Click for next page ( 60


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 59
2 Bromoacetone1 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 Cheryl B. Bast (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Roberta Grant (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 scientifi- cally valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 59

OCR for page 59
60 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 re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Bromoacetone is a colorless liquid with a pungent odor. It is described as a dermal, ocular, and respiratory irritant. Bromoacetone was first used as a chemi- cal weapon during World War I, and may currently be used in organic synthesis, although production data were not found. Bromoacetone is prepared by treating acetone with bromine and sodium chlorate. It occurs naturally in the essential oil of a seaweed species that grows in the ocean around the Hawaiian Islands (HSDB 2011). AEGL-1 values for bromoacetone were based on a concentration of 0.1 ppm that caused ocular irritation in humans (Dow Chemical 1968). An intraspe- cies uncertainty factor of 3 was applied because contact irritation is a portal-of- entry effect and is not expected to vary widely between individuals. An inter- species uncertainty factor of 1 was applied because the study was conducted in humans. Time scaling was not performed, because the critical effect (ocular irri- tation) is a function of direct contact with the bromoacetone vapor and is unlikely to increase with duration of exposure (NRC 2001). However, because of the lack of human data on exposure to bromoacetone longer than a few sec- onds and because the point of departure was a nominal concentration, a modify- ing factor of 3 was applied. When rat irritation data were used to derive AEGL-2 values for bromoace- tone, it yielded values essentially identical to the AEGL-3 values calculated from lethality data. Thus, although the concentration-response relationship for bromoacetone is not particularly steep, the AEGL-3 values were divided by 3 to calculate AEGL-2 values.

OCR for page 59
Bromoacetone 61 AEGL-3 values were based on lethality studies in rats exposed to bro- moacetone at concentrations of 1-131 ppm and for durations of 6-120 min (Dow Chemical 1968). The threshold for lethality at each AEGL-3 exposure duration was calculated using probit analysis, based on the dose-response program of ten Berge (2006) (see Appendix B). The threshold for lethality was set at LC01 (le- thal concentration, 1% lethality). The LC01 was chosen over the BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) be- cause values derived using the BMCL05 were less consistent with human data (2.5 ppm for 10 min, 0.94 ppm for 30 min, 0.44 ppm for 1 h, 0.089 ppm for 4 h, and 0.039 ppm for 8 h; and only ocular irritation was found in humans exposed at 0.1 and 1.0 ppm). A time-scaling value of 1.3 (C1.3 × t = k) was derived from the data. Interspecies and intraspecies uncertainty factors of 3 each were applied (total of 10), because bromoacetone is an irritant (causes lacrimation, nasal dis- charge, gasping, wheezing, and labored breathing in rats and ocular irritation in humans), and clinical signs are likely caused by a direct chemical effect on the tissues. This type of portal-of-entry effect is not likely to vary greatly between species or among individuals. The AEGL values for bromoacetone are summarized in Table 2-1. 1. INTRODUCTION Bromoacetone is a colorless liquid that rapidly turns violet, even in the ab- sence of air. It has a pungent odor. It was first used as a chemical weapon during World War I, and was referred to as BA by the British and B-stoff (white cross) by the Germans. It might currently be used in organic synthesis, although pro- duction data were not found. It is prepared by treating acetone with bromine and sodium chlorate. Bromoacetone occurs naturally in the essential oil of a seaweed species that grows in the ocean around the Hawaiian Islands (HSDB 2011). Chemical and physical data for bromoacetone is provided in Table 2-2. TABLE 2-1 AEGL Values for Bromoacetone End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 0.011 ppm 0.011 ppm 0.011 ppm 0.011 ppm 0.011 ppm Ocular irritation (nondisabling) (0.062 (0.062 (0.062 (0.062 (0.062 in humans (Dow mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Chemical 1968) AEGL-2 1.4 ppm 0.57 ppm 0.33 ppm 0.11 ppm 0.063 ppm One-third (disabling) (7.8 (3.2 (1.8 (0.62 (0.35 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 4.1 ppm 1.7 ppm 0.98 ppm 0.32 ppm 0.19 ppm Threshold for (lethality) (23 (9.5 (5.5 (1.8 (1.1 lethality (LC01) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in rats (Dow Chemical 1968)

