10-04-2012, 02:55 PM
SULFURIC ACID
[attachment=19842]
I. Chronic Toxicity Summary
Inhalation reference exposure level 1 μg/m3
Critical effect(s) Bronchiolar epithelial hyperplasia, and thickening
of the bronchial walls in monkeys
Hazard index target(s) Respiratory system
II. Physical and Chemical Properties (HSDB, 1995; CRC, 1994; CARB, 1997)
Description Colorless liquid
Molecular formula H2SO4
Molecular weight 98.1 g/mol
Density 1.84 g/cm3 @ 15° C
Boiling point 330±0.5°C (100%)
Melting point 10.36°C (100%)
Vapor pressure <0.001 torr @ 25° C; 1 torr @ 145.8° C
Solubility Soluble in water
Conversion factor Not applicable
III. Major Uses or Sources
Sulfuric acid is a strong acid used as an intermediate in the synthesis of linear alkylbenzene
sulfonation surfactants used in dyes, in petroleum refining, for the nitration of explosives, in the
manufacture of nitrocellulose, in caprolactam manufacturing, as the electrolyte in lead-acid
batteries, and as a drying agent for chlorine and nitric acid. Sulfuric acid is formed in the
atmosphere from sulfur dioxide, from sulfur trioxide, and from oleum (a combination of sulfur
trioxide and sulfuric acid used industrially). The annual statewide industrial emissions from
facilities reporting under the Air Toxics Hot Spots Act in California based on the most recent
inventory were estimated to be 4460 pounds of sulfuric acid (CARB, 1999).
IV. Effects of Human Exposures
Workers in the lead battery industry showed etching and erosion of the teeth after 4 months
exposure to an average concentration of 0.23 mg/m3 H2SO4 (Gamble et al., 1984). Dental
erosion increased in a dose-dependent manner with longer duration of exposure.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 101
Sulfuric acid
A study of 33 storage battery plant workers exposed to H2SO4 concentrations as high as 35
mg/m3 showed a greater group mean decrease in FEVl across the time of their work shift
compared to workers who were not exposed to sulfuric acid (El-Saddik et al., 1972). The
salivary pH of the sulfuric acid exposed workers, a qualitative measure of acid exposure, was
lower than the controls during the course of the work shift.
OEHHA recently reviewed the California Ambient Air Quality Standard (CAAQS) for sulfates
(25 mg/m3 for 24 hours) to see if it adequately protects children (OEHHA, 2000). The report was
peer-reviewed by the Air Quality Advisory Committee. The report indicates that H+ itself may
play a role in the effects seen in epidemiological studies of sulfate air pollution. Controlled acute
inhalation studies in humans and laboratory animals of pH neutral or nearly neutral sulfate salts
(e.g., ammonium sulfate) (Utell et al., 1983; Lippman et al., 1987; Schlesinger et al., 1990), even
at relatively high concentrations, do not produce the effects reported from epidemiologic studies
of sulfates (asthma exacerbation, bronchoconstriction, decrements in lung function) that might be
expected from short-term excursions. The controlled exposure studies show that sulfate aerosols
containing strong acids, such as sulfuric acid and, to a lesser extent, ammonium bisulfate,
produce functional and structural changes in healthy subjects consistent with those observed in
epidemiological studies. A working hypothesis is that H+ is a causal factor for adverse human
health effects (e.g., see Lippmann and Thurston, 1996) and that, among the commonly measured
particulate matter (PM) indices, SO4
= is the best surrogate metric for H+.
A large number of epidemiologic studies have been conducted showing that elevated levels of
several air pollutants, including acid aerosols, sulfur and nitrogen oxides, and particulate sulfates
are correlated with an increased prevalence of pulmonary disease (U.S. EPA, 1989; OEHHA
2000). Elevated sulfate levels (1.6 ppb or 6.6 mg/m3) have been associated with statistically
significant decrements in FVC and FEV1 in a cohort of Canadian children (Stern et al., 1989).
Further analysis of these data led Bates and Sitzo (1989) to conclude that H2SO4 was the most
likely cause for the pulmonary changes observed. Similarly, Ostro et al. (1989) reported a
statistical association between asthma-related symptoms reported by 209 asthmatics and sulfate
and acidity levels in ambient air in Denver. Delfino et al. (1997) found that ambient H+ was
associated with emergency room visits by children for respiratory symptoms in a study in
Montreal. Additionally, Damokosh et al. (1993) in a follow-up analysis of the 6-City study
suggested associations between average H+ concentration and chronic bronchitic symptoms.
The relative odds of bronchitic symptoms with the highest acid concentration (58 nmoles/m3
H+)_ versus the lowest concentration (16 nmoles/m3) was 2.4 (95% CI:1.9 to 3.2). Furthermore
in a study of children in 24 U.S. and Canadian communities (Dockery et al., 1996) in which the
analysis was adjusted for the effects of gender, age, parental asthma, parental education, and
parental allergies, bronchitic symptoms were confirmed to be significantly associated with
strongly acidic PM (OR= 1.66; 95% CI 1.11-2.48). It was also found that FVC and FEV1 were
lower in locales with high particle acidity (Raizenne et al., 1996). Gwynn et al. (2000) reported
an association between both H+ and sulfate particles and respiratory hospital admissions and
mortality in Buffalo, NY. Acidic sulfates may act to increase the toxicity of particles by
enhancing the availability of metals present in the particles to generate reactive oxygen species in
the respiratory epithelium. This may account for some of the effects seen in these
epidemiological studies and makes it difficult to use these studies as a basis for a Reference
Exposure Level for sulfuric acid. The relationship between the effect levels observed in these
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 102
Sulfuric acid
studies and the proposed REL is discussed in the section below on the potential for differential
impacts on children's health.
