: AIHA. Bui, B., T.J. Tsay, M.C. Lin, and C.F. Melius. 2007. Theoretical and experimental studies of the diketene system: Product branching decomposition rate constants and ener- getics of isomers. Int. J. Chem. Kinet. 39(10):580-590. Danishevskii, S.L. 1948. Farmakologija i Toksilkologija, No. 3, p. 58 (as cited in Feld- man 1967).

Diketene 53 Danishevskii, S.L. 1951. P. 187 in Voprosy Gigieny Truda i Professional’nih Zabolevan- ii, Vol. 10. Moskva: VOZ (as cited in Feldman 1967). Feldman, Y.G. 1967. The experimental determination of the maximum permissible one- time concentration of diketene in the atmosphere. Hyg. Sanit. 32(1-3):9-14. HSDB (Hazardous Substances Data Bank). 2003. Acetyl ketene (CAS Reg. No. 674-82- 8). TOXNET, Specialized Information Services, U.S. National Library of Medi- cine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/html gen?HSDB [accessed September 10, 2013]. Katz, G.V. 1987. Acute Inhalation Toxicity and One-Hour LC10 Value of Diketene in the Rat. Study No. TX-86-265, February 4, 1967. Toxicological Sciences Section, Health and Environment Laboratories, Eastman Kodak Company, Rochester, NY. Lewis, Sr., R.J. 2007. Diketene (CAS Reg. No. 674-42-8). P. 437 in Hawley’s Condensed Chemical Dictionary, 14th Ed. New York: Wiley-Interscience. 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. RTECS (Registry of Toxic Effects of Chemical Substances). 2006. 4-methylene-2-oxeta- none (CASRN 674-82-8). RTECS No. RQ8225000 [online]. Available: http://www. cdc.gov/niosh/rtecs/rq7d80e8.html [accessed Nov. 21, 2014]. Wooster, H.A., C.C. Lushbaugh, and C.E. Redemann. 1947. The inhalation toxicity of ketene and ketene dimer. J. Ind. Hyg. Toxicol. 29(1):56-57.

54 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR DIKETENE Derivation of AEGL-1 Values Insufficient data were available for deriving AEGL-1 values for diketene. There- fore, AEGL-1 values are not recommended. Absence of AEGL-1 values does not im- ply that exposures below the AEGL-2 values are without effect. Derivation of AEGL-2 Values The AEGL-2 values for diketene were estimated by dividing the respective AEGL-3 values by 3. That procedure is in accordance with the standing operating pro- cedures for deriving AEGL values for chemicals with steep concentration-response curves (NRC 2001). Calculations: 10-min AEGL-2: 5.5 ppm ÷ 3 = 1.8 ppm 30-min AEGL-2: 3.8 ppm ÷ 3 = 1.3 ppm 1-h AEGL-2: 3.0 ppm ÷ 3 = 1.0 ppm 4-h AEGL-2: 0.75 ppm ÷ 3 = 0.25 ppm 8-h AEGL-2; 0.38 ppm ÷ 3 = 0.13 ppm Derivation of AEGL-3 Values Key study: Katz, G.V. 1987. Acute Inhalation Toxicity and One-Hour LC10 Value of Diketene in the Rat. Study No. TX-86-265, February 4, 1967. Toxicological Sciences Section, Health and Environment Laboratories, Eastman Kodak Company, Rochester, NY. Toxicity end point: Lethality (1-h BMCL05 of 181 ppm) Time scaling: Cn × t = k; default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations (181 ppm ÷ 60)3 × 60 min = 1,647 ppm-min (181 ppm ÷ 60)1 × 60 min = 181 ppm-min Uncertainty factors: 10 for interspecies differences 3 for intraspecies variability

Diketene 55 Modifying factor: 2 for limited database Calculations: 10-min AEGL-3: C3 = (1,647 ppm-min ÷ 10 min) C = 5.5 ppm 30-min AEGL-3: C3 = (1,647 ppm-min ÷ 30 min) C = 3.8 ppm 1-h AEGL-3: C = (181 ppm-min ÷ 60 min) C = 3.0 ppm 4-h AEGL-3: C1 = 181 ppm-min ÷ 240 min C = 0.75 ppm 8-h AEGL-3: C1 = 181 ppm-min ÷ 480 min C = 0.38 ppm

56 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR DIKETENE AEGL-1 VALUES Insufficient data were available for deriving AEGL-1 values for diketene. Therefore, AEGL-1 values are not recommended. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without effect. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1.8 ppm 1.3 ppm 1.0 ppm 0.25 ppm 0.13 ppm Data adequacy: No adequate studies were available for deriving AEGL-2 values for diketene. The AEGL-2 values were estimated by dividing the respective AEGL-3 values by 3. That procedure is in accordance with the standing operating procedures for deriving AEGL values for chemicals with steep concentration-response curves (NRC 2001). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 5.5 ppm 3.8 ppm 3.0 ppm 0.75 ppm 0.38 ppm Key reference: Katz, G.V. 1987. Acute Inhalation Toxicity and One-Hour LC10 Value of Diketene in the Rat. Study No. TX-86-265, February 4, 1967. Toxicological Sciences Section, Health and Environment Laboratories, Eastman Kodak Company, Rochester, NY. Test species/Strain/Number: Rat; CRL:CD®(SD)BR; 5 males and 5 females per group Exposure route/Concentrations/Durations: Inhalation; 250, 500, and 750 ppm for 1 h Effects: 250 ppm: Signs of ocular (lacrimation) and respiratory tract irritation (gasping and rales). 500 ppm: Three rats died (2 male, 1 female); clinical signs were the same as those observed at 250 ppm, plus porphyrin discharge from the nose. 750 ppm: Seven rats died (4 male, 3 female); clinical signs were same as those observed at 500 ppm. End point/Concentration/Rationale: Lethality, 1-h BMCL05 of 181 ppm Uncertainty factors/Rationale: Total uncertainty factor: 30 Interspecies: 10 Intraspecies: 3, because diketene is irritating and much of its toxicity is likely caused by a direct chemical effect on the tissue. That type of portal-of-entry effect is not expected to vary greatly among individuals. A factor of 3 is further supported by the fact that mortality incidences and clinical signs were similar between male and female rats exposed to diketene (Katz 1987). Modifying factor: 2 for limited database Animal-to-human dosimetric adjustment: None (Continued)