OCR for page 59
62 Acute Exposure Guideline Levels TABLE 2-2 Chemical and Physical Data for Bromoacetone Parameter Value Reference Synonyms Acetonyl bromide; acetylmethyl bromide; HSDB 2011 bromomethyl methyl ketone; 1-bromo-2- propanone; bromo-2-propanone; monobromoacetone CAS registry no. 598-31-2 HSDB 2011 Chemical formula C3H5BrO HSDB 2011 Molecular weight 136.98 HSDB 2011 Physical state Colorless liquid HSDB 2011 Melting point -36.5°C HSDB 2011 Boiling point 138°C HSDB 2011 Specific gravity 1.634 (air = 1) at 23°C HSDB 2011 Relative vapor density 4.75 (air = 1) HSDB 2011 Solubility in water “Slightly” soluble; soluble in alcohol, HSDB 2011 acetone, and ether Vapor pressure 9 mm Hg at 20°C HSDB 2011 Flash point 51.1°C IPCS 2005 3 Conversion factors in air 1 ppm = 5.6 mg/m HSDB 2011 1 mg/m3 = 0.18 ppm 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Human lethality data on bromoacetone were not located. 2.2. Nonlethal Toxicity Six human volunteers (age and sex not specified) were self-exposed to bromoacetone at 0.1 ppm (nominal concentration) or 1.0 ppm (analytic concen- tration) to investigate acute irritative effects and odor (Dow Chemical 1968). Exposure duration was not report, but it appears to have been no more than a few seconds. The ocular irritation test was conducted by passing the prepared vapor sample from a Saran™ bag into modified chemical-worker goggles worn by the subject. The odor test was conducted by having the subjects sniff the gas from the exposure chamber or gas sampling bag. All six subjects reported con- siderable ocular irritation at 1.0 ppm, and two at 0.1 ppm. None of the subjects reported an objectionable odor at 1.0 ppm. No information on respiratory irrita- tion or other respiratory effects was provided in the study report.

OCR for page 59
Bromoacetone 63 2.3. Case Reports No case reports were found. 2.4. Developmental and Reproductive Effects No information on the developmental or reproductive toxicity of bro- moacetone in humans was available. 2.5. Genotoxicity No information on the genotoxicity of bromoacetone in humans was available. 2.6. Carcinogenicity No information on the carcinogenicity of bromoacetone in humans was available. 2.7. Summary There is little human inhalation data on bromoacetone. Bromoacetone caused ocular irritation in two of six subjects at 0.1 ppm and in all six subjects at 1.0 ppm; however, no information on respiratory irritation or other respiratory effects was provided in the study report. No objectionable odor was reported at 1.0 ppm. No data on the developmental toxicity, reproductive toxicity, genotox- icity, or carcinogenicity of bromoacetone were available. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Groups of five male rats (strain not specified) were exposed to bromoace- tone at 17-131 ppm (analytic concentrations) for durations of 6-120 min, fol- lowed by a 14-day observation period (Dow Chemical 1968). Concentration- duration information is presented in Table 2-3. The tests were performed in a 160-L glass exposure chamber. Constant chamber airflow was maintained by means of a rotary air pump located at the exhaust side of the chamber; airflow was monitored with a rotameter. Bromoacetone was vaporized by aerosolizing a metered quantity of liquid with a positive pressure spray nozzle enclosed within a temperature-controlled round bottomed flask. Vapor laden air was then diluted with filtered room air, and passed through an aerosol trap before being drawn into the exposure chamber. Chamber concentrations were measured by gas chromatography.

