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7
Sulfuryl Chloride1
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 min to 8 h. Three
levels—AEGL-1, AEGL-2 and AEGL-3—are developed for each of five expo-
sure periods (10 and 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying
degrees of severity of toxic effects. The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or
milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is
predicted that the general population, including susceptible individuals, could
experience notable discomfort, irritation, or certain asymptomatic, non-sensory
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 Robert
Young (Oak Ridge National Laboratory) and Steven Barbee (National Advisory Commit-
tee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). 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 concludes 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).
282
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283
Sulfuryl Chloride
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 levels that
could produce mild and progressively increasing but transient and nondisabling
odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects.
With increasing airborne concentrations above each AEGL, there is a progres-
sive increase in the likelihood of occurrence and the severity of effects described
for each corresponding AEGL. Although the AEGL values represent threshold
levels for the general public, including susceptible subpopulations, such as in-
fants, children, the elderly, persons with asthma, and those with other illnesses,
it is recognized that individuals, subject to unique or idiosyncratic responses,
could experience the effects described at concentrations below the correspond-
ing AEGL.
SUMMARY
Sulfuryl chloride, a colorless to light yellow liquid with a pungent odor, is
used as chlorinating, sulfonating, and chlorosulfonating agent in organic synthe-
sis. It is generally used in closed systems, thereby limiting exposure potential.
No information is available regarding exposure of humans to sulfuryl
chloride. Because it decomposes to hydrochloric acid and sulfuric acid upon
contact with water, it may assumed that exposure would result in notable irrita-
tion and corrosive action on the eyes and respiratory tract. Due to this decompo-
sition, metabolism is irrelevant in the toxic response to sulfuryl chloride.
Inhalation exposure data in animals are limited to lethality studies in labo-
ratory rats, all of which confirm toxic effects (dyspnea, ocular irritation, and
respiratory tract irritation leading to pulmonary hemorrhage and death) consis-
tent with severe irritation and /or corrosive activity. One-hour LC50 values of 59
to 242 ppm and a 4-h LC50 of 159 ppm have been reported for rats. There was
some discrepancy regarding the lethal toxicity of sulfuryl chloride in rats ex-
posed for one or four hours. However, all studies demonstrated that exposure of
rats produces clinical signs of ocular and respiratory tract irritation, dyspnea,
and body weight loss. Necropsy findings consistently indicated concentration-
related pulmonary involvement. Although death may occur during exposure at
higher concentrations, post-exposure observation has shown that lethality may
be delayed for several days at lower concentrations.
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284 Acute Exposure Guideline Levels
Data were insufficient for development of AEGL-1 values. All exposure
regimens in the rat studies resulted in effects that were considered of greater
severity than those of the AEGL-1 tier. Specifically, signs of ocular and respira-
tory tract irritation in rats exposed for one hour to sulfuryl chloride concentra-
tions as low as 31 ppm also exhibited pulmonary hemorrhage upon necropsy.
Toxicity studies on sulfuryl chloride were conducted primarily to assess
lethality. All nonlethal exposures in these studies resulted in respiratory tract
damage (necrosis, hemorrhage) that was detectable at the end of the 3 to14-day
post-exposure observation periods. Lethality threshold estimates (e.g., LC01,
BMCL05) from all studies resulted in exposure concentrations that were less than
the nonlethal concentrations in the respective studies. Therefore, it was not pos-
sible to determine a data-driven estimate of the threshold for AEGL-2 severity
effects. Because lethality threshold estimates tended to be less than nonlethal
experimental exposures and because of the apparent steep exposure-response
curve for sulfuryl chloride, AEGL-2 values were estimated by a three-fold re-
duction of the AEGL-3 values (NRC 2001).
A 4-h BMCL05 of 70.1 ppm calculated from the Haskell Laboratory study
(DuPont 1982; Kelly and Stula 1983) was used as the POD for deriving AEGL-
3 values. Although this is a somewhat more conservative approach than use of
an LC01 (70.6 ppm) as an estimate of the lethality threshold, its selection may be
justified by the known respiratory tract damage observed from nonlethal expo-
sures and the potential uncertainty regarding latent-occurring health effects
(including lethality beyond the 3 to 14-day observation periods of the animal
studies). Because the effects of sulfuryl chloride appear to be contact tissue
damage resulting from the degradation products (sulfuric acid and hydrochloric
acid) not resulting from metabolic processes and because rodents will receive a
greater dose to target tissues than would humans, the uncertainty factor for inter-
species variability was limited to 3. An intraspecies uncertainty factor of 3 was
considered sufficient to account for individual variability in direct-contact toxic
response to corrosive agents. Additional uncertainty was considered unnecessary
because a 4-h exposure of rats to 84 ppm in the DuPont (1982) study was not
lethal, and multiple exposures of rats to 55 ppm was not lethal (Kelly and Stula
1983). The exposure concentration-exposure time relationship for many irritant
and systemically acting vapors and gases may be described by Cn × t = k, where
the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of
an empirically derived chemical-specific scaling exponent, temporal scaling for
AEGL-3 values was performed using n = 3 when extrapolating to shorter time
points and n = 1 when extrapolating to longer time points using the Cn × t = k
equation (NRC 2001).
