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3
Chloroacetone1
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 Cheryl
Bast (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager
Susan Ripple (National Advisory Committee [NAC] on Acute Exposure Guideline Lev-
els for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection
Agency). The NAC reviewed and revised the document and AEGLs as deemed neces-
sary. Both the document and the AEGL values were then reviewed by the National Re-
search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com-
mittee 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).
87
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88 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 sus-
ceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure con-
centrations that could produce mild and progressively increasing but transient
and nondisabling odor, taste, and sensory irritation or certain asymptomatic,
nonsensory 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
subpopulations, such as infants, children, the elderly, persons with asthma, and
those with other illnesses, it is recognized that individuals, subject to
idiosyncratic responses, could experience the effects described at concentrations
below the corresponding AEGL.
SUMMARY
Chloroacetone is produced by the direct chlorination of acetone. It also has
been manufactured by reacting chlorine with diketene followed by boiling with
water. It is used in the manufacture of couplers for color photography, as a
photosensitizer for polyester-vinyl polymerization, as a fungicide and
bactericide, and as an intermediate in the production of perfumes, antioxidants,
and pharmaceuticals (Sargent et al. 1986). Chloroacetone has a pungent,
suffocating odor similar to hydrogen chloride. It is toxic by inhalation, ingestion,
and dermal contact, and causes immediate lacrimation at low concentrations.
Other effects from exposure to chloroacetone include contact burns of the skin
and eyes, nausea, bronchospasm, delayed pulmonary edema, and death.
Data were insufficient for deriving AEGL-1 and AEGL-2 values for
chloroacetone. The available data on acute toxicity suggest that chloroacetone
has a steep dose-response relationship. Therefore, the AEGL-2 values were
calculated by taking a three-fold reduction in the corresponding AEGL-3 values;
those values are considered estimates of a threshold for irreversible effects.
A 1-h BMCL05 (benchmark concentration, 95% lower confidence limit
with 5% response) of 131 ppm in the male rat was used as the basis of the
AEGL-3 values (Arts and Zwart 1987). Interspecies and intraspecies uncertainty
factors of 3 each were applied, because the preponderance of the data suggests
that the effects of inhaled chloroacetone are likely caused by a direct chemical
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Chloroacetone 89
effect on the tissues; this type of port-of-entry effect does not exhibit
toxicokinetic variability and, thus, is not expected to vary greatly between
species or among individuals. The interspecies uncertainty factor of 3 also is
supported by data suggesting little species variability in lethality from oral and
dermal exposure to chloroacetone (rat oral LD50 values: 100-141 mg/kg; mouse
oral LD50 values: 127-141 mg/kg; rabbit dermal LD50 = 141 mg/kg), and the 1-h
LC50 of 500 ppm for male and female rats (Arts and Zwart 1987) is approxi-
mately a dose of 114 mg/kg, which corresponds to the oral LD50 values
(assuming 100% retention, 245 mL minute volume, and a rat body weight of
250 g). The intraspecies uncertainty factor of 3 also is considered sufficient
because data from male rats, which are more sensitive than female rats, were
used as the point-of-departure. Thus, the total uncertainty factor is 10. It has
been shown that the concentration-exposure time relationship for many irritant
and systemically acting vapors and gases may be described by the equation Cn ×
t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data
were unavailable for an empirical derivation of n for chloroacetone, so default
values were applied (NRC 2001). An n of 3 was applied to extrapolate to the 10-
and 30-min AEGL durations, and an n of 1 was applied to extrapolate to the
4- and 8-h durations (NRC 2001). The calculated values are presented Table 3-1.
1. INTRODUCTION
Chloroacetone is a colorless to amber liquid at ambient temperature and
pressure. It has a pungent, suffocating odor similar to hydrogen chloride
(Sargent et al. 1986). It is toxic by inhalation, ingestion, and dermal contact, and
causes immediate lacrimation at low concentrations. Other effects from
exposure to chloroacetone include contact burns of the skin and eyes, nausea,
bronchospasm, delayed pulmonary edema, and death (HSDB 2011).
TABLE 3-1 Summary of AEGL Values for Cloroacetone
Classification 10 min 30 min 1h 4h 8h End Point (Reference)
AEGL-1 NRa NRa NRa NRa NRa Insufficient data
(nondisabling)
AEGL-2 8.0 ppm 5.5 ppm 4.4 ppm 1.1 ppm 0.53 ppm One-third of
(disabling) (30 (21 (17 (4.2 (2.0 AEGL-3 values
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3)
AEGL-3 24 ppm 17 ppm 13 ppm 3.3 ppm 1.6 ppm Estimated lethality
(lethal) (91 (65 (49 (13 (6.1 threshold for male
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) rats (BMD05) (Arts
and Zwart 1987)
a
Not recommended. Absence of an AEGL-1 value does not imply that exposure below
the AEGL-2 value is without adverse effects.
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90 Acute Exposure Guideline Levels
Chloroacetone is produced by the direct chlorination of acetone. It has also
been manufactured by reacting chlorine with diketene followed by boiling with
water (Sargent et al. 1986). In 1914, the French introduced chloroacetone as a
war gas in hand and rifle grenades. It is now used in the manufacture of couplers
for color photography, as a photosensitizer for polyester-vinyl polymerization,
as a fungicide and bactericide, and as an intermediate in the production of
perfumes, antioxidants, and pharmaceuticals (Sargent et al. 1986). Production is
listed for only one manufacturer in the United States and four manufacturers
worldwide (HSDB 2011). In 1977, U.S. production was reported to be at least
4.54 × 107 g, and U.S. imports were at least 4.54 × 105 g. In 1982, U.S.
production was reported to be greater than 4.54 × 106 g (HSDB 2011).