Diketene 57 AEGL-3 VALUES Continued Time scaling: Cn × t = k; default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations. Data adequacy: Only one adequate animal study was available for evaluating the acute inhalation toxicity of diketene. Additional studies in rats exposed for other durations and studies in at least one other species are needed to better characterize the acute inhalation toxicity of diketene.

58 Acute Exposure Guideline Levels APPENDIX C CATEGORY PLOT FOR DIKETENE FIGURE C-1 Category plot of toxicity data and AEGL values for diketene. TABLE C-1 Data Used in Category Plot for Diketene Source Species ppm Minutes Category Comments AEGL-2 1.8 10 AEGL AEGL-2 1.3 30 AEGL AEGL-2 1.0 60 AEGL AEGL-2 0.25 240 AEGL AEGL-2 0.13 480 AEGL AEGL-3 5.5 10 AEGL AEGL-3 3.8 30 AEGL AEGL-3 3.0 60 AEGL AEGL-3 0.75 240 AEGL AEGL-3 0.38 480 AEGL Danishevskii 1948, 1951; Human 0.58 1 1 Mild irritation of the Feldman 1967 conjunctiva and mucosa of nose and throat (Continued)

Diketene 59 TABLE C-1 Continued Source Species ppm Minutes Category Comments Katz 1987 Rat 250 60 1 No mortality, lacrimation Katz 1987 Rat 500 60 SL 30% mortality Katz 1987 Rat 750 60 SL 70% mortality Wooster et al. 1947 Mouse 194 10 0 No mortality Wooster et al. 1947 Mouse 580 10 0 No mortality Wooster et al. 1947 Mouse 870 10 SL 1/20 died Wooster et al. 1947 Guinea pig 194 10 3 3/3 died For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethality.

60 Acute Exposure Guideline Levels APPENDIX D BENCHMARK CONCENTRATION CALCULATION Probit Model. (Version: 2.8; Date: 02/20/2007) Input Data File: C:\BMDS\DATA\DIKETENE.(d) Gnuplot Plotting File: C:\BMDS\DATA\DIKETENE.plt Mon Apr 09 09:49:14 2007 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 4 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values background = 0 intercept = -13.4507 slope = 2.10082 Asymptotic Correlation Matrix of Parameter Estimates (*** The model parameter(s) – background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix) intercept slope intercept 1 -1 slope -1 1

Diketene 61 Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit Background 0 NA Intercept -16.3675 5.52762 -27.2014 -5.53353 Slope 2.55065 0.87102 0.843482 4.25782 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of Deviance Table Model Log (likelihood) # Parameters Deviance Test d.f. P-value Full model -12.2173 4 Fitted model -12.5124 2 0.590315 2 0.7444 Reduced model -22.4934 1 20.5522 3 0.0001304 AIC: 29.0249 Goodness of Fit Dose Est. Prob. Expected Observed Size Scaled Residual 0.0000 0.0000 0.000 0 10 0.000 271.0000 0.0188 0.188 0 10 -0.438 466.0000 0.2433 2.433 3 10 0.418 778.0000 0.7296 7.296 7 10 -0.211 Chi-square = 0.41 d.f. = 2 P-value = 0.8142 Benchmark Dose Computation Specified effect = 0.05 Risk type = Extra risk Confidence level = 0.95 BMD = 321.212 BMDL = 180.893

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 19 Get This Book
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Extremely hazardous substances can be released accidentally as a result of chemical spills, industrial explosions, fires, or accidents involving railroad cars and trucks transporting EHSs. Workers and residents in communities surrounding industrial facilities where these substances are manufactured, used, or stored and in communities along the nation's railways and highways are potentially at risk of being exposed to airborne EHSs during accidental releases or intentional releases by terrorists. Pursuant to the Superfund Amendments and Reauthorization Act of 1986, the U.S. Environmental Protection Agency (EPA) has identified approximately 400 EHSs on the basis of acute lethality data in rodents.

Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 19 identifies, reviews, and interprets relevant toxicologic and other scientific data for selected AEGL documents for cyanide salts, diketene, methacrylaldehyde, pentaborane, tellurium hexafluoride, and tetrafluoroethylene in order to develop acute exposure guideline levels (AEGLs) for these high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits (exposure levels below which adverse health effects are not likely to occur) for the general public and are applicable to emergency exposures ranging from 10 minutes (min) to 8 h. Three levels - AEGL-1, AEGL-2, and AEGL-3 - are developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. This report will inform planning, response, and prevention in the community, the workplace, transportation, the military, and the remediation of Superfund sites.

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