Results of gentoxicity assays of sulfuryl chloride are equivocal and no car-
cinogenicity bioassays have been conducted. The AEGL values for sulfuryl
chloride are summarized in Table 7-1.
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Sulfuryl Chloride
1. INTRODUCTION
Sulfuryl chloride, a colorless to light yellow liquid with a pungent odor, is
used as chlorinating, sulfonating, and chlorosulfonating agent in organic synthe-
sis of such chemicals as chlorophenol and chlorothymol (O’Neil et al. 2001).
Approximately 10,000 to 20,000 metric tons of sulfuryl chloride were produced
worldwide in 2001 (OECD 2005).
The chemical and physical data on DMF are presented in Table 7-2.
TABLE 7-1 Summary of AEGL Values for Sulfuryl Chloride
Classification 10-min 30-min 1-h 4-h 8-h End Point (Reference)
AEGL-1 NR NR NR NR NR Not recommended;
(Nondisabling) insufficient data
AEGL-2 4.7 ppm 4.7 ppm 3.7 ppm 2.3 ppm 1.2 ppm Data insufficient for
(Disabling) 26 26 20 13 6.6 derivation of AEGL-2
mg/m3 mg/m3 mg/m3 mg/m3 mg/m3 threshold. Due to steep
exposure-response
relationship, AEGL-2
values estimated as one-
third reduction of AEGL-3
values (NRC 2001)
AEGL-3 14 ppm 14 ppm 11 ppm 7.0 ppm 3.5 ppm BMCL05 of 70.1 ppm
(Lethality) 77 77 61 39 19 estimated as lethality
mg/m3 mg/m3 mg/m3 mg/m3 mg/m3 threshold in rats following
4-h exposure to sulfuryl
chloride (DuPont 1982;
Kelly and Stula 1983)
TABLE 7-2 Chemical and Physical Data for Sulfuryl Chloride
Parameter Value Reference
Synonyms Sulfuryl dichloride; sulfonyl IUCLID 2000; O’Neil et
chloride; sulphuric acid dichloride; al. 2001
sulfuric oxychloride
CAS Registry No. 7791-25-5 O’Neil et al. 2001
Chemical formula Cl2O2S O’Neil et al. 2001
Molecular weight 134.96 O’Neil et al. 2001
Physical state Liquid O’Neil et al. 2001
Boiling/melting point 69.3°C/-54.1°C O’Neil et al. 2001
1.67 g/cm3 at 20°C
Density OECD 2005
Solubility in water Hydrolyzes in water O’Neil et al. 2001
Vapor pressure 148 hPa at 20°C OECD 2005
3
Conversion factors in air 1 mg/m = 0.18 ppm
1 ppm = 5.51 mg/m3
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286 Acute Exposure Guideline Levels
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
No data were available regarding lethality in humans following inhalation
exposure to sulfuryl chloride.
2.2. Nonlethal Toxicity
No information was available regarding the nonlethal effects of sulfuryl
chloride in humans. No odor threshold or odor detection limits were available
for sulfuryl chloride.
2.3. Developmental/Reproductive Effects
No human developmental/reproductive toxicity data were available re-
garding sulfuryl chloride.
2.4. Genotoxicity
No human genotoxicity data were available.
2.5. Carcinogenicity
No data were found in the available literature regarding the carcinogenic
potential of sulfuryl chloride in humans.
2.6. Summary
There are no human exposure data regarding inhalation of sulfuryl chlo-
ride.
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
3.1.1. Rats
In a Haskell Laboratory study (DuPont 1982; Kelly and Stula 1983),
groups of 10 male Crl:CD7 rats (7-8 weeks old, 233-274g) were exposed (head-
only) to 84.4, 134, 155, 207, or 273 ppm sulfuryl chloride (100% purity) for four
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Sulfuryl Chloride
hours. The rats were observed for 14 days post exposure. All exposed rats exhib-
ited red nasal discharge lasting up to two days post exposure. Rats surviving the
exposures exhibited severe weight loss for one to two days post exposure. The
response of exposure groups are summarized in Table 7-3. The estimated 4-h
LC50 was reported as 159 ppm. A lethality threshold estimate (4-h LC01) of 70.6
ppm was independently estimated using the method of Litchfield and Wilcoxon
(1949) (see Appendix B).