The occupational standard for sulfuric acid is based on a study in human subjects by Amdur et
al. (1952). In their study, 22 healthy male subjects were exposed to 0, 0.35, 0.4, 0.5, 1, 2, or 5
mg/m3 for 5-15 minutes. The odor, taste, and irritation threshold was 1 mg/m3. Since the basis
for this standard is an acute exposure, it is not useful in determining a chronic non-cancer REL
for sulfuric acid. A review of chronic human exposures to sulfuric acid and resulting
carcinogenicity outcomes can be found in IARC (1992). However, none of the studies in that
review examined non-cancer endpoints.
Sulfuric acid and oleum (supersaturated anhydrous sulfuric acid with varying concentrations of
free sulfur trioxide) are absorbed as salts of sulfate anion (SO4
2-), and are excreted as organic
sulfates, neutral sulfur, or neutral sulfur compounds such as sulfur-containing amino acids. The
low systemic toxicity of these metabolites is likely of secondary importance to the irritation
caused by the inhaled acid.
V. Effects of Animal Exposures
An exposure of 9 cynomolgus monkeys per group to H2SO4 concentrations of 0, 0.38, 0.48, 2.43,
and 4.79 mg/m3 continuously for 78 weeks resulted in dose-dependent adverse histological
changes in lung and bronchiolar epithelial and parenchymal tissue in addition to a dosedependent
decrease in blood oxygenation (Alarie et al., 1973). In the animals exposed to
0.38 mg/m3, significant bronchiolar epithelial hyperplasia was observed in 5 of 9 animals;
thickening of the bronchiolar walls was observed in 3 of 9 animals. A slight focal bronchial
epithelial hyperplasia was present in 4 of the 9 animals. One animal died after 4 weeks exposure
to 0.38 mg/m3. Although signs of pulmonary edema and cardiac hypertrophy were found, the
cause of death was not determined.
Respiratory system effects of H2SO4 exposure in monkeys (Alarie et al., 1973)
H2SO4
(g/m3)
Particle
size
MMD
Bronchiolar epithelial
hyperplasia
Incidence – severity
Thickening of walls of
respiratory bronchioles
Incidence – severity
Increase in thickness of
alveolar walls
Incidence – severity
0 0/9 0/9 0/9
0.38 2.15 5/8 – slight 3/8 - slight 0/8
0.48 0.54 0/8 0/8 0/8
2.43 3.60 8/8 – moderate 8/8 – moderate 8/8 – moderate
4.79 0.73 8/8 – moderate to severe 8/8 – moderate to severe 0/8
Alarie et al. (1973) also exposed groups of 50 guinea pigs of each sex to 0, 0.08, or 0.1 mg/m3
H2SO4 continuously for 52 weeks. The group exposed to 0.1 mg/m3 also received larger sized
particulates than the 0.08 mg/m3 group (2.78 mm vs. 0.84 mm, respectively). No exposure related
effects were observed in the animals exposed to 0.08 mg/m3, whereas exposure of 0.1 mg/m3
resulted in decreased body weights in the female guinea pigs. No other histological changes in
any organs were observed at the end of the 52-week study.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 103
Sulfuric acid
Rabbits (4 per group) were exposed to 250 mg/m3 H2SO4 1 hour/day, 5 days/week for 4, 8, or 12
months. They showed significantly increased bronchoconstriction upon acetylcholine challenge
after 8 and 12 months exposure, compared with a control group of 4 animals that received no
H2SO4 (Gearhart and Schlesinger, 1986, 1988). Mucociliary clearance was also impaired by
H2SO4 exposure and did not improve 3 months after cessation of exposure. A decline in
dynamic lung compliance was observed after 12 months exposure. There was no evidence of
inflammatory cell infiltration in the lungs of the exposed animals.
In guinea pigs, significantly slower and irregular breathing patterns were noted when the animals
had inhaled albumin followed by 30 minute exposures to H2SO4 at 1.91 mg/m3 twice per week
for 5 weeks (Kitabatake et al., 1979). Similarly, when guinea pigs were exposed to 2.49 mg
H2SO4/m3 for 4 hours/day, 6 days/week for 4 weeks, in vitro lung histamine release was
significantly enhanced following heterogeneous albumin inhalation, compared to control animals
unexposed to albumin (Fujisawa et al., 1986; Iguchi et al., 1986). In guinea pigs, sulfuric acid
caused significantly greater lung function changes when adsorbed on the surface of zinc oxide
particles as compared with pure sulfuric acid (Amdur and Chen, 1989). An exposure to
24 μg/m3 sulfuric acid, layered on zinc oxide, produced significant reductions in lung function
when followed by a brief exposure to 0.15 ppm ozone (Chen et al., 1991).
A chronic exposure of beagle dogs to an average concentration of 889 mg/m3 H2SO4 for 21
hours/day over a 620 day period resulted in increased expiratory resistance, reduced carbon
monoxide diffusing capacity, reduced total and residual lung volume, and decreased lung and
heart weights (Lewis et al., 1973).
In apparent contrast to the above studies, rats and guinea pigs exposed to H2SO4 at 10 mg/m3 for
6 hours/day, 5 days/week for 6 months exhibited no adverse histologic changes in lung tissue.
Lung function measurements were not reported in this study (Cavender et al., 1978).
Mice inhaled sulfuric acid mist at a concentration of 1.4 mg/m3 in combination with a carbon
particle mixture (1.5 mg/m3) for 3 hours/day, 5 days/week for up to 20 weeks. The exposure
resulted in significant alterations in specific antibody titer (decreased IgG, Ig2a, IgM; increased
IgG2b), depression of primary splenic antibody response, and decreased resistance to respiratory
infection as measured by mortality and survival time compared to controls (Fenters et al., 1979).