The chemical structure of chloroacetone is depicted below, and the
physicochemical properties of chloroacetone are presented in Table 3-2.
H O
│ ║
Cl ─ C─ C ─ CH3
│
H
TABLE 3-2 Physical and Chemical Properties for Chloroacetone
Parameter Data Reference
Common name Chloroacetone IPCS 2006
Synonyms 1-Chloro-2-propanone; IPCS 2006
chloropropanone; acetonyl
chloride; monochloroacetone
CAS registry no. 78-95-5 IPCS 2006
Chemical formula ClCH2COCH3 IPCS 2006
Molecular weight 92.5 IPCS 2006
Physical state Colorless liquid (turns dark on IPCS 2006
exposure to light)
Melting point -45°C IPCS 2006
Boiling point 120°C IPCS 2006
Specific gravity 1.123 (25°C) HSDB 2011
Relative Vapor density 3.2 (air = 1) IPCS 2006
Solubility Soluble in water; miscible with HSDB 2011
alcohol, ether, and chloroform
Vapor pressure 12.0 mm Hg (25°C) HSDB 2011
Flash point 40°C (open cup) OSHA 2012
Octanol/water partition 0.28 IPCS 2006
coefficient (log Pow)
Conversion factors in air 1 ppm = 3.8 mg/m3
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Chloroacetone 91
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
Chloroacetone at a concentration of 605 ppm was reported to be lethal to
humans after 10 min (Prentiss 1937). No further details were available.
2.2. Nonlethal Toxicity
Prentiss (1937) reported that chloroacetone was extremely effective as a
war gas unless a full-face gas mask was deployed quickly; a concentration of 26
ppm was reportedly intolerable after 1 min of exposure. No further details were
provided.
Sargent et al. (1986) provided the only information on human exposure to
chloroacetone. The authors reported that employee occupational health
monitoring in 1981-1986 indicated that 25 employees reported to “Health
Services” as a result of exposure to chloroacetone. Of these, eight had ocular
irritation, seven had localized dermal irritation, one had contact dermatitis, and
the remaining nine showed no clinical signs.
Sargent et al. (1986) also reported a case of direct exposure of one
employee to hot chloroacetone as a result of a line break. The line break resulted
in the release of chloroacetone vapors and hot liquid under pressure with
combined inhalation and dermal exposure. The employee was hospitalized.
Effects included immediate lacrimation and ocular irritation, upper-respiratory-
tract irritation, and dermal irritation, producing slight erythema. Erythema
subsided, but the exposed skin began to blister and the eyelids reddened and
swelled and became painful to touch 8-h after exposure. After 24 h, the skin
areas had completely blistered, were swollen, and were painful to touch,
suggesting that some major dermal effects are delayed. All effects resolved
within 7 days, and there was no evidence of pulmonary edema at the low
concentration, despite the initial upper-respiratory-tract irritation. No additional
information to quantify exposure for this worker was available from the investi-
gators.
The Sargent et al. (1986) report included a summary table in which a
chloroacetone concentration of 4.7 ppm was associated with lacrimation and
burning sensation of the skin. However, the study authors did not provide
information regarding the basis for that value (e.g., method of sampling or
analysis, exposure duration, number of exposed individuals, number of affected
individuals). An odor threshold for chloroacetone was not found.
2.3. Developmental and Reproductive Toxicity
Developmental and reproductive studies regarding acute human exposure
to chloroacetone were not available.
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92 Acute Exposure Guideline Levels
2.4. Genotoxicity
Genotoxicity studies on acute human exposure to chloroacetone were not
available.
2.5. Carcinogenicity
Carcinogenicity studies on human exposure to chloroacetone were not
available.
2.6. Summary
There are few human studies of the toxicity of chloroacetone. The chemi-
cal is highly irritating and causes ocular, upper-respiratory tract, and dermal
irritation. Immediate lacrimation has been reported at a concentration of
approximately 5 ppm. Chloroacetone was reportedly intolerable at 26 ppm after
1 min, and lethal after 10 min of exposure at 605 ppm. No reports on
developmental and reproductive toxicity, genotoxicity, or carcinogenicity of
chloroacetone in humans were available.
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
3.1.1. Rats
Groups of five male and five female SPF (Bor:WISW) rats were exposed
to chloroacetone at 132, 263, 553, 816, 1,105, or 2,079 ppm (analytic
concentrations) for 1 h, followed by a 14-day observation period (Arts and
Zwart 1987). Animals were exposed in a horizontally placed glass tube that
allowed observation of all animals during exposure. The volume of the exposure
chamber was 0.015 m3, and air flow was 1.2 m3/h; relative humidity and
temperature were measured at least once per hour. The test atmosphere was
generated by delivering appropriate quantities of chloroacetone to an evaporator
at the inlet port of the chamber, and the concentration of chloroacetone was
determined by vapor phase infrared spectrometry and calibrated in a closed-loop
system. Exposure concentration was calculated as the mean of recorded
concentrations during the entire exposure period. Rats were observed during
exposure and daily during the observation period for clinical signs. Body weight
was recorded before exposure and on days 1, 2, 4, 7, and 14. Surviving rats were
killed at the end of the observation period and subjected to gross necropsy.
“Shortly” after the start of exposure, restlessness, rubbing of snouts, closed eyes,
and humped posture were observed. Salivation, wet nares, and nasal discharge
was observed within 3-5 min; these effects were noted “especially in those
animals exposed to higher concentrations.” The skin of the extremities became
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Chloroacetone 93
red during the second half of the exposure period in rats exposed at the higher
concentrations. In the “highest concentration groups,” all rats showed labored
respiration, accompanied by dyspnea and mouth breathing. Treatment-related
mortality occurred shortly after exposure, usually within hours, or within 1-2
days after exposure. Mortality was greater in males than in females. The rats that
died within the first two days of the observation period had pulmonary edema,
accompanied by hydrothorax. The stomachs of these rats were filled with air,
and some also had air in the cecum and intestine. Grey, discolored lungs was the
only effect noted in animals necropsied at the end of the observation period.