One-hour LC50 values (Table 7-4) for sulfuryl chloride indicating a gen-
der-related variability in lethal response have been reported (Bayer AG 1993a;
IUCLID 2000). No experimental details were available regarding these values.
An acute inhalation exposure experiment conducted by Western Research
Center (Stauffer Chemical Company 1969) provided lethality data for rats ex-
posed to sulfuryl chloride for one hour. In this study, groups of 10 rats (200 g,
gender and strain not specified) were exposed to sulfuryl chloride at concentra-
tions of 0.240, 0.394, 0.600, 1.110, 1.400, or 2.180, mg/l (equivalent to 43, 71,
108, 200, 252, and 392 ppm). Rats in all exposure groups exhibited dyspnea and
hyperactivity. Exposures at “larger doses” exhibited heavy nasal and pulmonary
discharges that were expelled from the mouth. Nasal irritation increased with
exposure concentration. Necropsy at 14 days following the 0.240 mg/l (43 ppm)
exposure revealed necrosis and erythema in the nasal passages. The lethality
data are summarized in Table 7-5.
TABLE 7-3 Toxicity of Sulfuryl Chloride in Male Rats Following a Single 4-h
Head Only Inhalation Exposure
Exposure in ppm Exposure concentration Mortality
(mean ± s.d) range (ppm)
84.4 ± 7.7 80-103 0/10
134 ± 39.9 70-110 2/10 (1 During exposure and
1 within 24 h)
155 ± 19.9 135-195 8/10 (6 During exposure;
2 within 24 h)
207 ± 23.4 172-240 7/10 (All died during exposure)
273 ±16.5 225-294 10/10 (All during exposure)
Source: DuPont 1982.
TABLE 7-4 Inhalation Toxicity in Rats Exposed to Sulfuryl Chloride
Gender Lethality Value Source
Male 1-h LC50 = 131 ppm Bayer AG 1993a; IUCLID 2000
Female 1-h LC50 = 242 ppm Bayer AG 1993a; IUCLID 2000
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288 Acute Exposure Guideline Levels
TABLE 7-5 Lethality in Rats Following 1-h Inhalation Exposure
to Sulfuryl Chloride
Exposure
concentration (ppm) Mortality ratio Time-to-death
43 0/10 –
71 8/10 1-18 h
108 8/10 1-16 h
200 10/10 1-10 h
252 10/10 1-5 h
392 10/10 1-5 h
Source: Stauffer Chemical Company 1969.
In a later study, a 1-h LC50 of 0.33 mg/L (~59.4 ppm) for male and female
rats (200 g, strain, age not specified) was reported by Western Research Center
(Stauffer Chemical Company 1970). Purity of the test article was specified as “>
1% < 100%”. Results of this study are shown in Table 7-6. Exposed rats exhib-
ited concentration-related increased severity of lacrimation, erythema around the
eyes and ears, salivation, and dyspnea. All dead rats exhibited grossly hemor-
rhagic lungs with severe erythema of the gastrointestinal tract. Rats in the low-
dose groups also exhibited areas of pulmonary hemorrhage. Total post-exposure
observation time was not specified although it may be inferred that the rats were
observed for at least 72 h.
3.2. Nonlethal Toxicity
3.2.1. Rats
In the study reported by Kelly and Stula (1983), male Sprague-Dawley
rats (10/group) exposed head-only to a nonlethal exposure of 84.4 ppm sulfuryl
chloride exhibited reddish exudate around the eyes and nostrils. Notable body
weight loss for two days following exposure was also reported for these rats.
The rats were observed for up to 14 days post exposure. No gross or histopa-
thologic findings were reported.
In a 14-day inhalation exposure study, groups of 10 male Sprague-Dawley
rats were exposed to sulfuryl chloride (17, 55, or 166 mg/m3, equivalent to 3.1,
9.9, or 29.9 ppm) for 6 h/day, 5 days/week (Kelly and Stula 1983). The highest
concentration caused excessive weight loss after two exposures and was reduced
to 100 mg/m3 (19.8 ppm) which resulted in the death of two rats after only 8
exposures. Fourteen-day exposure to the lower concentrations was not lethal but
produced a concentration-related increase in blood urea nitrogen and histopa-
thologic evidence of respiratory tract damage. Exposure to the lowest dose also
exacerbated naturally occurring murine pneumonitis.