OCR for page 59
64 Acute Exposure Guideline Levels During exposure, all animals showed severe ocular and nasal irritation, as evidenced by profuse lacrimation and salivation. Dyspnea followed these ef- fects. After exposure ended, all animals exhibited mucoid nasal and oral secre- tions, respiratory wheezing, and severe dyspnea. Death occurred within hours and at up to 2 weeks, depending on exposure concentration and duration. Gross necropsies of animals dying during the observation period showed congested nasal passages and slight congestion and patchy hemorrhages in the lungs. The most notable observation was enormous distension of the stomach and intestines by gas, to the extent that pressure on the diaphragm may have interfered with respiratory function. No abnormalities were noted in the liver, kidneys, or other major organs. Necropsies of animals surviving the 14-day observation period showed only moderate focal pneumonia. Experimental parameters, clinical signs, and mortality incidence data are summarized in Table 2-3. TABLE 2-3 Acute Inhalation Toxicity of Bromoacetone in Male Rats Concentration Duration Day of Effects During Effects After (ppm) (min) Mortality Death Exposure Exposure 17 12 0/5 – Lacrimation, None. nasal discharge, 28 30 2/5 1 and labored Bloody nasal discharge breathing. and weight loss. 28 60 4/5 14 Gasping, wheezing, bloody nasal discharge, and weight loss. 28 120 5/5 1 Gasping, wheezing, and bloody nasal discharge. 48 60 5/5 12 Same as above, Wheezing and bloody except more nasal discharge. rapid onset and 48 120 5/5 1 more severe. Gasping, wheezing, and bloody nasal discharge. 51 6 0/5 – Weight loss 51 12 0/5 – None 51 30 3/5 2 Wheezing, bloody nasal discharge, and weight loss. 131 10 5/5 11 Same as above, Wheezing, bloody nasal except much discharge, and weight faster onset and loss. more severe. 131 30 5/5 3 Gasping, wheezing, and bloody nasal discharge. Source: Dow Chemical 1968.

OCR for page 59
Bromoacetone 65 3.1.2. Summary of Animal Lethality Data Only one study on lethality from bromoacetone was available. That study demonstrated that bromoacetone is an irritant in rats, causing lacrimation, nasal discharge, gasping, wheezing, and labored breathing). 3.2. Nonlethal Toxicity 3.2.1. Rats In a companion study to the acute lethality study described earlier, groups of four male rats (strain not specified) were exposed to bromoacetone at 0-18 ppm (analytic concentrations) for 15-87 min, followed by a 14-day observation period (Dow Chemical 1968). The experimental methodology was as described in Section 3.1.1, and concentration-duration information is presented in Table 2- 4. The purpose of the study was to determine an irritation threshold in rats. Rats exposed to bromoacetone at 2 ppm showed definite signs of ocular irritation, and those exposed at 10 ppm had signs of respiratory tract irritation. Postexpo- sure nasal discharge persisted only in rats exposed at 18 ppm. During the obser- vation period, weight loss was reported in the 10 and 18 ppm groups; however, the magnitude of the weight loss was not reported. No treatment-related abnor- malities were observed in any of the rats at necropsy. Experimental parameters, clinical signs, and mortality incidence data are summarized in Table 2-4. TABLE 2-4 Acute Irritation of Bromoacetone in Male Rats Concentration Duration Effects During Time to Effects After (ppm) (min) Mortality Exposure Response (sec) Exposure 0 15 0/4 None – None 1.0 15 0/4 Mild blinking 101 None (reported as +/-) 2.0 20 0/4 Blinking 98 None 6.3 74 0/4 Blinking 56 None 10.0 43 0/4 Blinking, 68 Body weight lacrimation, loss and sneezing 18.0 87 Not Blinking, 25 Nasal discharge reported lacrimation, and body weight sneezing, and loss dyspnea. Source: Dow Chemical 1968.