There are no reliable studies indicating that sulfuric acid is a developmental or reproductive
toxicant. In the absence of massive overexposure leading to maternal acidemia, H2SO4 will be
neutralized in the maternal circulation and is unlikely to reach the fetus.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 104
Sulfuric acid
VI. Derivation of Chronic Reference Exposure Level
Study Alarie et al., 1973
Study population Cynomolgus monkeys (5 males and 4 females per
group or vice versa)
Exposure method Continuous inhalation exposures (0, 380, 480,
2400, or 4800 mg/m3) for 78 weeks
Critical effects Significantly increased bronchial epithelial
hyperplasia and bronchial thickening
LOAEL 380 mg/m3
NOAEL Not observed
Exposure continuity The exposure was continuous during the
experiment.
Exposure duration 78 weeks
Average experimental exposure 380 mg/m3 for the LOAEL group
Human equivalent concentration 380 mg/m3
LOAEL uncertainty factor 3 (slight effects)
Subchronic uncertainty factor 3
Interspecies uncertainty factor 3 (non-human primate)
Intraspecies uncertainty factor 10
Cumulative uncertainty factor 300
Reference exposure level 1 mg/m3
The study by Alarie et al. (1973) identified a LOAEL for chronic exposure to sulfuric acid of
380 mg/m3. The principal uncertainties of this study are the small sample size of the test groups
and the absence of an observed NOAEL. A lower chronic LOAEL for bronchial reactivity is
presented by Gearhart and Schlesinger (1986, 1988) for rabbits (250 mg/m3). This study was not
selected as the basis of the REL because Gearhart and Schlesinger used only a single
concentration of sulfuric acid, exposed the animals only for 1 hour per day for 5 days/week, used
only 4 animals per group, and measured effects over the course of up to 12 months. The
predominant weakness in the rabbit study, however, was the extreme discontinuity of the
exposures (1 hour/day, 5 days/week), which would have necessitated use of a very large
continuity adjustment. For these reasons, in addition to obvious physiological and genetic
similarity arguments, the study in monkeys by Alarie et al. (1973) was felt to be more
appropriate as the basis for the chronic REL for sulfuric acid. Alarie et al. (1975) determined a
NOAEL for sulfuric acid in monkeys of 0.1 mg/m3. However, other particulate matter (fly ash)
was also present during the exposure. The Alarie et al. (1973) report provides data from
exposure to sulfuric acid alone.
A free-standing NOAEL for histological changes in 100 guinea pigs exposed continuously for 1
year to 0.08 mg/m3 was reported by Alarie et al. (1973). Guinea pigs respond to high
concentrations of sulfuric acid by occasional laryngeal spasms that appear similar to a human
asthmatic attack (Silbaugh et al., 1981; Amdur and Chen, 1989). As a result, guinea pigs are
thought to be sensitive models for the acute effects of sulfuric acid. For chronic effects of
sulfuric acid on the lung, monkeys are likely a suitable model due to their physiological and
structural similarites to humans.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 105
Sulfuric acid
For comparison, a chronic REL based on the guinea pig free-standing NOAEL of 0.08 mg/m3 in
animals exposed continuously for one year (Alarie et al., 1973) would be 0.8 mg/m3.
VII. Data Strengths and Limitations for Development of the REL
The major strength of the study on sulfuric acid is the use of health effects observations from
continuous long-term exposures to a primate. The major weaknesses are the lack of adequate
human health effects data and the lack of a NOAEL observation.
VIII. Potential for Differential Impacts on Children's Health
There are no reliable studies indicating that sulfuric acid is a developmental or reproductive
toxicant. Children are likely to be at greater risk from long-term exposures because their bodies
are growing, and their developmental processes, especially in the lung, may well be impacted by
air pollution exposures. Elevated sulfate levels (1.6 ppb or 6.6 mg/m3) have been associated with
statistically significant decrements in FVC and FEV1 in a cohort of Canadian children (Stern et
al., 1989). The chronic REL for sulfuric acid of 1 mg/m3 is below the level associated with those
decrements in pulmonary function. However, in a study of moderately to severe asthmatic
children (ages 7-13) (Thurston et al., 1997), a sensitive subpopulation for sulfate effects,
approximately 1 mg/m3 was the lowest level of ambient sulfate measured. The mean daily
morning to afternoon peak airflow change, the use of beta-agonist medication, and the number of
chest symptoms versus sulfate concentration in these children extrapolated linearly down to 1
mg/m3. Thurston et al. (1997) also examined earlier data from Ontario (Burnett et al., 1994) on
respiratory admissions to hospitals, and concluded that the sulfate threshold of effects, if it exists,
lies below 5 mg/m3, perhaps at about 2 mg/m3. It should be noted that the sulfate and hydrogen
ion effects are difficult to disentangle from each other and from the effcts of other PM
constituents. The chronic REL of 1 mg/m3 appears to have a relatively low margin of safety with
respect to the epidemiological studies, but these observations are consistent with the proposed
REL of 1 mg/m3 since asthmatic children appear to be the critically sensitive human population
for exposure to sulfuric acid (or sulfate).
IX. References
Alarie Y, Busey WM, Krumm AA, Ulrich CE, and Va V. 1973. Long-term continuous exposure
to sulfuric acid mist in cynomolgus monkeys and guinea pigs. Arch. Environ. Health 27:16-24.
Alarie YC, Krumm AA, Busey WM, Urich CE, and Kantz RJ. 1975. Long-term exposure to
sulfur dioxide, sulfuric acid mist, fly ash, and their mixtures. Results of studies in monkeys and
guinea pigs. Arch. Environ. Health 30(5):254-262.
Amdur MO, and Chen LC. 1989. Furnace-generated acid aerosols: Speciation and pulmonary
effects. Environ. Health Perspect. 79:147-150.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 106
Sulfuric acid
Amdur MO, Silverman L, and Drunker P. 1952. Inhalation of sulfuric acid mist by human
subjects. Arch. Ind. Hyg. Occup. Med. 6:305-313.
Bates DV, and Sitzo R. 1989. The Ontario air pollution study: Identification of the causative
agent. Environ. Health Perspect. 79:69-72.