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Sulfuryl Chloride
TABLE 7-6 Lethality of Rats Exposed to Sulfuryl Chloride for 1 h
Exposure concentration Mortality ratio Time to death
0.174 mg/l (31.3 ppm) 0/10 –
0.346 mg/l (62.3 ppm) 6/10 16-72 h
0.695 mg/l (125.1 ppm) 10/10 8-12 h
Source: Stauffer Chemical Company 1970.
3.3. Developmental/Reproductive Effects
Information was not available regarding the developmental/reproducetive
toxicity of sulfuryl chloride.
3.4. Genotoxicity
Sulfuryl chloride was negative in an Ames test with Salmonella typhi-
murium TA 100 (up to 4000 µg/plate) with and without metabolic activation
(Bayer AG 1993b). In another assay (Bayer AG 1989) with Salmonella typhi-
murium TA 100, there was a significant dose-dependent increase in the number
of revertants with no metabolic activation. However, tests with strains TA98,
TA 1535, and TA 1537 were negative with and without activation (Bayer AG
1989).
3.5. Carcinogenicity
Information was not available regarding the carcinogenicity of sulfuryl
chloride.
3.6. Summary
Toxicity data for sulfuryl chloride are limited to lethality studies in rats.
One-hour LC50 values for rats ranged from 59-242 ppm. The 1-h LC50 estimates
from one study (Bayer 1987) suggested a gender-related sensitivity in lethality;
1-h LC50 of 131 and 242 ppm for male and females, respectively. A 4-h LC50 of
159 ppm was reported for male rats. Because sulfuryl chloride decomposes to
hydrochloric acid and sulfuric acid upon contact with water, it may be assumed
that much of its toxicity is attributable to corrosive activity of these products on
contacted tissues (e.g., respiratory tract). Exposure of test animals to nonlethal
concentrations of sulfuryl chloride was associated with signs of ocular and respi-
ratory irritation, body weight loss, and respiratory tract damage. There is a nota-
ble discrepancy among the available toxicity data; results of the Stauffer Chemi-
cal Company 1-h exposure studies appear to suggest much greater toxicity for
sulfuryl chloride than do data from other studies.
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290 Acute Exposure Guideline Levels
4. SPECIAL CONSIDERATIONS
4.1. Metabolism and Disposition
No information was available regarding the metabolism of sulfuryl chlo-
ride. Substantial decomposition to sulfuric acid and hydrochloric acid upon con-
tact with moisture (e.g., respiratory tract epithelial surfaces) is expected based
upon the chemical properties of sulfuryl chloride.
4.2. Mechanism of Toxicity
No experimental data were available regarding the mechanism of toxicity
of sulfuryl chloride. Corrosive activity and subsequent damage to epithelial tis-
sue would be expected from the decomposition products of sulfuric acid and
hydrochloric acid.
4.3. Structure-Activity Relationships
Structure-activity relationships were not utilized for AEGL development.
Sulfur chloride (S2Cl2) is sufficiently different from sulfuryl chloride in its water
solubility (less soluble), its degradation products (hydrochloric acid, sulfur, and
sulfur dioxide for sulfur chloride versus hydrochloric acid and sulfuric acid for
sulfuryl chloride), and acute toxicity (animal data indicate that sulfur chloride is
notably less toxic than sulfuryl chloride). Acute inhalation exposure toxicity
data in animals show that sulfuryl chloride is notably more toxic than its degra-
dation products.
5. DATA ANALYSIS FOR AEGL-1
5.1. Human Data Relevant to AEGL-1
No human exposure data are available with which to develop AEGL-1
values.
5.2. Animal Data Relevant to AEGL-1
There were no data with which to develop AEGL-1 values for sulfuryl
chloride.
5.3. Derivation of AEGL-1
The lowest concentrations tested in available animal studies were associ-
ated with evidence of respiratory tract damage. No exposure-response data are
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Sulfuryl Chloride
available to differentiate AEGL-1 type effects from those that may progress to
more serious effects. The continuum of toxic responses is likely a function of the
corrosive action of the sulfuryl chloride degradation products, hydrochloric and
sulfuric acid. The sulfur chloride concentrations at which the corrosive activity
of these products becomes more than minor irritation is unclear. Therefore,
AEGL-1 values are not recommended (Table 7-7).
6. DATA ANALYSIS FOR AEGL-2
6.1. Human Data Relevant to AEGL-2
No human exposure data were available with which to develop AEGL-2
values.