OCR for page 59
66 Acute Exposure Guideline Levels 3.2.2. Summary of Nonlethal Toxicity in Animals Only one study on nonlethal effects from acute inhalation of bromoace- tone was available (Dow Chemical 1968). Bromoacetone was an irritant in rats, causing blinking, lacrimation, sneezing, and shortness of breath. 3.3. Developmental and Reproductive Effects No developmental or reproductive data on bromoacetone were found. 3.4. Genotoxicity No genotoxicity data on bromoacetone were found. 3.5. Carcinogenicity No carcinogenicity data on bromoacetone were found. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition No metabolism data on bromoacetone were available. 4.2. Mechanism of Toxicity The few inhalation studies available on bromoacetone suggest that bro- moacetone is an irritant. Two of six human subjects reported ocular irritation at 0.1 ppm, and all six had irritation at 1 ppm. Rats exhibited lacrimation, nasal discharge, gasping, wheezing, and labored breathing after being exposed to bromoacetone (Dow Chemical 1968). HSDB (2011 also describes bromoacetone as a dermal, ocular, and respiratory irritant. 4.3. Structure-Activity Relationships Bromoacetone is structurally similar to chloroacetone, which is also an ir- ritant. However, bromoacetone appears to be a more potent irritant than chloroacetone. Humans exposed to chloroacetone first experience lacrimation at approximately 5 ppm (Sargent et al. 1986), whereas ocular irritation from bro- moacetone has been reported at lower concentrations of 0.1 and 1.0 ppm (Dow Chemical 1968). A 1-h LC50 of 316 ppm was reported for chloroacetone in male rats, and no mortality occurred in rats exposed at 132 ppm for 1 h (Arts and Zwart 1987).

OCR for page 59
Bromoacetone 67 However, in studies with bromoacetone, death occurred in four of five male rats exposed at 28 ppm and in all five rats exposed at 48 ppm for 1 h (Dow Chemical 1968). 4.4. Species Variability Data are insufficient to determine species variability for bromoacetone. Bromoacetone is an irritant and clinical signs are likely caused by a direct chemical effect on tissues. This type of portal-of-entry effect is not likely to vary greatly between species. 4.5. Temporal Extrapolation The concentration-time relationship for many irritant and systemically- acting vapors and gases can be described by the relationship Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). The value of n was determined by analyzing the available lethality data on bromoacetone in rats using the DoseResp software of ten Berge (2006). On the basis of the concentra- tion-specific data presented in Tables 2-3 and 2-4, the analysis produced an ex- ponent value of 1.3, with confidence limits of 0.80 and 1.7. Details of the analy- sis are provided in Appendix B. 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 Immediate ocular irritation was observed in six of six humans exposed to bromoacetone at 1.0 ppm, and in two of six humans exposed at 0.1 ppm (Dow Chemical 1968). 5.2. Animal Data Relevant to AEGL-1 Slight blinking was observed in rats exposed to bromoacetone at 1.0 ppm for 15 min (Dow Chemical 1968). 5.3. Derivation of AEGL-1 Values A concentration of 0.1 ppm was selected as the point of departure for de- riving AEGL-1 values for bromoacetone. That concentration caused ocular irri- tation in two of six humans (Dow Chemical 1968). An intraspecies uncertainty factor of 3 was applied because contact irritation is a portal-of-entry effect and is not expected to vary widely between individuals. An interspecies uncertainty factor of 1 was applied because the study was conducted in humans. Time scal-

OCR for page 59
68 Acute Exposure Guideline Levels ing was performed, because ocular irritation is a function of direct contact with the bromoacetone vapor and is unlikely to increase with duration of exposure (NRC 2001). However, because of the lack of human data on exposures longer than a few seconds and because the point of departure is a nominal concentra- tion, a modifying factor of 3 was applied. AEGL-1 values for bromoacetone are presented in Table 2-5, and their derivation presented in Appendix A. 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data relevant to derivation of AEGL-2 values were found. 6.2. Animal Data Relevant to AEGL-2 Blinking, lacrimation, sneezing, and body weight loss were observed in rats exposed to bromoacetone at 10 ppm for 43 min (Dow Chemical 1968). 6.3. Derivation of AEGL-2 Values Although the concentration-response relationship for bromoacetone is not particularly steep, the AEGL-3 values were divided by 3 to calculate AEGL-2 values for bromoacetone. This approach was used instead of basing the values on rat data, because when rat irritation data were used to calculate AEGL-2 val- ues, they were essentially identical to the AEGL-3 values based on lethality data. (AEGL-2 values derived with a point of departure of 10 ppm for 43 min, with interspecies and intraspecies uncertainty factors of 3 each, and with a time- scaling exponent of 1.3 [see Section 4.5] resulted in the following values: 3.2 ppm for 10 min, 1.3 ppm for 30 min, 0.77 ppm for 1 h, 0.26 ppm for 4 h, and 0.15 ppm for 8 h.) AEGL-2 values for bromoacetone are presented in Table 2-6, and calcula- tions are presented in Appendix A. 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data relevant to derivation of AEGL-3 values were found. TABLE 2-5 AEGL-1 Values for Bromoacetone 10 min 30 min 1h 4h 8h 0.011 ppm 0.011 ppm 0.011 ppm 0.011 ppm 0.011 ppm (0.062 mg/m3) (0.062 mg/m3) (0.062 mg/m3) (0.062 mg/m3) (0.062 mg/m3)