Animals surviving the study showed no treatment-related effect on body weight
gain. One-hour LC50 values of 500 ppm (95% confidence interval [CI]: 421-579
ppm; males and females combined), 316 ppm (95% CI: 289-342 ppm; male
rats), and 710 ppm (95% CI: 658-753 ppm; female rats) were calculated. One-
hour BMC01 (benchmark concentration, 1% response) values of 170 ppm (males
and females combined), 223 ppm (males), and 394 ppm (females) were
calculated. One-hour BMCL05 (benchmark concentration, 95% lower confidence
limit with 5% response) values of 144 ppm (males and females combined), 131
(males), and 258 ppm (females) were calculated. Mortality data are summarized
in Table 3-3.
TABLE 3-3 Mortality in Rats Exposed to Chloroacetone for One Hour
Concentration (ppm) Males Females Males and Females
Observed
132 0/5 0/5 0/10
263 1/5 0/5 1/10
553 5/5 1/5 6/10
816 5/5 3/5 8/10
1,105 5/5 5/5 10/10
2,079 5/5 5/5 10/10
Calculated
316 (289-342) LC50 — —
500 (421-579) — — LC50
710 (658-753) — LC50 —
170 BMC01
223 BMC01 — —
394 — BMC01 —
131 BMCL05 — —
144 — — BMCL05
258 — BMCL05 —
Abbreviations: BMC01, benchmark concentration, 5% response; BMCL01, benchmark
concentration, 95% lower confidence limit with 5% response; LC50, lethal concentration,
50% lethality.
Source: Arts and Zwart 1987.
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94 Acute Exposure Guideline Levels
Eastman Kodak (1992) conducted a series of experiments each using
groups of three male rats (strain not specified). Rats exposed to chloroacetone at
462 ppm exhibited nasal irritation, gasping, and pink extremities within 1 h,
rough coat after 2 h, and all were dead after 4.5 h. Another group exposed at
3,120 ppm exhibited nasal irritation, gasping, and pink extremities in 0.5 h, and
all were dead after 1.5 h. Finally, groups of rats was sequentially exposed to
chloroacetone at 52 and 105 ppm for 6 h at each concentration. At 52 ppm, pink
extremities were noted in 2.25 h, but no rats died. Nasal irritation, gasping, and
pink extremities were noted after 2.5 h at 105 ppm, and all rats died within 24 h
of the initiation of exposure. The authors estimated a 6-h LC50 of 50-100 ppm.
No other experimental details were provided.
Sargent et al. (1986) exposed a group of five male and five female
Sprague-Dawley rats to chloroacetone at 7,522 ppm for up to 1 h. A vapor-laden
stream of chloroacetone was produced by bubbling air through the test material
at a flow rate of 4 L/min. Lacrimation and excessive salivation were observed
immediately, and all rats died within 55 min. No other experimental details were
provided.
In another experiment, Sargent et al. (1986) exposed groups of five male
and five female Sprague-Dawley rats to chloroacetone at 95, 204, 254, 302, or
874 ppm (nominal concentrations) for 1 h, followed by a 14-day observation
period. An LC50 of 262 ppm was calculated. No other experimental details were
provided.
Groups of five male and five female Wistar rats were administered
chloroacetone at 0, 50, 71, 100, 140, or 200 mg/kg by gavage in corn oil,
followed by a 2-day and 14-day observation period (Sargent et al. 1986).
Clinical signs observed in all treatment groups included ataxia, red nasal
discharge, urinary and fecal staining of the abdomen, decreased activity, and
piloerection. An oral LD50 of 100 mg/kg was determined with the 14-day
observation period, and an oral LD50 of 113 mg/kg was determined with the 2-
day observation period.
Eastman Kodak (1992) reported an oral LD50 of 141 mg/kg for male rats.
Clinical signs included rough coat, diarrhea, ataxia, and prostration. No other
experimental details were provided.
3.1.2. Mice
Groups of five female CF1S mice were administered chloroacetone at 0,
50, 71, 100, 140, or 200 mg/kg by gavage in corn oil, followed by a 14-day
observation period (Sargent et al. 1986). Clinical signs included ataxia, lethargy,
prostration, piloerection, and a generally unhealthy appearance. An oral LD50 of
127 mg/kg was determined.
Eastman Kodak (1992) reported an oral LD50 of 141 mg/kg for male mice.
Clinical signs included rough coat, diarrhea, ataxia, and prostration. No other
experimental details were provided.
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Chloroacetone 95
3.1.3. Rabbits
In an acute dermal toxicity study, four New Zealand white rabbits were
administered chloroacetone at 50, 100, 200, or 400 mg/kg and were observed for
14 days (Sargent et al. 1986). The test substance was applied to the clipped skin,
covered with impervious plastic sheeting, and allowed to remain in contact with
the skin for 24 h. The rabbits were fitted with collars to prevent ingestion of the
chloroacetone. In the high-dose groups, signs of toxicity presented within 24 h
and included ataxia, clear oral discharge, general unhealthy appearance, soft
stools, and decreased activity. Moderate to severe erythema and edema were
observed in all treatment groups, and eschar formation and necrosis were
observed in all surviving animals during the second week of the study. An acute
dermal LD50 of 141 mg/kg was calculated.