6.2. Animal Data Relevant to AEGL-2
Rats exposed to 0.174 mg/l (31.3 ppm sulfuryl chloride for one hour ex-
hibited signs of toxicity consistent with contact irritation and respiratory tract
damage (lacrimation, erythema around the eyes and ears, salivation, dyspnea,
and pulmonary hemorrhage) (Stauffer Chemical Company 1970). Reddish exu-
date around the eyes and nostrils was also observed in rats exposed to 84.4 ppm
(lowest concentration tested) for four hours (DuPont 1982; Kelly and Stula
1983). Neither of these exposures were associated with lethality. Overall, the
animal data clearly showed evidence of pulmonary damage in the absence of
lethality. In addition, body weight losses were reported for rats at nonlethal con-
centrations. Repeated (3.1 or 9.9 ppm for 6 h/day, 5 days/week) nonlethal expo-
sures exacerbated naturally occurring murine pneumonitis (Kelly and Stula
1983).
6.3. Derivation of AEGL-2
The reviewed toxicity studies were conducted primarily to assess lethality.
Lethality threshold estimates (e.g., LC01, BMCL05) from all studies resulted in
exposure concentrations that were less than the nonlethal concentrations in the
respective studies. However, all nonlethal exposures resulted in respiratory tract
damage (necrosis, hemorrhage) that was detectable at the end of the 3 to 14-day
post-exposure observation periods. Because lethality threshold estimates tended
to be less than nonlethal experimental exposures and because of the apparent
steep exposure-response curve for sulfuryl chloride, AEGL-2 values (Table 7-8)
were estimated by a three-fold reduction of the AEGL-3 values (NRC 2001).
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292 Acute Exposure Guideline Levels
TABLE 7-7 AEGL-1 Values for Sulfuryl Chloride
Classification 10-min 30-min 1-h 4-h 8-h
AEGL-1 NR NR NR NR NR
NR: not recommended; insufficient data.
TABLE 7-8 AEGL-2 Values for Sulfuryl Chloride
Classification 10-min 30-min 1-h 4-h 8-h
AEGL-2 4.7 ppm 4.7 ppm 3.7 ppm 2.3 ppm 1.2 ppm
26 mg/m3 26 mg/m3 20 mg/m3 13 mg/m3 6.6 mg/m3
7. DATA ANALYSIS FOR AEGL-3
7.1. Human Data Relevant to AEGL-3
No human exposure data were available with which to develop AEGL-3
values.
7.2. Animal Data Relevant to AEGL-3
Lethality data in animals are limited to rats. In acute inhalation studies
conducted at Haskell Laboratory (DuPont 1982; Kelly and Stula 1983), rats
were exposed (head-only) to 84.4, 134, 155, 207, or 273 ppm sulfuryl chloride
(100% purity) for four hours. Exposure to 84.4 ppm was without lethality and
provided a 4-h LC50 of 159 ppm. Stauffer Chemical Company (1970) reported a
1-h LC50 value of 59 ppm and Bayer (1987) reported 1-h LC50 values of 131
ppm and 242 ppm for male and female rats, respectively. A 4-h BMCL05 of 70.1
ppm (EPA 2005) and an LC01 of 70.6 ppm (Litchfield and Wilcoxon 1949) were
derived from the 4-h exposure-response data of the DuPont (Kelly and Stula
1983) study.
7.3. Derivation of AEGL-3
The 4-h BMCL05 of 70.1 ppm calculated from the Haskell Laboratory
study (DuPont 1982; Kelly and Stula 1983) was used as the point-of-departure
for deriving AEGL-3 values (Appendix B). This is a more conservative ap-
proach than use of the LC01 (70.6 ppm) as an estimate of the lethality threshold
using these data. This may be justified by the known respiratory tract damage
observed in nonlethal exposures and the potential uncertainty regarding latent-
occurring health effects, including lethality, beyond the observation periods util-
ized in the animal studies. The Haskell Laboratory studies were used for AEGL
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296 Acute Exposure Guideline Levels
APPENDIX A
DERIVATION OF AEGL VALUES FOR SULFURYL CHLORIDE
Derivation of AEGL-1 for Sulfuryl Chloride
Data were insufficient for developing AEGL-1 values for sulfuryl chlo-
ride. All exposure regimens in the available studies resulted in effects greater
than those consistent with AEGL-1.
Derivation of AEGL-2 for Sulfuryl Chloride
Lethality thresholds (e.g., LC01, BMCL05, one-third of LC50) estimated
from the Stauffer Chemical (1969, 1970) and from the DuPont studies (DuPont
1982; Kelly and Stula 1983) reports were less than the respective nonlethal ex-
posures reported in these studies. For this reason and because exposure-response
data were insufficient for determination of a threshold for AEGL-2 severity ef-
fects, derivation of AEGL-2 values by a three-fold reduction of AEGL-3 values
was considered appropriate. The resulting AEGL-2 values are:
10-min AEGL-2: 4.7 ppm
30-min AEGL-2: 4.7 ppm
1-h AEGL-2: 3.7 ppm
4-h AEGL-2: 2.3 ppm
8-h AEGL-2: 1.2 ppm
Derivation of AEGL-3 Sulfuryl Chloride
Key studies: DuPont (E.I. du Pont de Nemours & Co). 1982.