OCR for page 59
Bromoacetone 69 TABLE 2-6 AEGL-2 Values for Bromoacetone 10 min 30 min 1h 4h 8h 1.4 ppm 0.57 ppm 0.33 ppm 0.11 ppm 0.063 ppm (7.8 mg/m3) (3.2 mg/m3) (1.8 mg/m3) (0.62 mg/m3) (0.35 mg/m3) 7.2. Animal Data Relevant to AEGL-3 Animal lethality data were available for rats exposed to varying concentra- tions of bromoacetone for different time periods (Dow Chemical 1968). Expo- sure durations ranged from 6 to 120 min and concentrations ranged from 1.0 to 131 ppm. Mortality incidences ranged from 0 to 100%, depending on concentra- tion-duration pairings. The experimental parameters were summarized earlier in Tables 2-3 and 2-4. 7.3. Derivation of AEGL-3 Values Using the data from the studies by Dow Chemical (1968) presented in Ta- bles 2-3 and 2-4, the lethality threshold at each AEGL-3 exposure duration was calculated using the probit analysis based on the dose-response program of ten Berge (2006) (see Appendix B). The lethality threshold was set at the LC01 (le- thal concentration, 1% lethality). The LC01 was chosen over the BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) be- cause values derived with the BMCL05 were less consistent with human data (2.5 ppm for 10 min, 0.94 ppm for 30 min, 0.44 ppm for 1 h, 0.089 ppm for 4 h, and 0.039 ppm for 8 h; and only ocular irritation was noted in humans at 0.1 and 1.0 ppm). A time-scaling value of 1.3 (C1.3 × t = k) was determined from the data. These calculated values were used as the basis for the AEGL-3 values. Interspecies and intraspecies uncertainty factors of 3 each were applied (total of 10) and were considered sufficient because bromoacetone is an irritant, and clinical signs are likely caused by a direct chemical effect on the tissues. This type of portal-of-entry effect is not likely to vary greatly between species or among individuals. The resulting AEGL-3 values are shown in Table 2-7, and their derivation summarized in Appendix A. 8. SUMMARY OF AEGLs 8.1. AEGL Values and Toxicity End Points AEGL values for bromoacetone are summarized in Table 2-8. AEGL-1 values are based on ocular irritation in humans, and AEGL-3 values are based on a lethality threshold (LC01) in rats. AEGL-2 values were derived by dividing the AEGL-3 values by 3.

OCR for page 59
76 Acute Exposure Guideline Levels Calculations: 10-min AEGL-3: 40.69 ppm ÷ 10 4.1 ppm 30-min AEGL-3: 16.97 ppm ÷ 10 1.7 ppm 1-h AEGL-3: 9.773 ppm ÷ 10 0.98 ppm 4-h AEGL-3: 3.241 ppm ÷ 10 0.32 ppm 8-h AEGL-3: 1.867 ppm ÷ 10 0.19 ppm