Burnett RT, Dales RE, Raizenne ME, Krewski D, Summers PW, Roberts GR, Raad-Young M,
Dann T, and Brook J. 1994. Effects of low ambient levels of ozone and sulfates on the
frequency of respiratory admissions to Ontario hospitals. Environ Res 65:172-194.
CARB. 1997. California Air Resources Board. Toxic Air Contaminant Identification List
Summaries.
CARB. 2000. California Air Resources Board. California Emissions Inventory Development and
Reporting System (CEIDARS). Data from Data Base Year 1998. February 12, 2000.
CRC. 1994. CRC Handbook of Chemistry and Physics, 75th edition. Lide DR, ed. Boca Raton,
FL: CRC Press Inc.
Cavender FL, Singh B, and Cockrell BY. 1978. The effects in rats and guinea pigs from six
months exposures to sulfuric acid mist, ozone, and their combination. J. Environ. Pathol.
Toxicol. 2:485-492.
Chen LC, Miller PD, Lam HF, Guty J, and Amdur MO. 1991. Sulfuric acid-layered ultrafine
particles potentiate ozone-induced airway injury. J. Toxicol. Environ. Health 34:337-352.
Damokosh AI, Spengler JD, Dockery DW, Ware JH, and Speizer FE. 1993. Effects of acidic
particles on respiratory symptoms in 7 US communities. Am Rev Respir Dis 147:A632.
Delfino RJ, Murphy-Moulton AM, Burnett RT, Brook JR, and Becklake MR. 1997. Effects of air
pollution on emergency room visits for respiratory illnesses in Montreal, Quebec. Am J Respir
Crit Care Med 155:568-576.
Dockery DW, Cunningham J, Damokosh AI, Neas LM, Spengler JD, Koutrakis P, Ware JH, and
Speizer FE 1993. Health effects of acid aerosols on North American children: respiratory
symptoms. Environ Health Perspect 104:500-505.
El-Saddik YM, Osman HA, and El-Gazzar RM. 1972. Exposure to sulfuric acid in
manufacturing of storage batteries. J. Occup. Med. 14:224-226.
Fenters JD, Bradof JN, Aranyi C, Ketels K, Ehrlich R, and Gardner DE. 1979. Health effects of
long-term inhalation of sulfuric acid mist-carbon particle mixtures. Environ. Res. 19:244-257.
Fujisawa T, Iguchi K, and Uchida Y. 1986. Effects of exposure to sulfuric acid mist on the
induction of experimental asthma in guinea pigs. Japan J. Allergol. 35(2):137-144.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 107
Sulfuric acid
Gamble J, Jones W, Hancock J, and Meckstroth R. 1984. Epidemiologic environmental study of
lead acid battery workers. III. Chronic effects of sulfuric acid on the respiratory system and teeth.
Environ. Res. 35:30-52.
Gearhart JM, and Schlesinger RB. 1986. Sulfuric acid-induced airway hyperresponsiveness.
Fundam. Appl. Toxicol. 7:681-689.
Gearhart JM, and Schlesinger RB. 1988. Response of the tracheobronchial mucociliary clearance
system to repeated irritant exposure: effect of sulfuric acid mist on function and structure. Exp.
Lung Res. 14:587-605.
Gwynn RC, Burnett RT, and Thurston GD. 2000. A time-series analysis of acidic particulate
matter and daily mortality and morbidity in the Buffalo, New York region. Environ Health
Perspect. 108:125-133.
HSDB. 1995. Hazardous Substances Data Bank. National Library of Medicine, Bethesda, MD
(TOMESÒ CD-ROM Version). Denver, CO: Micromedex, Inc. (Edition expires 7/31/96).
IARC. 1992. International Agency for Research on Cancer. IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans. Vol. 54. Occupational Exposure to Mists and
Vapours from Strong Inorganic Acids and other Industrial Chemicals. Lyon, France: IARC, pp.
41-130
Iguchi K, Fujisawa T, and Uchida Y. 1986. Effects of exposure to sulfuric acid mist on the
induction of experimental asthma in guinea pigs. Japan J. Allergol. 35(6):402-408.
Kitabatake M, Imai M, Kasama K, Kobayashi I, Tomita Y, and Yoshida K. 1979. Effects of air
pollutants on the experimental induction of asthma attacks in guinea pigs: Sulfuric acid mist and
mixture of the mist and sulfur dioxide. Mie Med. J. 29(1):29-37.
Lewis TR, Moorman WJ, Ludmann WF, and Campbell KI. 1973. Toxicity of long-term exposure
to oxides of sulfur. Arch. Environ. Health 26:16-21.
Lippman M, Gearhart JM, Schlesinger RB. 1987. Basis for a particle size-selective TLV for
sulfuric acid aerosols. Appl Ind Hyg 2:188-199.
Lippmann M, Thurston GD. 1996. Sulfate concentrations as an indicator of ambient particulate
matter air pollution for health risk evaluations. J. Expo. Anal. Environ. Epidemiol. 6(2):123-146.
OEHHA. 2000. Office of Environmental Health Hazard Assessment. Staff report. Adequacy of
California Ambient Air Quality Standards: Senate Bill No. 25 - Children's Environmental Health
Protection.
Ostro B, Lipsett M, Wiener M, and Selner JC. 1989. A panel study of the effect of acid aerosols
on asthmatics. J. Air Waste Management Assoc. 89-94.1:1-15.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 108
Sulfuric acid
Raizenne M, Neas LM, Damokosh AI, Dockery DW, Spengler JD, Koutrakis P, Ware JH, and
Speizer FE. 1996. Health effects of acid aerosols on North American children: pulmonary
function. Environ Health Perspect 104: 506-514.
Schlesinger RB, Chen LC, Finkelstein I, and Zelikoff JT. 1990. Comparative potency of inhaled
acidic sulfates: speciation and the role of hydrogenion. Environ Res 52:210-224.