Inhalation Median Lethal Concentration (LC50) of
Sulfuryl Chloride. Haskell Laboratory Report No.
387-82. Haskell Laboratory for Toxicology and
Industrial Medicine. E. I. du Pont de Nemours and
Co., Inc.
Kelly, D.P., and E.F. Stula. 1983. Acute and
subacute inhalation toxicity of sulfuryl chloride
in rats. Toxicologist 3(1):62 [Abstract 248].
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Sulfuryl Chloride
Critical effect: BMCL05 of 70.1 ppm estimated as lethality threshold
in rats following 4-h exposure to sulfuryl chloride.
Cn × t = k where n = 1 or 3. In the absence of an
Time scaling:
empirically derived chemical-specific scaling
exponent, temporal scaling for both AEGL-2 and
AEGL-3 values was performed using n = 3 when
extrapolating to shorter time points and n = 1
when extrapolating to longer time points using the
Cn × t = k equation (NRC 2001).
Uncertainty factors: Total uncertainty factor adjustment was 10.
Interspecies: The effects of sulfuryl chloride are
mediated by contact tissue damage resulting from
the degradation of sulfuryl chloride to sulfuric acid
and hydrochloric acid and not the result of metabolic
processes. In addition, rodents will receive a greater
dose to target tissues than would humans. Therefore,
the uncertainty factor for interspecies variability was
limited to 3.
Intraspecies: An intraspecies uncertainty factor of 3
was considered sufficient to account for individual
variability in direct-contact toxic response to
corrosive agents and for individuals with
compromised respiratory function.
(70.1 ppm)1 × 4 h = 280.4-ppm-h
Calculations:
(70.1 ppm)3 × 4 h = 1,377,888 ppm3-h
10-min AEGL-3 Due to uncertainties in extrapolating from the 4-h
POD to 10-min exposure duration, the 10-min
AEGL-3 is set equivalent to the 30 min AEGL-3
(14 ppm)
C3 × 0.5 h = 1,377,888 ppm3-h
30-min AEGL-3
C3 = 2,755,777 ppm3-h
C = 140 ppm
UF application: 140 ppm/10 = 14 ppm
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298 Acute Exposure Guideline Levels
C3 × 1 h = 1,377,888 ppm3-h
1-h AEGL-3
C3 = 1,377,888 ppm3-h
C = 111 ppm
UF application: 111 ppm/10 = 11 ppm
C1 × 4 h = 280.4 ppm-h
4-h AEGL-3
C = 70 ppm
UF application: 70 ppm/10 = 7.0 ppm
C1 × 8 h = 280.4 ppm-h
8-h AEGL-3
C = 35 ppm
UF application: 35 ppm/10 = 3.5 ppm
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Sulfuryl Chloride
APPENDIX B
LC50 AND BENCHMARK DOSE CALCULATIONS FOR
SULFURYL CHLORIDE
DuPont (E.I. du Pont de Nemours & Co). 1982. Inhalation Median Lethal
Concentration (LC50) of Sulfuryl Chloride. Haskell Laboratory Report No. 387-
82. Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de
Nemours and Co., Inc.
Rats (male); all exposure concentrations expressed in ppm
Observed-
Dose Mortality Observed% Expected% Expected Chi-Square
84.400 0/10 0 (2.60) 2.81 -0.21 0.0002
134.000 2/10 20.00 30.77 -10.77 0.0544
155.000 8/10 80.00 51.23 28.77 0.3314
207.000 7/10 70.00 85.30 -15.30 0.1866
273.000 10/10 100 (97.40) 96.75 0.65 0.0013
Values in parentheses are corrected for 0 or 100% Total = 0.5739
LC50 = 153.718 (133.380 - 177.158)*
Slope = 1.32 (1.19 - 1.47)*
*These values are 95% confidence limits
Total animals = 50
Total doses = 5
Animals/dose = 10.00
Chi-square = total chi-square × animals/dose = 5.7391
Table value for chi-square with 3 degrees of freedom = 7.8200
LC84 = 203.516
LC16 = 116.105
FED = 1.15
FS = 1.11
A = 1.08
Probit Model $Revision: 2.1
$ Date: 2000/02/26 03:38:53 $
Input Data File: C:\BMDS\SO2CL2.(d)
Gnuplot Plotting File: C:\BMDS\SO2CL2.plt
Mon Nov 27 11:22:45 2006
OCR for page 300
300 Acute Exposure Guideline Levels
Exposure Expected Lethal Dose Values (ppm)
LC0.1 47.752
LC1.0 70.619
LC5.0 93.383
LC10 105.974
LC25 127.633
LC50 153.718
LC75 185.134
LC90 222.972
LC99 334.600
Benchmark Dose: BMCL05 Rat lethality data DuPont 1982; Kelly and Stula 1983).