OCR for page 59
Bromoacetone 77 APPENDIX B Time-Scaling Calculations for Bromoacetone An n of 1.3 was obtained after analysis of lethality data in rats (Dow Chemical 1968) using the software of ten Berge (2006). This exposure-time relationship for lethality was considered appropriate for AEGL-3 development but because bromoacetone-induced ocular irritation is the result of direct-contact irritation. No time scaling was used in the development of AEGL-1 values. AEGL-2 values were derived by taking one-third of the AEGL-3 values, so no time scaling was necessary. Used Probit Equation Y = B0 + B1*X1 + B2*X2 X1 = Concentration (ppm), ln-transformed X2 = Min, ln-transformed Chi-square = 4.50 Degrees of freedom = 12 Probability Model = 9.73E-01 Ln(Likelihood) = -5.61 B 0 = -1.3833E+01 Student t = -2.8141 B 1 = 2.9799E+00 Student t = 3.6728 B 2 = 2.3722E+00 Student t = 3.6582 Variance B 0 0 = 2.4161E+01 Covariance B 0 1 = -3.8264E+00 Covariance B 0 2 = -2.9135E+00 Variance B 1 1 = 6.5827E-01 Covariance B 1 2 = 4.0467E-01 Variance B 2 2 = 4.2051E-01 Estimation ratio between regression coefficients of ln(concentration) and ln(min) Point estimate = 1.256 Lower limit (95% CL) = 0.800 Upper limit (95% CL) = 1.713 Estimation of concentration (ppm) at response of 1% Min = 10 Point estimate concentration (ppm) = 4.069E+01 for response of 1% Lower limit (95% CL) concentration (ppm) = 1.623E+01 for response of 1% Upper limit (95% CL) concentration (ppm) = 5.881E+01 for response of 1%

OCR for page 59
78 Acute Exposure Guideline Levels Filename: Bromoacetone Dow Chemical Rat for Log Probit Model Date: 08 September 2008 Time: 11:14:28 Sequence Number Concentration (ppm) Min Sex Exposed Responded 1 28 120 1 5 5 2 28 60 1 5 4 3 28 30 1 5 2 4 17 12 1 5 0 5 48 120 1 5 5 6 48 60 1 5 5 7 51 30 1 5 3 8 51 12 1 5 0 9 51 6 1 5 0 10 131 30 1 5 5 11 131 10 1 5 5 12 10 43 1 4 0 13 6 74 1 4 0 14 2 20 1 4 0 15 1 15 1 4 0 Observations 1 through 15 considered 1 28 120 5 5 2 28 60 5 4 3 28 30 5 2 4 17 12 5 0 5 48 120 5 5 6 48 60 5 5 7 51 30 5 3 8 51 12 5 0 9 51 6 5 0 10 131 30 5 5 11 131 10 5 5 12 10 43 4 0 13 6 74 4 0 14 2 20 4 0 15 1 15 4 0

OCR for page 59
Bromoacetone 79 Estimation of concentration (ppm) at response of 1% Min = 30 Point estimate concentration (ppm) = 1.697E+01 for response of 1% Lower limit (95% CL) concentration (ppm) = 5.890E+00 for response of 1% Upper limit (95% CL) concentration (ppm) = 2.405E+01 for response of 1% Estimation of concentration (ppm) at response of 1% Min = 60 Point estimate concentration (ppm) = 9.773E+00 for response of 1% Lower limit (95% CL) concentration (ppm) = 2.829E+00 for response of 1% Upper limit (95% CL) concentration (ppm) = 1.503E+01 for response of 1% Estimation of concentration (ppm) at response of 1% Min = 120 Point estimate concentration (ppm) = 5.628E+00 for response of 1% Lower limit (95% CL) concentration (ppm) = 1.303E+00 for response of 1% Upper limit (95% CL) concentration (ppm) = 9.794E+00 for response of 1% Estimation of concentration (ppm) at response of 1% Min = 240 Point estimate concentration (ppm) = 3.241E+00 for response of 1% Lower limit (95% CL) concentration (ppm) = 5.857E-01 for response of 1% Upper limit (95% CL) concentration (ppm) = 6.537E+00 for response of 1% Estimation of concentration (ppm) at response of 1% Min = 480 Point estimate concentration (ppm) = 1.867E+00 for response of 1% Lower limit (95% CL) concentration (ppm) = 2.597E-01 for response of 1% Upper limit (95% CL) concentration (ppm) = 4.424E+00 for response of 1%