Silbaugh SA, Mauderly JL, Macken CA. 1981. Effects of sulfuric acid and nitrogen dioxide on
airway responsiveness of the guinea pig. J. Toxicol. Environ. Health 8(1-2):31-45.
Stern B, Jones L, Raizenne M, Burnett R, Meranger JC, Franklin CA. 1989. Respiratory health
effects associated with ambient sulfates and ozone in two rural Canadian communities. Environ.
Res. 49(1):20-39.
Thurston GD, Lippmann M, Scott MB, Fine JM. 1997. Summertime haze air pollution and
children with asthma. Am. J. Respir. Crit. Care Med. 155(2):654-660.
U.S. EPA. 1989. U.S.Environmental Protection Agency. An Acid Aerosols Issue Paper: Health
Effects and Aerometrics. EPA/600/8-88/00SF. OHEA/ORD. Research Triangle Park, NC: U.S.
EPA.
Utell MJ, Morrow PE, Speers DM, Darling J, Hyde RW. 1983. Airway responses to sulfate and
sulfuric acid aerosols in asthmatics: an exposure-response relationship. Am Rev Resp Dis
128:444-450.
[attachment=19842]
I. Chronic Toxicity Summary
Inhalation reference exposure level 1 μg/m3
Critical effect(s) Bronchiolar epithelial hyperplasia, and thickening
of the bronchial walls in monkeys
Hazard index target(s) Respiratory system
II. Physical and Chemical Properties (HSDB, 1995; CRC, 1994; CARB, 1997)
Description Colorless liquid
Molecular formula H2SO4
Molecular weight 98.1 g/mol
Density 1.84 g/cm3 @ 15° C
Boiling point 330±0.5°C (100%)
Melting point 10.36°C (100%)
Vapor pressure <0.001 torr @ 25° C; 1 torr @ 145.8° C
Solubility Soluble in water
Conversion factor Not applicable
III. Major Uses or Sources
Sulfuric acid is a strong acid used as an intermediate in the synthesis of linear alkylbenzene
sulfonation surfactants used in dyes, in petroleum refining, for the nitration of explosives, in the
manufacture of nitrocellulose, in caprolactam manufacturing, as the electrolyte in lead-acid
batteries, and as a drying agent for chlorine and nitric acid. Sulfuric acid is formed in the
atmosphere from sulfur dioxide, from sulfur trioxide, and from oleum (a combination of sulfur
trioxide and sulfuric acid used industrially). The annual statewide industrial emissions from
facilities reporting under the Air Toxics Hot Spots Act in California based on the most recent
inventory were estimated to be 4460 pounds of sulfuric acid (CARB, 1999).
IV. Effects of Human Exposures
Workers in the lead battery industry showed etching and erosion of the teeth after 4 months
exposure to an average concentration of 0.23 mg/m3 H2SO4 (Gamble et al., 1984). Dental
erosion increased in a dose-dependent manner with longer duration of exposure.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 101
Sulfuric acid
A study of 33 storage battery plant workers exposed to H2SO4 concentrations as high as 35
mg/m3 showed a greater group mean decrease in FEVl across the time of their work shift
compared to workers who were not exposed to sulfuric acid (El-Saddik et al., 1972). The
salivary pH of the sulfuric acid exposed workers, a qualitative measure of acid exposure, was
lower than the controls during the course of the work shift.
OEHHA recently reviewed the California Ambient Air Quality Standard (CAAQS) for sulfates
(25 mg/m3 for 24 hours) to see if it adequately protects children (OEHHA, 2000). The report was
peer-reviewed by the Air Quality Advisory Committee. The report indicates that H+ itself may
play a role in the effects seen in epidemiological studies of sulfate air pollution. Controlled acute
inhalation studies in humans and laboratory animals of pH neutral or nearly neutral sulfate salts
(e.g., ammonium sulfate) (Utell et al., 1983; Lippman et al., 1987; Schlesinger et al., 1990), even
at relatively high concentrations, do not produce the effects reported from epidemiologic studies
of sulfates (asthma exacerbation, bronchoconstriction, decrements in lung function) that might be
expected from short-term excursions. The controlled exposure studies show that sulfate aerosols
containing strong acids, such as sulfuric acid and, to a lesser extent, ammonium bisulfate,
produce functional and structural changes in healthy subjects consistent with those observed in
epidemiological studies. A working hypothesis is that H+ is a causal factor for adverse human
health effects (e.g., see Lippmann and Thurston, 1996) and that, among the commonly measured
particulate matter (PM) indices, SO4
= is the best surrogate metric for H+.
A large number of epidemiologic studies have been conducted showing that elevated levels of
several air pollutants, including acid aerosols, sulfur and nitrogen oxides, and particulate sulfates
are correlated with an increased prevalence of pulmonary disease (U.S. EPA, 1989; OEHHA
2000). Elevated sulfate levels (1.6 ppb or 6.6 mg/m3) have been associated with statistically
significant decrements in FVC and FEV1 in a cohort of Canadian children (Stern et al., 1989).
Further analysis of these data led Bates and Sitzo (1989) to conclude that H2SO4 was the most
likely cause for the pulmonary changes observed. Similarly, Ostro et al. (1989) reported a
statistical association between asthma-related symptoms reported by 209 asthmatics and sulfate
and acidity levels in ambient air in Denver. Delfino et al. (1997) found that ambient H+ was
associated with emergency room visits by children for respiratory symptoms in a study in
Montreal. Additionally, Damokosh et al. (1993) in a follow-up analysis of the 6-City study
suggested associations between average H+ concentration and chronic bronchitic symptoms.