3.1.4. Guinea Pigs
Eastman Kodak (1992) reported that the dermal LD50 of chloroacetone in
guinea pigs is “probably between 0.1 and 1.0 mL/kg.” No other information was
provided.
3.2. Nonlethal Toxicity
No acute toxicity studies of nonlethal effect of chloroacetone in animals
were found.
3.3. Repeated-Exposure Studies
Eastman Kodak (1992) conducted a series of experiments each using one
rat (strain and sex not specified). The rats were repeatedly exposed to
chloroacetone by inhalation for up to 11 exposures. No additional experimental
details were reported. Data are summarized in Table 3-4.
Groups of five male rats (strain not specified) were administered
chloroacetone at 0, 10, 50, or 100 mg/kg by gavage, 5 days/week for up to 13
days (Eastman Kodak 1992). One rat in the 100-mg/kg group died after three
doses, and the other four were sacrificed on day four because of poor condition.
Food intake and body weight gain were “severely depressed” at 100 mg/kg, and
food intake was “moderately depressed” and weight gain “severely depressed”
50 mg/kg. At 10 mg/kg, food consumption and body weight gain were
“moderately depressed.” Clinical signs in the 50-mg/kg group included
salivation, slight hyperactivity, pale eyes, and dark urine. No clinical signs were
noted in the 10-mg/kg group. Gross necropsy of high-dose animals revealed
necrotizing gastritis, fluid in the thoracic and abdominal cavities, adhesions
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96 Acute Exposure Guideline Levels
TABLE 3-4 Effects of Chloroacetone on Rats Repeatedly Exposed to
Chloroacetone
Average No. of
Concentration (ppm) exposures No. of rats Observations
20 11 1 Pink extremities, gasping, nasal irritation,
rough hair, body weight loss, survived
22 9 1 Pink extremities, gasping, nasal irritation,
rough hair, body weight loss
25 11 1 Pink extremities, gasping, nasal irritation,
rough hair, body weight loss, survived
39 4 1 Pink extremities, gasping, nasal irritation,
rough hair, body weight loss, death
58 2 1 Pink extremities, gasping, nasal irritation,
death in 2 days
Source: Eastman Kodak 1992.
between abdominal viscera, pale livers, and small seminal vesicles. In the 50-
mg/kg group, one rat had adhesions between the stomach and diaphragm and
thickening of the nonglandular mucosa of the stomach; another rat in this group
had a raised firm red area on the visceral surface of the stomach. No gross
abnormalities were noted in the 10-mg/kg group. Histopathologic observations
in the 100-mg/kg rats included gastric necrosis, ulceration, and perforation.
Necrosis of the liver, spleen, adrenal glands, and testes were considered
secondary to severe gastric irritation and subsequent peritonitis. Moderate to
severe cortical atrophy of the thymus was noted in all rats of the 100-mg/kg
group. In the 50-mg/kg group, one rat had necrosis of the nonglandular stomach
mucosa, one had necrosis of the glandular stomach mucosa, one had ulceration
of the nonglandular stomach, and all had hyperkeratosis of the esophageal
mucosa. Three rats in the 10-mg/kg group had minor hyperkeratosis of the
gastric nonglandular stomach.
3.4. Developmental and Reproductive Toxicity
Developmental and reproductive toxicity studies of animal exposure to
chloroacetone were not available.
3.5. Genotoxicity
Chloroacetone at concentrations of 100-2,000 nmole/plate did not induce
mutation in Salmonella typhimurium strains TA1535 or TA100, with or without
exogenous metabolic activation (Merrick et al. 1987). Negative results were also
obtained in S. typhimurium strains TA1535, TA1537, TA98, TA100, and hisG46
at concentrations of 1,500-3,000 μg/plate, with and without metabolic activation
(Sargent et al. 1986). Chloroacetone was negative in the SOS chromotest at
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Chloroacetone 97
concentrations of 0.01-3,000 μg/mL without S9 activation and at 0.1-100 μg/mL
with activation, and was also negative for clastogenicity in a newt micronucleus
test at 0.1-0.4 μg/mL (Le Curieux et al. 1994). Chloroacetone was positive in an
Ames-fluctuation test with S. typhimurium strain TA100 at concentrations of 1-
30 μg/mL with metabolic activation, but was negative without activation (Le
Curieux et al. 1994). Chloroacetone increased the frequency of sex-linked
recessive lethals in Drosophila melanogaster exposed via inhalation (Lee et al.
1983).
3.6. Carcinogenicity
Robinson et al. (1989) gave 40 female SENCAR mice dermal treatments
of chloroacetone at 0 or 50 mg/kg in 0.2 mL ethanol six times over a 2-week
period or oral doses of chloroacetone at 0 or 50 mg/kg three times over a 2-week
period (total dermal dose was 300 mg/kg; total oral dose was 150 mg/kg). Two-
weeks after the final doses, 1.0 μg TPA (12-O-tetradecanoly-phorbol-13-acetate)
in 0.2 mL acetone was applied to the skin three times per week for 20 weeks. No
evidence of increased tumor incidence was found in animals treated with
chloroacetone by either route compared with controls.
In another study, groups of 10 male and 10 female outbred stock albino
mice were given dermal treatments of chloroacetone (0.2 mL of a 0.3%
chloroacetone solution in acetone) twice a week for 12 weeks (Searle 1966).
Mice were then given dermal treatments of croton oil (0.2 mL, 0.5% in acetone)
twice a week for 20 weeks; surviving mice were killed after another 20 weeks
without treatment. Controls were treated with acetone followed by croton oil.