OCR for page 59
80 Acute Exposure Guideline Levels APPENDIX C ACUTE EXPOSURE GUIDELINE LEVESL FOR BROMOACETONE Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.011 ppm 0.011 ppm 0.011 ppm 0.011 ppm 0.011 ppm (0.062 mg/m3) (0.062 mg/m3) (0.062 mg/m3) (0.062 mg/m3) (0.062 mg/m3) Reference: Dow Chemical. 1968. Inhalation Exposure Toxicity of Bromoacetone and a Fumigant Mixture Containing Bromoacetone with Cover Letter Dated 041086. EPA Document No. 86860000027. Microfiche No. OTS0510179. Test Species/Strain/Number: Human subjects (age and sex not specified); six subjects Exposure route/Concentrations/Durations: Vapor exposure at 0.1 or 1 ppm; duration not reported, but appears to be seconds. Effects: Ocular irritation in two of six subjects at 0.1 ppm; considerable ocular irritation in all six subjects at 1 ppm. No objectionable odor reported. End point/Concentration/Rationale: Ocular irritation at 0.1 ppm in two of six subjects. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, because human data were used. Intraspecies: 3, because contact irritation is a portal-of-entry effect and is not expected to vary widely between individuals. Modifying factor: 3, because of the lack of human data on exposures longer than a few seconds and because the point of departure is a nominal concentration. Animal-to-human dosimetric adjustment: None Time scaling: none Data adequacy: Sparse data set; modifying factor necessary. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1.4 ppm 0.57 ppm 0.33 ppm 0.11 ppm 0.063 ppm (7.8 mg/m3) (3.2 mg/m3) (1.8 mg/m3) (0.62 mg/m3) (0.35 mg/m3) End point/Concentration/Rationale: Values were calculated as one-third the AEGL-3 values, because AEGL-2 values derived from relevant rat data were essentially identical to the AEGL-3 values calculated from lethality data.

OCR for page 59
Bromoacetone 81 Data adequacy: Sparse data set for AEGL-2 effects. AEGL-2 values derived using clinical signs in rats exposed at 10 ppm for 43 min, with interspecies and intraspecies uncertainty factors of 3 each, and with a time-scaling exponent of 1.3 [see Section 4.5] would have resulted in the following values: 3.2 ppm for 10 min, 1.3 ppm for 30 min, 0.77 ppm for 1 h, 0.26 ppm for 4 h, and 0.15 ppm for 8 h. AEGL-2 values based on one-third of the AEGL-3 values are considered protective. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 4.1 ppm 1.7 ppm 0.98 ppm 0.32 ppm 0.19 ppm (23 mg/m3) (9.5 mg/m3) (5.5 mg/m3) (1.8 mg/m3) (1.1 mg/m3) Reference: Dow Chemical, 1968. Inhalation Exposure Toxicity of Bromoacetone and a Fumigant Mixture Containing Bromoacetone with Cover Letter dated 041086. EPA Document No. 86860000027. Microfiche No. OTS0510179. Test species/Strain/Sex/Number: Rat, strain not specified, male, 4-5 per group Exposure route/Concentrations/Durations: Inhalation, 1.0-131 ppm for 6-120 min Effects: Lethality Concentration (ppm) Duration (min) Mortality 28 120 5/5 28 60 4/5 28 30 2/5 17 12 0/5 48 120 5/5 48 60 5/5 51 30 3/5 51 12 0/5 51 6 0/5 131 30 5/5 131 10 5/5 1 15 0/4 2 20 0/4 6.3 74 0/4 10 43 0/4 End point/Concentration/Rationale: Threshold for lethality in rats (L01) calculated using probit-analysis dose-response program of ten Berge (2006). The LC01 was chosen over the BMCL05 because values derived with the BMCL05 were less consistent with human data (2.5 ppm for 10 min, 0.94 ppm for 30 min, 0.44 ppm for 1 h, 0.089 ppm for 4 h, and 0.039 ppm for 8 h; and only ocular irritation was noted in humans at 0.1 and 1.0 ppm). (Continued)