The relative odds of bronchitic symptoms with the highest acid concentration (58 nmoles/m3
H+)_ versus the lowest concentration (16 nmoles/m3) was 2.4 (95% CI:1.9 to 3.2). Furthermore
in a study of children in 24 U.S. and Canadian communities (Dockery et al., 1996) in which the
analysis was adjusted for the effects of gender, age, parental asthma, parental education, and
parental allergies, bronchitic symptoms were confirmed to be significantly associated with
strongly acidic PM (OR= 1.66; 95% CI 1.11-2.48). It was also found that FVC and FEV1 were
lower in locales with high particle acidity (Raizenne et al., 1996). Gwynn et al. (2000) reported
an association between both H+ and sulfate particles and respiratory hospital admissions and
mortality in Buffalo, NY. Acidic sulfates may act to increase the toxicity of particles by
enhancing the availability of metals present in the particles to generate reactive oxygen species in
the respiratory epithelium. This may account for some of the effects seen in these
epidemiological studies and makes it difficult to use these studies as a basis for a Reference
Exposure Level for sulfuric acid. The relationship between the effect levels observed in these
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 102
Sulfuric acid
studies and the proposed REL is discussed in the section below on the potential for differential
impacts on children's health.
The occupational standard for sulfuric acid is based on a study in human subjects by Amdur et
al. (1952). In their study, 22 healthy male subjects were exposed to 0, 0.35, 0.4, 0.5, 1, 2, or 5
mg/m3 for 5-15 minutes. The odor, taste, and irritation threshold was 1 mg/m3. Since the basis
for this standard is an acute exposure, it is not useful in determining a chronic non-cancer REL
for sulfuric acid. A review of chronic human exposures to sulfuric acid and resulting
carcinogenicity outcomes can be found in IARC (1992). However, none of the studies in that
review examined non-cancer endpoints.
Sulfuric acid and oleum (supersaturated anhydrous sulfuric acid with varying concentrations of
free sulfur trioxide) are absorbed as salts of sulfate anion (SO4
2-), and are excreted as organic
sulfates, neutral sulfur, or neutral sulfur compounds such as sulfur-containing amino acids. The
low systemic toxicity of these metabolites is likely of secondary importance to the irritation
caused by the inhaled acid.
V. Effects of Animal Exposures
An exposure of 9 cynomolgus monkeys per group to H2SO4 concentrations of 0, 0.38, 0.48, 2.43,
and 4.79 mg/m3 continuously for 78 weeks resulted in dose-dependent adverse histological
changes in lung and bronchiolar epithelial and parenchymal tissue in addition to a dosedependent
decrease in blood oxygenation (Alarie et al., 1973). In the animals exposed to
0.38 mg/m3, significant bronchiolar epithelial hyperplasia was observed in 5 of 9 animals;
thickening of the bronchiolar walls was observed in 3 of 9 animals. A slight focal bronchial
epithelial hyperplasia was present in 4 of the 9 animals. One animal died after 4 weeks exposure
to 0.38 mg/m3. Although signs of pulmonary edema and cardiac hypertrophy were found, the
cause of death was not determined.
Respiratory system effects of H2SO4 exposure in monkeys (Alarie et al., 1973)
H2SO4
(g/m3)
Particle
size
MMD
Bronchiolar epithelial
hyperplasia
Incidence – severity
Thickening of walls of
respiratory bronchioles
Incidence – severity
Increase in thickness of
alveolar walls
Incidence – severity
0 0/9 0/9 0/9
0.38 2.15 5/8 – slight 3/8 - slight 0/8
0.48 0.54 0/8 0/8 0/8
2.43 3.60 8/8 – moderate 8/8 – moderate 8/8 – moderate
4.79 0.73 8/8 – moderate to severe 8/8 – moderate to severe 0/8
Alarie et al. (1973) also exposed groups of 50 guinea pigs of each sex to 0, 0.08, or 0.1 mg/m3
H2SO4 continuously for 52 weeks. The group exposed to 0.1 mg/m3 also received larger sized
particulates than the 0.08 mg/m3 group (2.78 mm vs. 0.84 mm, respectively). No exposure related
effects were observed in the animals exposed to 0.08 mg/m3, whereas exposure of 0.1 mg/m3
resulted in decreased body weights in the female guinea pigs. No other histological changes in
any organs were observed at the end of the 52-week study.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 103
Sulfuric acid
Rabbits (4 per group) were exposed to 250 mg/m3 H2SO4 1 hour/day, 5 days/week for 4, 8, or 12
months. They showed significantly increased bronchoconstriction upon acetylcholine challenge
after 8 and 12 months exposure, compared with a control group of 4 animals that received no
H2SO4 (Gearhart and Schlesinger, 1986, 1988). Mucociliary clearance was also impaired by
H2SO4 exposure and did not improve 3 months after cessation of exposure. A decline in
dynamic lung compliance was observed after 12 months exposure. There was no evidence of
inflammatory cell infiltration in the lungs of the exposed animals.
In guinea pigs, significantly slower and irregular breathing patterns were noted when the animals
had inhaled albumin followed by 30 minute exposures to H2SO4 at 1.91 mg/m3 twice per week
for 5 weeks (Kitabatake et al., 1979). Similarly, when guinea pigs were exposed to 2.49 mg
H2SO4/m3 for 4 hours/day, 6 days/week for 4 weeks, in vitro lung histamine release was
significantly enhanced following heterogeneous albumin inhalation, compared to control animals
unexposed to albumin (Fujisawa et al., 1986; Iguchi et al., 1986). In guinea pigs, sulfuric acid
caused significantly greater lung function changes when adsorbed on the surface of zinc oxide
particles as compared with pure sulfuric acid (Amdur and Chen, 1989). An exposure to
24 μg/m3 sulfuric acid, layered on zinc oxide, produced significant reductions in lung function
when followed by a brief exposure to 0.15 ppm ozone (Chen et al., 1991).
A chronic exposure of beagle dogs to an average concentration of 889 mg/m3 H2SO4 for 21
hours/day over a 620 day period resulted in increased expiratory resistance, reduced carbon
monoxide diffusing capacity, reduced total and residual lung volume, and decreased lung and
heart weights (Lewis et al., 1973).