There was no treatment-related effect on mortality; however, a greater number
of papillomas wasfound in treated mice than in controls during subsequent
croton oil treatment. The overall tumor incidences appeared to be similar
between treated and control groups (cumulative incidence was not reported, and
statistical analysis was not performed), but the total number of tumors was
higher in treated mice compared with controls, and males developed more
tumors than females. Total numbers of tumors observed at 40 weeks were as
follows: three for male controls, seven for female controls, 29 for chloroacetone-
treated males, and 16 for chloroacetone-treated females. Both the incidences and
the total number of tumors were lower at 40 weeks than at 30 weeks, suggesting
that some of the tumors regressed; the authors reported that there were no
malignant tumors in chloroacetone-treated mice.
3.7. Summary
Animal toxicity data are limited to acute lethality studies in rats, mice, and
rabbits, and repeated-exposure studies in rats. The data suggest that male rats are
approximately 2.3 times more sensitive than female rats to the effects of
chloroacetone administered by inhalation. Oral lethality data suggest that mice
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Chloroacetone 101
and dermal LD50 values show little variability with regard to species and route of
exposure (see Table 3-5). For example, oral LD50 values range from 100 to 141
mg/kg for rats and from 127 to 141 mg/kg in mice, and a dermal LD50 of 141
mg/kg was reported for rabbits. Furthermore, the 1-h LC50 of 500 ppm for male
and female rats (Arts and Zwart 1987) gives an approximate dose of 114 mg/kg,
which corresponds to the oral LD50 values (assuming 100% retention, 245 mL
minute volume, and a rat body weight of 250 g).
4.6. Concentration-Exposure Duration Relationship
The concentration-time relationship for many irritant and systemically-
acting vapors and gases may be described by the equation Cn × t = k, where the
exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data were inadequate
for deriving an empirically-derived chemical-specific scaling exponent for
chloroacetone. Available toxicity data for chloroacetone are limited to 1-h
exposures (calculated LC50 values) and 6-h exposures (0/3 deaths at 52 ppm and
3/3 deaths at the 105 ppm). Thus, data from different exposure durations were
not adequate for use in plotting and calculating a value for n. However, the
available data suggest that exposure duration may alter the lethal concentration
of chloroacetone; specifically, the 1-h LC50 in male and female rats (combined)
was estimated to be in the range of 262-500 ppm (Sargent et al. 1986; Arts and
Zwart 1987) whereas an estimate of the 6-h rat LC50 is 50-100 ppm (Eastman
Kodak 1992). To obtain conservative and protective AEGL values in the
absence of an empirically-derived chemical-specific scaling exponent, temporal
scaling was be performed using the default values of n = 3 when extrapolating to
shorter time points and n = 1 when extrapolating to longer time points.
5. DATA ANALYSIS FOR AEGL-1
5.1. Human Data Relevant to AEGL-1
The study by Sargent et al. (1986) provides the only information on
human experience with chloroacetone. A concentration of 4.7 ppm was
associated with lacrimation and a burning sensation of the skin, but no further
information (e.g., ambient or personal monitoring, method of analysis, exposure
duration, number of individuals affected, number of exposed individuals) was
provided to support this association. This information is not considered adequate
for the purpose of deriving AEGL-1 values.
5.2. Animal Data Relevant to AEGL-1
No animal data consistent with the definition of AEGL-1 were available.
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102 Acute Exposure Guideline Levels
5.3. Derivation of AEGL-1
The available data on chloroacetone are insufficient, so AEGL-1 values
are not recommended.
6. DATA ANALYSIS FOR AEGL-2
6.1. Human Data Relevant to AEGL-2
No adequate human data consistent with the definition of AEGL-2 were
available. Immediate lacrimation and ocular and upper respiratory irritation were
noted in a worker accidentally exposed to chloroacetone vapors and hot liquid
for an undetermined duration at an unspecified concentration; the exposure
included inhalation and dermal components (Sargent et al. 1986).
6.2. Animal Data Relevant to AEGL-2
Restlessness, rubbing of snouts, lacrimation, salivation, and humped
posture were noted in male and female rats exposed to chloroacetone at 132 ppm
for 1 h (Arts and Zwart 1987).
6.3. Derivation of AEGL-2
The only data consistent with the definition of AEGL-2 are the clinical
signs observed in rats exposed to chloroacetone at 132-2,079 ppm for 1 h (Arts
and Zwart 1987). Chloroacetone exhibited a steep dose-response relationship. In
that study, 132 ppm was the only concentration causing no mortality and is
greater than the concentration used as the point-of-departure for AEGL-3 values
(BMCL05 of 131 ppm; see below). Due to the steep dose-response relationship
and limitations in the available data, the AEGL-2 values for chloroacetone were
determined by a taking 3-fold reduction in the AEGL-3 values (see below); this
was considered an estimate of a threshold for irreversible effects (NRC 2001).
AEGL-2 values for chloroacetone are presented in Table 3-6, and the
calculations for these AEGL-2 values are presented in Appendix A.
7. DATA ANALYSIS FOR AEGL-3
7.1. Human Data Relevant to AEGL-3
No human data consistent with the definition of AEGL-3 were available.
7.2. Animal Data Relevant to AEGL-3
There are few animal studies with data consistent with the definition of
AEGL-3. One-hour LC50 values of 500 ppm (95% CI: 421-579 ppm for male
OCR for page 103
Chloroacetone 103
and female rats combined), 316 ppm (95% CI: 289-342 ppm for male rats), and
710 ppm (95% CI: 658-753 ppm for female rats) were calculated. One-hour
BMC01 values of 170 ppm (males and females combined), 223 ppm (males
only), and 394 ppm (females only) were calculated. One-hour BMCL05 values of
144 ppm (males and females combined), 131 ppm (males only), and 258 ppm
(females only) also were calculated (Arts and Zwart 1987).