OCR for page 59
82 Acute Exposure Guideline Levels AEGL-3 Continued Uncertainty factors/Rationale Total uncertainty factor: 10 Interspecies: 3, considered sufficient because bromoacetone is an irritant and clinical signs are likely caused by a direct chemical effect on the tissues. This type of portal- of-entry effect is not likely to vary greatly between species. Intraspecies: 3, considered sufficient because bromoacetone is an irritant and clinical signs are likely caused by a direct chemical effect on the tissues. This type of portal- of-entry effect is not likely to vary greatly among individuals. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k, where n = 1.3 as determined by analysis of rat lethality data using ten Berge (2006) software. Data adequacy: Sparse data set. One well-conducted study in rats with effects relevant to AEGL-3 values.

OCR for page 59
Bromoacetone 83 APPENDIX C CATEGORY PLOT OF TOXICITY DATA AND AEGL VALUES FOR BROMOACETONE Chemical Toxicity Bromoacetone 1000 Human - No Effect Human - Discomfort 100 Human - Disabling Animal - No Effect 10 ppm Animal - Discomfort 1 Animal - Disabling AEGL-3 Animal - Partially Lethal 0 AEGL-2 Animal - Lethal AEGL-1 AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category graph of toxicity data on bromoacetone compared with AEGL values.

OCR for page 59
84 TABLE C-1 Data Used in the Category Graph Source Species Sex No. of Exposures ppm Min Category Comments AEGL-1 0.011 10 AEGL AEGL-1 0.011 30 AEGL AEGL-1 0.011 60 AEGL AEGL-1 0.011 240 AEGL AEGL-1 0.011 480 AEGL AEGL-2 1.4 10 AEGL AEGL-2 0.57 30 AEGL AEGL-2 0.33 60 AEGL AEGL-2 0.11 240 AEGL AEGL-2 0.063 480 AEGL AEGL-3 4.1 10 AEGL AEGL-3 1.7 30 AEGL AEGL-3 0.98 60 AEGL AEGL-3 0.32 240 AEGL AEGL-3 0.19 480 AEGL Rat Male 1 28 120 3 5/5 mortality; lacrimation, gasping, wheezing, and nasal discharge.

OCR for page 59
Rat Male 1 28 60 PL 4/5 mortality; lacrimation, gasping, wheezing, nasal discharge, and body weight loss. Rat Male 1 28 30 PL 2/5 mortality; lacrimation, gasping, wheezing, nasal discharge, and body weight loss. Rat Male 1 17 12 0 No effects. Rat Male 1 48 120 3 5/5 mortality; lacrimation, gasping, wheezing, and nasal discharge. Rat Male 1 48 60 5 5/5 mortality; lacrimation, wheezing, and nasal discharge. Rat Male 1 51 30 PL 3/5 mortality; lacrimation, wheezing, nasal discharge, and body weight loss. Rat Male 1 51 12 1 Lacrimation and nasal discharge. Rat Male 1 51 6 1 Lacrimation and nasal discharge. Rat Male 1 131 30 3 5/5 mortality; lacrimation, gasping, wheezing, and nasal discharge. Rat Male 1 131 10 3 5/5 mortality; lacrimation, gasping, wheezing, nasal discharge, and body weight loss. Rat Male 1 1 15 1 Mild blinking. (Continued) 85

OCR for page 59
86 TABLE C-1 Continued Source Species Sex No. of Exposures ppm Min Category Comments Rat Male 1 2 20 1 Blinking. Rat Male 1 6.3 74 2 Blinking, lacrimation, sneezing, and body weight loss. Rat Male 1 10 43 2 Blinking, lacrimation, sneezing, dyspnea, and body weight loss. Human 1 0.1 1 1 2/6 ocular irritation; estimated duration. Human 1 1 1 1 6/6 considerable ocular irritation; estimated duration. Categories: 0 = no effect; 1 = discomfort; 2 = disabling; PL = partially lethal; 3 = lethal.