In apparent contrast to the above studies, rats and guinea pigs exposed to H2SO4 at 10 mg/m3 for
6 hours/day, 5 days/week for 6 months exhibited no adverse histologic changes in lung tissue.
Lung function measurements were not reported in this study (Cavender et al., 1978).
Mice inhaled sulfuric acid mist at a concentration of 1.4 mg/m3 in combination with a carbon
particle mixture (1.5 mg/m3) for 3 hours/day, 5 days/week for up to 20 weeks. The exposure
resulted in significant alterations in specific antibody titer (decreased IgG, Ig2a, IgM; increased
IgG2b), depression of primary splenic antibody response, and decreased resistance to respiratory
infection as measured by mortality and survival time compared to controls (Fenters et al., 1979).
There are no reliable studies indicating that sulfuric acid is a developmental or reproductive
toxicant. In the absence of massive overexposure leading to maternal acidemia, H2SO4 will be
neutralized in the maternal circulation and is unlikely to reach the fetus.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 104
Sulfuric acid
VI. Derivation of Chronic Reference Exposure Level
Study Alarie et al., 1973
Study population Cynomolgus monkeys (5 males and 4 females per
group or vice versa)
Exposure method Continuous inhalation exposures (0, 380, 480,
2400, or 4800 mg/m3) for 78 weeks
Critical effects Significantly increased bronchial epithelial
hyperplasia and bronchial thickening
LOAEL 380 mg/m3
NOAEL Not observed
Exposure continuity The exposure was continuous during the
experiment.
Exposure duration 78 weeks
Average experimental exposure 380 mg/m3 for the LOAEL group
Human equivalent concentration 380 mg/m3
LOAEL uncertainty factor 3 (slight effects)
Subchronic uncertainty factor 3
Interspecies uncertainty factor 3 (non-human primate)
Intraspecies uncertainty factor 10
Cumulative uncertainty factor 300
Reference exposure level 1 mg/m3
The study by Alarie et al. (1973) identified a LOAEL for chronic exposure to sulfuric acid of
380 mg/m3. The principal uncertainties of this study are the small sample size of the test groups
and the absence of an observed NOAEL. A lower chronic LOAEL for bronchial reactivity is
presented by Gearhart and Schlesinger (1986, 1988) for rabbits (250 mg/m3). This study was not
selected as the basis of the REL because Gearhart and Schlesinger used only a single
concentration of sulfuric acid, exposed the animals only for 1 hour per day for 5 days/week, used
only 4 animals per group, and measured effects over the course of up to 12 months. The
predominant weakness in the rabbit study, however, was the extreme discontinuity of the
exposures (1 hour/day, 5 days/week), which would have necessitated use of a very large
continuity adjustment. For these reasons, in addition to obvious physiological and genetic
similarity arguments, the study in monkeys by Alarie et al. (1973) was felt to be more
appropriate as the basis for the chronic REL for sulfuric acid. Alarie et al. (1975) determined a
NOAEL for sulfuric acid in monkeys of 0.1 mg/m3. However, other particulate matter (fly ash)
was also present during the exposure. The Alarie et al. (1973) report provides data from
exposure to sulfuric acid alone.
A free-standing NOAEL for histological changes in 100 guinea pigs exposed continuously for 1
year to 0.08 mg/m3 was reported by Alarie et al. (1973). Guinea pigs respond to high
concentrations of sulfuric acid by occasional laryngeal spasms that appear similar to a human
asthmatic attack (Silbaugh et al., 1981; Amdur and Chen, 1989). As a result, guinea pigs are
thought to be sensitive models for the acute effects of sulfuric acid. For chronic effects of
sulfuric acid on the lung, monkeys are likely a suitable model due to their physiological and
structural similarites to humans.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 105
Sulfuric acid
For comparison, a chronic REL based on the guinea pig free-standing NOAEL of 0.08 mg/m3 in
animals exposed continuously for one year (Alarie et al., 1973) would be 0.8 mg/m3.
VII. Data Strengths and Limitations for Development of the REL
The major strength of the study on sulfuric acid is the use of health effects observations from
continuous long-term exposures to a primate. The major weaknesses are the lack of adequate
human health effects data and the lack of a NOAEL observation.
VIII. Potential for Differential Impacts on Children's Health
There are no reliable studies indicating that sulfuric acid is a developmental or reproductive
toxicant. Children are likely to be at greater risk from long-term exposures because their bodies
are growing, and their developmental processes, especially in the lung, may well be impacted by
air pollution exposures. Elevated sulfate levels (1.6 ppb or 6.6 mg/m3) have been associated with
statistically significant decrements in FVC and FEV1 in a cohort of Canadian children (Stern et
al., 1989). The chronic REL for sulfuric acid of 1 mg/m3 is below the level associated with those
decrements in pulmonary function. However, in a study of moderately to severe asthmatic
children (ages 7-13) (Thurston et al., 1997), a sensitive subpopulation for sulfate effects,
approximately 1 mg/m3 was the lowest level of ambient sulfate measured. The mean daily
morning to afternoon peak airflow change, the use of beta-agonist medication, and the number of
chest symptoms versus sulfate concentration in these children extrapolated linearly down to 1
mg/m3. Thurston et al. (1997) also examined earlier data from Ontario (Burnett et al., 1994) on
respiratory admissions to hospitals, and concluded that the sulfate threshold of effects, if it exists,
lies below 5 mg/m3, perhaps at about 2 mg/m3. It should be noted that the sulfate and hydrogen
ion effects are difficult to disentangle from each other and from the effcts of other PM
constituents. The chronic REL of 1 mg/m3 appears to have a relatively low margin of safety with
respect to the epidemiological studies, but these observations are consistent with the proposed
REL of 1 mg/m3 since asthmatic children appear to be the critically sensitive human population
for exposure to sulfuric acid (or sulfate).