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 = 5
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 = -14.2564
Slope = 2.83606
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)
OCR for page 301
301
Sulfuryl Chloride
Intercept Slope
Intercept 1 -1
Slope -1 1
Parameter Estimates
Variable Estimate Std. Err.
Background 0 NA
Intercept -17.8499 4.6632
Slope 3.54497 0.917185
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) Deviance Test DF P-value
Full model -16.1167
Fitted model -19.3819 6.53043 3 0.08847
Reduced model -34.4972 36.761 4 < .0001
AIC: 42.7638
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
84.4000 0.0168 0.168 0 10 -0.4128
134.0000 0.3131 3.131 2 10 -0.7709
155.0000 0.5115 5.115 8 10 1.825
207.0000 0.8542 8.542 7 10 -1.381
273.0000 0.9791 9.791 10 10 0.462
Chi-square = 6.22
DF = 3
P-value = 0.1015
Benchmark Dose Computation
Specified effect = 0.05
Risk Type = Extra risk
Confidence level = 0.95
BMD = 96.6681
BMDL = 70.1015
OCR for page 302
302 Acute Exposure Guideline Levels
APPENDIX C
TIME SCALING CALCULATIONS
The relationship between dose and time for any given chemical is a func-
tion of the physical and chemical properties of the substance and the unique
toxicological and pharmacological properties of the individual substance. His-
torically, the relationship according to Haber (1924), commonly called Haber’s
Law or Haber’s Rule (i.e., C × t = k, where C = exposure concentration, t = ex-
posure duration, and k = a constant) has been used to relate exposure concentra-
tion and duration to effect (Rinehart and Hatch 1964). This concept states that
exposure concentration and exposure duration may be reciprocally adjusted to
maintain a cumulative exposure constant (k) and that this cumulative exposure
constant will always reflect a specific quantitative and qualitative response. This
inverse relationship of concentration and time may be valid when the toxic re-
sponse to a chemical is equally dependent upon the concentration and the expo-
sure duration. However, an assessment by ten Berge et al. (1986) of LC50 data
for certain chemicals revealed chemical-specific relationships between exposure
concentration and exposure duration that were often exponential. This relation-
ship can be expressed by the equation Cn × t = k, where n represents a chemical
specific, and even a toxic end point specific, exponent. The relationship de-
scribed by this equation is basically the form of a linear regression analysis of
the log-log transformation of a plot of C vs t. Ten Berge et al. (1986) examined
the airborne concentration (C) and short-term exposure duration (t) relationship
relative to death for approximately 20 chemicals and found that the empirically
derived value of n ranged from 0.8 to 3.5 among this group of chemicals. Hence,
it was shown that the value of the exponent (n) in the equation Cn × t = k quanti-
tatively defines the relationship between exposure concentration and exposure
duration for a given chemical and for a specific health effect end point. Haber's
Rule is the special case where n = 1. As the value of n increases, the plot of con-
centration vs time yields a progressive decrease in the slope of the curve. In the
absence of an empirically derived chemical-specific scaling exponent, temporal
scaling for both AEGL-2 and AEGL-3 values for sulfuryl chloride was per-
formed using n = 3 when extrapolating to shorter time points and n = 1 when
extrapolating to longer time points using the Cn × t = k equation (NRC 2001).
OCR for page 303
303
Sulfuryl Chloride
APPENDIX D
ACUTE EXPOSURE GUIDELINES FOR SULFURYL CHLORIDE
Derivation Summary for Sulfuryl Chloride
AEGL-1 VALUES
10 min 30 min 1h 4h 8h
Not Not Not Not Not
recommended recommended recommended recommended recommended
Reference: Not applicable
Test Species/Strain/Number: Not applicable
Exposure Route/Concentrations/Durations: Not applicable
Effects: Not applicable
End Point/Concentration/Rationale: Not applicable
Uncertainty Factors/Rationale: Not applicable
Modifying Factor: None applied
Animal to Human Dosimetric Adjustment: Not applicable
Time Scaling: Not applicable
Data Adequacy: Data were insufficient for developing AEGL-1 values.