7.3. Derivation of AEGL-3
The BMCL05 of 131 ppm (Arts and Zwart 1987) was be used as the basis
for calculating AEGL-3 values for chloroacetone. Interspecies and intraspecies
uncertainty factors of 3 each were applied. The mechanism of chloroacetone
toxicity is uncertain; although direct irritation effects are observed after
exposure through all routes, some information suggests the potential for
systemic effects after dermal and oral exposure (see Section 4.2). However, the
preponderance of the available information suggests that the primary effects of
chloroacetone inhalation are due to direct-acting irritation; this type of port-of-
entry effect does not exhibit toxicokinetic variability and thus is not expected to
vary greatly between species or among individuals. The interspecies uncertainty
factor of 3 is also supported by data suggesting little species variability with
regard to lethality from oral and dermal exposure to chloroacetone (rat oral LD50
values: 100-141 mg/kg; mouse oral LD50 values: 127-141 mg/kg; rabbit dermal
LD50 = 141 mg/kg). Furthermore, the 1-h LC50 of 500 ppm for male and female
rats (Arts and Zwart 1987) is approximately a dose of 114 mg/kg, which
corresponds to the oral LD50 values (assuming 100% retention, 245 mL minute
volume, and a rat body weight of 250 g). The intraspecies uncertainty factor of 3
is also considered sufficient because data from the more sensitive males were
used as the point-of-departure. Thus, the total adjustment was 10.
It has been shown that the concentration-time relationship for many
irritant and systemically acting vapors and gases may be described by the equa-
tion Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al.
1986). Data on chloroacetone were inadequate to derive an empirical value for
n. The available information suggests that the lethal concentration is lower after
longer exposure durations; the 1-h LC50 in male and female rats was 262-500
ppm (Sargent et al. 1986; Arts and Zwart 1987), while the 6-h LC50 is
approximately 50-100 ppm (Eastman Kodak 1992). Therefore, default estimates
of n were used to extrapolate from the 1-h point-of-departure to other time
points. An n of 3 was applied to extrapolate to the 10- and 30-min time periods,
TABLE 3-6 AEGL-2 Values for Chloroacetone
10 min 30 min 1h 4h 8h
8.0 ppm 5.5 ppm 4.4 ppm 1.1 ppm 0.53 ppm
(30 mg/m3) (21 mg/m3) (17 mg/m3) (4.2 mg/m3) (2.0 mg/m3)
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104 Acute Exposure Guideline Levels
and an n of 1 was applied to extrapolate to the 4- and 8-h time periods to provide
AEGL values that would be protective of human health (NRC 2001). AEGL-3
values for chloroacetone are presented in Table 3-7, and the calculations for
these AEGL-3 values are presented in Appendix A.
8. SUMMARY OF PROPOSED AEGLS
8.1. AEGL Values and Toxicity End Points
AEGL values for chloroacetone are summarized in Table 3-8. AEGL-1
values are not recommended because of insufficient data. AEGL-2 values were
set at one-third the AEGL-3 values, and AEGL-3 values were based on a 1-h
estimated threshold for lethality in male rats.
8.2. Comparison with Other Standards and Guidelines
Table 3-9 shows exposure criteria for chloroacetone that have been
established. ACGIH (2012) recommended a threshold limit value (TLV) ceiling
of 1.0 ppm for chloroacetone. The TLV-ceiling is a concentration that should
not be exceeded during any part of the working exposure; as such, there is no
parallel value among the AEGL exposure durations. The Dutch maximal
accepted concentration (MAC) of 1 ppm is equivalent to an 8-h TLV. However,
there is no published method for measuring occupational exposure to chloro-
acetone (OSHA 2012), and efforts to locate occupational monitoring data on
chloroacetone were not successful. Thus, there is no information with which to
determine whether workers have been exposed at concentrations at or
approaching the 1 ppm limit without adverse effects.
TABLE 3-7 AEGL-3 Values for Chloroactone
10 min 30 min 1h 4h 8h
24 ppm 17 ppm 13 ppm 3.3 ppm 1.6 ppm
(91 mg/m3) (65 mg/m3) (49 mg/m3) (13 mg/m3) (6.1 mg/m3)
TABLE 3-8 Summary of AEGL Values for Chloroacetone
Classification 10 min 30 min 1h 4h 8h
AEGL-1 NRa NRa NRa NRa NRa
(nondisabling)
AEGL-2 8.0 ppm 5.5 ppm 4.4 ppm 1.1 ppm 0.53 ppm
(disabling) (30 mg/m3) (21 mg/m3) (17 mg/m3) (4.2 mg/m3) (2.0 mg/m3)
AEGL-3 24 ppm 17 ppm 13 ppm 3.3 ppm 1.6 ppm
(lethality) (91 mg/m3) (65 mg/m3) (49 mg/m3) (13 mg/m3) (6.1 mg/m3)
a
Not recommended; absence of an AEGL-1 value does not imply that exposure below the
AEGL-2 value is without adverse effects.
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Chloroacetone 105
TABLE 3-9 Extant Standards and Guidelines for Chloroacetone
Exposure Duration
Guideline 10 min 30 min 1h 4h 8h
AEGL-1 NR NR NR NR NR
AEGL-2 8.0 ppm 5.5 ppm 4.4 ppm 1.1 ppm 0.53 ppm
AEGL-3 24 ppm 17 ppm 13 ppm 3.3 ppm 1.6 ppm
TLV-Ceiling (ACGIH)a 1 ppm 1 ppm 1 ppm 1 ppm 1 ppm
b
MAC (The Netherlands) 1 ppm
a
TLV-Ceiling (threshold limit value - ceiling) (American Conference of Governmental
Industrial Hygienists [ACGIH 2012]) is based on human exposure data (lacrimation and
other irritation) reported by Sargent et al. (1986). The TLV-ceiling is a concentration that
should not be exceeded during any part of the working exposure. Includes a skin notation.
b
MAC (maximaal aanvaaarde concentratie [maximal accepted concentration]). SDU Uit-
gevers (under the auspices of the Ministry of Social Affairs and Employment), The
Hague, The Netherlands, (MSZW 2004) is defined analogous to the ACGIH TLV-TWA
(a time-weighted average concentration 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).
8.3 Data Adequacy and Research Needs
The available human data have limitations because they are anecdotal and
do not provide robust concentration or duration exposure parameters. Animal
data also had limitations; however, oral exposure data corresponded well with
inhalation data, showing similar effects at similar dose equivalents. Data were
insufficient for derivation of AEGL-1 values.
9. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2012. Chloroace-
tone (CAS Reg. No.78-95-5). TLVs and BEIs Threshold Limit Values and Bio-
logical Exposure Indices. American Conference of Governmental Industrial Hy-
gienists, Cincinnati, OH.
Arts, J.H.E., and A. Zwart. 1987. Acute (One-Hour) Inhalation Toxicity Study of
Chloroacetone in Rats. TNO Report No. V87.093/261236. CIVO Institutes, Zeist,
The Netherlands. EPA Document No. 88870000029. Microfiche No. OTS0513
466.
Eastman Kodak. 1992. Initial Submission: Basic Toxicity of Chloroacetone with Cover
Letter Dated 090192. EPA Document No. 88920008853. Microfiche No. OTS057
0898.
HSDB (Hazardous Substances Data Bank). 2011. 1-Chloro-2-propanone (CAS Reg.
No.78-95-5). TOXNET, Specialized Information Services, U.S. National Library
of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/
sis/htmlgen?HSDB [accessed May 25, 2012].
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106 Acute Exposure Guideline Levels
IPCS (International Programme on Chemical Safety). 2006. Chloroacetone. International
Chemical Safety Cards (ICSCs). International Programme on Chemical Safety
[online]. Available: http://www.inchem.org/documents/icsc/icsc/eics0760.htm [ac-
cessed May 25, 2012].
Le Curieux, F., D. Marzin, and F. Erb. 1994. Study of the genotoxic activity of five chlo-
rinated propanones using the SOS chromotest, the Ames-fluctuation test and the
newt micronucleus test. Mutat. Res. 341(1):1-15.
Lee, W.R., R. Abrahamson, R. Valencia, E.S. Von Halle, F.E. Wurgler, and S. Zimmer-
ing. 1983. The sex-linked recessive lethal test for mutagenesis in Drosophila
melanogaster. Mutat. Res. 123(2):183-279.
Merrick, B.A., C.L. Smallwood, J.R. Meier, D.L. McKean, W.H. Kaylor, and L.W. Con-
die. 1987. Chemical reactivity, cytotoxicity, and mutagenicity of chloropro-
panones. Toxicol. Appl. Pharmacol. 91(1):46-54.
MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst
2004: Chlooraceton. Den Haag: SDU Uitgevers [online]. Available: http://www.la
srook.net/lasrookNL/maclijst2004.htm [accessed Sept. 11, 2012].
NRC (National Research Council). 1993. Guidelines for Developing Community Emer-
gency Exposure Levels for Hazardous Substances. Washington, DC: National
Academy Press.NRC (National Research Council). 2001. Standing Operating Pro-
cedures for Developing Acute Exposure Guideline Levels for Hazardous Chemi-
cals. Washington, DC: National Academy Press.
OSHA (Occupational Safety and Health Administration). 2012. Occupational Safety and
Health Guideline for Chloroacetone. Occupational Safety and Health Administra-
tion, Washington, DC [online]. Available: http://www.osha.gov/SLTC/healthguide
lines/chloroacetone/recognition.html [accessed May 25, 2012].
Prentiss, A.M. 1937. P. 121 in Chemicals in War: A Treatise on Chemical Warfare. New
York: McGraw Hill.
Robinson, M., R.J. Bull, G.R. Olson, and J. Stober. 1989. Carcinogenic activity associ-
ated with halogenated acetones and acroleins in the mouse skin assay. Cancer Lett.
48(3):197-203.
Sargent, E.V., G.D. Kirk, and M. Hite. 1986. Hazard evaluation of monochloroacetone.
Am. Ind. Hyg. Assoc. J. 47(7):375-378.
Searle, C.E. 1966. Tumor initiatory activity of some chloromononitrobenzenes and other
compounds. Cancer Res. 26:12-17.
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.
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Chloroacetone 107
APPENDIX A
DERIVATION OF AEGL VALUES FOR CHLOROACETONE
Derivation of AEGL-1 Values
Data are insufficient for derivation of AEGL-1 values for chloroacetone.
Derivation of AEGL-2 Values
Key study: Arts, J.H.E., and A. Zwart. 1987. Acute (one-hour)
inhalation toxicity study of chloroacetone in rats.
Civo Institutes, TNO. Report No. V87.093/261236.
The Netherlands. EPA Document No. 88870000029.
Microfiche No. OTS0513466.
Toxicity end point: One-third of the AEGL-3 values
10-min AEGL-2: 24 ppm ÷ 3 = 8.0 ppm
30-min AEGL-2: 17 ÷ 3 = 5.5 ppm
1-h AEGL-2: 13 ÷ 3 = 4.4 ppm
4-h AEGL-2: 3.3 ÷ 3 = 1.1 ppm
8-h AEGL-2: 1.6 ÷ 3 = 0.53 ppm
Derivation of AEGL-3 Values
Key study: Arts, J.H.E., and A. Zwart. 1987. Acute (one-hour)
inhalation toxicity study of chloroacetone in rats.