Test exposures in all available studies resulted in greater than AEGL-1
effects (respiratory tract damage) in animals.
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
4.7 ppm 4.7 ppm 3.7 ppm 2.3 ppm 1.2 ppm
Reference: NA
Test Species/Strain/Sex/Number: NA
Exposure Route/Concentrations/Durations: inhalation (see AEGL-3)
Effects: NA; estimated as one-third of AEGL-3
End Point/Concentration/Rationale: Due to inadequate data and uncertainties
regarding a definitive threshold for AEGL-2 level effects, the AEGL-2 values
were estimated as one-third of the AEGL-3.
Uncertainty Factors/Rationale: Total uncertainty factor: See AEGL-3
Modifying Factor: None applied
Animal to Human Dosimetric Adjustment: Not applicable
Time Scaling: See AEGL-3
Data Adequacy: Nonlethal exposure of rats to sulfuryl chloride produced effects
of respiratory irritation and pulmonary damage, dyspnea, and body weight loss.
Estimated lethality thresholds were less than experimental exposures that were
not lethal. Therefore, the AEGL-2 values were derived as one-third of the AEGL-3
values.
OCR for page 304
304 Acute Exposure Guideline Levels
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
14 ppm 14 ppm 11 ppm 7.0 ppm 3.5 ppm
References:
DuPont (E.I. du Pont de Nemours & Co). 1982. Inhalation Median Lethal
Concentration (LC50) of Sulfuryl Chloride. Haskell Laboratory Report No.
387-82. Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de
Nemours and Co., Inc.
Kelly, D.P., and E.F. Stula. 1983. Acute and subacute inhalation toxicity of sulfuryl
chloride in rats. Toxicologist 3(1):62 [Abstract 248].
Test Species/Strain/Sex/Number:10 male Crl:CD7 rats (7-8 weeks old, 233-274g)
Exposure Route/Concentrations/Durations: Inhalation (head-only) exposure to
84.4, 134, 155, 207, or 273 ppm sulfuryl chloride (100% purity) for four hours;
14-day observation
Effects:
Exposure Conc. (ppm) Mortality
84.4 0/10
134 2/10
155 8/10
207 7/10
273 10/10
End Point/Concentration/Rationale: The 4-h BMCL05 of 70.1 ppm calculated
from the Haskell Laboratory study (DuPont 1982; Kelly and Stula 1983) was used
as the point-of-departure for deriving AEGL-3 values. Although a somewhat more
conservative approach than use of the LC01 (70.6 ppm), it may be justified by the
known respiratory tract damage observed for nonlethal exposures and the potential
for latent-occurring health effects, including lethality, beyond the 3 to 14-day
observation periods utilized in the animal studies.
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: The interspecies uncertainty factor was limited to 3 because contact
tissue damage results from the degradation products (sulfuric acid and hydrochloric
acid) and not metabolism processes, and because rodents will receive a greater dose
to target tissues than would humans.
Intraspecies: An intraspecies uncertainty factor of 3 was considered sufficient to
account for individual variability in direct-contact toxic response to corrosive agents.
Additional uncertainty was considered unnecessary because a 4-h exposure of rats to
84 ppm in the DuPont (1982) study was not lethal, and multiple exposures of rats to
55 ppm was not lethal (Kelley and Stula 1983).
Modifying Factor: None applied
(Continued)
OCR for page 305
305
Sulfuryl Chloride
AEGL-3 VALUES Continued
10 min 30 min 1h 4h 8h
14 ppm 14 ppm 11 ppm 7.0 ppm 3.5 ppm
Animal to Human Dosimetric Adjustment: Not applicable
Time Scaling: In the absence of an empirically derived chemical-specific scaling
exponent, temporal scaling for both AEGL-2 and AEGL-3 values was performed
using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating
to longer time points using the Cn × t = k equation (NRC 2001).
Data Adequacy: Toxicity data were available for only one species, although the
mode of action is likely very similar across species. Data were sufficient for
AEGL-3 development.
OCR for page 306
306 Acute Exposure Guideline Levels
APPENDIX E: CATEGORY PLOT FOR SULFURYL CHLORIDE
Chemical Toxicity - TSD All Data
Sulfur Chloride
1000.0
Human - No Effect
Human - Discomfort
100.0
Human - Disabling
Animal - No Effect
ppm
10.0
Animal - Discomfort
AEGL-3
Animal - Disabling
AEGL-2
1.0
Animal - Some Lethality
Animal - Lethal
AEGL-1
0.1
AEGL
0 60 120 180 240 300 360 420 480
Minutes
FIGURE 7-1 Category plot for sulfuryl chloride.