Civo Institutes, TNO. Report No. V87.093/261236.
The Netherlands. EPA Document No. 88870000029.
Microfiche No. OTS0513466.
Toxicity end point: Male rat 1-hr BMCL05 = 131 ppm.
Scaling: C3 × t = k (10-min, 30-min)
(131 ppm)3 × 1 h = 2,248,091 ppm-h
C1 × t = k (4-h, 8-h)
(131 ppm)1 × 1 h = 131 ppm-h
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108 Acute Exposure Guideline Levels
Uncertainty factors: 3 for interspecies differences
3 for intraspecies variability
10-min AEGL-3: C3 × 0.167 h = 2,248,091 ppm-h
C3 = 13,461,623 ppm
C = 238 ppm
238 ÷ 10 = 24 ppm
30-min AEGL-3: C3 × 0.5 h = 2,248,091 ppm-h
C3 = 4,496,182 ppm
C = 165 ppm
165 ÷ 10 = 17 ppm
1-h AEGL-3: C3 × 1 h = 2,248,091 ppm-h
C3 = 2,248,091 ppm
C = 131 ppm
131 ÷ 10 = 13 ppm
4-h AEGL-3: C1 × 4 h = 131 ppm-h
C1 = 32.7 ppm
C = 32.7 ppm
32.7 ÷ 10 = 3.3 ppm
8-h AEGL-3: C1 × 8 h = 131 ppm-h
C1 = 16.4 ppm
C = 16.4 ppm
16.4 ÷ 10 = 1.6 ppm
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Chloroacetone 109
APPENDIX B
ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLOROACETONE
Derivation Summary
AEGL-1 VALUES
Data on chloroacetone were insufficient for derivation of AEGL-1 values.
Absence of AEGL-1 values does not imply that exposure below the AEGL-2
values are without adverse effects.
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
8.0 ppm 5.5 ppm 4.4 ppm 1.1 ppm 0.53 ppm
Data adequacy: No acute toxicity data relevant to deriving AEGL-2 values were
available. Therefore, the AEGL-3 values were divided by 3.
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
24 ppm 17 ppm 13 ppm 3.3 ppm 1.6 ppm
Key reference: Arts, J.H.E., and A. Zwart. 1987. Acute (one-hour) inhalation
toxicity study of chloroacetone in rats. Civo Institutes, TNO Report No.
V87.093/261236. The Netherlands. EPA Document No. 88870000029. Microfiche
No. OTS0513466.
Test species/Strain/Number: Rat; SPF (Bor:WISW); 5/sex/group
Exposure route/Concentrations/Durations: Inhalation; 132, 263, 553, 816, 1,105,
and 2,079 ppm for 1 h
Effects:
132 ppm: No mortality; clinical signs: restlessness, rubbing of snouts,
lacrimation, salivation, and humped posture
263 ppm: Clinical signs; mortality: 1/5 males; 0/5 females
553 ppm: Clinical signs; mortality: 5/5 males; 1/5 females
816 ppm: Clinical signs; mortality: 5/5 males; 3/5 females
1,105 ppm: Clinical signs; mortality: 5/5 males; 5/5 females
2,079 ppm: Clinical signs; mortality: 5/5 males; 5/5 females
LC50: 500 ppm for males and females; 316 ppm for males; 710 ppm
for females
(Continued)
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110 Acute Exposure Guideline Levels
AEGL-3 VALUES Continued
BMC01: 170 ppm for males and females; 223 ppm for males; 394 ppm
for females
BMLC05: 144 ppm for males and females; 131 ppm for males; 258 ppm
for females
End point/Concentration/Rationale: Threshold for death; BMCL05 for male rats
of 131 ppm
Uncertainty factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3, available information suggests that the primary effects of
chloroacetone via inhalation are due to direct-acting irritation; this type of port-of-
entry effect does not exhibit toxicokinetic variability and, thus, is not expected to
vary greatly between species. Factor is also supported by data suggesting little
species variability in lethality from oral and dermal exposure to chloroacetone
(rat oral LD50 values: 100-141 mg/kg; mouse oral LD50 values: 127-141 mg/kg;
rabbit dermal LD50 = 141 mg/kg), and the 1-h LC50 of 500 ppm for male and
female rats is approximately a dose of 114 mg/kg, which corresponds to the oral
LD50 values (assuming 100% retention, 245 mL minute volume, and a rat body
weight of 250 g).
Intraspecies: 3, available information suggests that the primary effects of
chloroacetone via inhalation are due to direct-acting irritation; this type of port-of-
entry effect does not exhibit toxicokinetic variability and, thus, is not expected to
vary greatly among individuals. A factor of 3 is also considered sufficient because
the point-of-departure was from more sensitive male rats.
Modifying factor: Not applicable
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Cn × t = k, where an n of 3 was applied to extrapolate to the 10- and
30-min durations and an n of 1 was applied to extrapolate to the 4- and 8-h durations
(NRC 2001).
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Chloroacetone 111
APPENDIX C
CATEGORY PLOT FOR CHLOROACETONE
Chemical Toxicity - TSD All Data
Chloroacetone
10000
Human - No Effect
Human - Discomfort
1000
Human - Disabling
Animal - No Effect
100
ppm
Animal - Discomfort
10
Animal - Disabling
AEGL-3
AEGL-2
Animal - Partially Lethal
1
Animal - Lethal
AEGL
0
0 60 120 180 240 300 360 420 480
Minutes
FIGURE C-1 Category plot of animal and human data and AEGL values for chloroace-
tone.