IX. References
Alarie Y, Busey WM, Krumm AA, Ulrich CE, and Va V. 1973. Long-term continuous exposure
to sulfuric acid mist in cynomolgus monkeys and guinea pigs. Arch. Environ. Health 27:16-24.
Alarie YC, Krumm AA, Busey WM, Urich CE, and Kantz RJ. 1975. Long-term exposure to
sulfur dioxide, sulfuric acid mist, fly ash, and their mixtures. Results of studies in monkeys and
guinea pigs. Arch. Environ. Health 30(5):254-262.
Amdur MO, and Chen LC. 1989. Furnace-generated acid aerosols: Speciation and pulmonary
effects. Environ. Health Perspect. 79:147-150.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 106
Sulfuric acid
Amdur MO, Silverman L, and Drunker P. 1952. Inhalation of sulfuric acid mist by human
subjects. Arch. Ind. Hyg. Occup. Med. 6:305-313.
Bates DV, and Sitzo R. 1989. The Ontario air pollution study: Identification of the causative
agent. Environ. Health Perspect. 79:69-72.
Burnett RT, Dales RE, Raizenne ME, Krewski D, Summers PW, Roberts GR, Raad-Young M,
Dann T, and Brook J. 1994. Effects of low ambient levels of ozone and sulfates on the
frequency of respiratory admissions to Ontario hospitals. Environ Res 65:172-194.
CARB. 1997. California Air Resources Board. Toxic Air Contaminant Identification List
Summaries.
CARB. 2000. California Air Resources Board. California Emissions Inventory Development and
Reporting System (CEIDARS). Data from Data Base Year 1998. February 12, 2000.
CRC. 1994. CRC Handbook of Chemistry and Physics, 75th edition. Lide DR, ed. Boca Raton,
FL: CRC Press Inc.
Cavender FL, Singh B, and Cockrell BY. 1978. The effects in rats and guinea pigs from six
months exposures to sulfuric acid mist, ozone, and their combination. J. Environ. Pathol.
Toxicol. 2:485-492.
Chen LC, Miller PD, Lam HF, Guty J, and Amdur MO. 1991. Sulfuric acid-layered ultrafine
particles potentiate ozone-induced airway injury. J. Toxicol. Environ. Health 34:337-352.
Damokosh AI, Spengler JD, Dockery DW, Ware JH, and Speizer FE. 1993. Effects of acidic
particles on respiratory symptoms in 7 US communities. Am Rev Respir Dis 147:A632.
Delfino RJ, Murphy-Moulton AM, Burnett RT, Brook JR, and Becklake MR. 1997. Effects of air
pollution on emergency room visits for respiratory illnesses in Montreal, Quebec. Am J Respir
Crit Care Med 155:568-576.
Dockery DW, Cunningham J, Damokosh AI, Neas LM, Spengler JD, Koutrakis P, Ware JH, and
Speizer FE 1993. Health effects of acid aerosols on North American children: respiratory
symptoms. Environ Health Perspect 104:500-505.
El-Saddik YM, Osman HA, and El-Gazzar RM. 1972. Exposure to sulfuric acid in
manufacturing of storage batteries. J. Occup. Med. 14:224-226.
Fenters JD, Bradof JN, Aranyi C, Ketels K, Ehrlich R, and Gardner DE. 1979. Health effects of
long-term inhalation of sulfuric acid mist-carbon particle mixtures. Environ. Res. 19:244-257.
Fujisawa T, Iguchi K, and Uchida Y. 1986. Effects of exposure to sulfuric acid mist on the
induction of experimental asthma in guinea pigs. Japan J. Allergol. 35(2):137-144.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 107
Sulfuric acid
Gamble J, Jones W, Hancock J, and Meckstroth R. 1984. Epidemiologic environmental study of
lead acid battery workers. III. Chronic effects of sulfuric acid on the respiratory system and teeth.
Environ. Res. 35:30-52.
Gearhart JM, and Schlesinger RB. 1986. Sulfuric acid-induced airway hyperresponsiveness.
Fundam. Appl. Toxicol. 7:681-689.
Gearhart JM, and Schlesinger RB. 1988. Response of the tracheobronchial mucociliary clearance
system to repeated irritant exposure: effect of sulfuric acid mist on function and structure. Exp.
Lung Res. 14:587-605.
Gwynn RC, Burnett RT, and Thurston GD. 2000. A time-series analysis of acidic particulate
matter and daily mortality and morbidity in the Buffalo, New York region. Environ Health
Perspect. 108:125-133.
HSDB. 1995. Hazardous Substances Data Bank. National Library of Medicine, Bethesda, MD
(TOMESÒ CD-ROM Version). Denver, CO: Micromedex, Inc. (Edition expires 7/31/96).
IARC. 1992. International Agency for Research on Cancer. IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans. Vol. 54. Occupational Exposure to Mists and
Vapours from Strong Inorganic Acids and other Industrial Chemicals. Lyon, France: IARC, pp.
41-130
Iguchi K, Fujisawa T, and Uchida Y. 1986. Effects of exposure to sulfuric acid mist on the
induction of experimental asthma in guinea pigs. Japan J. Allergol. 35(6):402-408.
Kitabatake M, Imai M, Kasama K, Kobayashi I, Tomita Y, and Yoshida K. 1979. Effects of air
pollutants on the experimental induction of asthma attacks in guinea pigs: Sulfuric acid mist and
mixture of the mist and sulfur dioxide. Mie Med. J. 29(1):29-37.
Lewis TR, Moorman WJ, Ludmann WF, and Campbell KI. 1973. Toxicity of long-term exposure
to oxides of sulfur. Arch. Environ. Health 26:16-21.
Lippman M, Gearhart JM, Schlesinger RB. 1987. Basis for a particle size-selective TLV for
sulfuric acid aerosols. Appl Ind Hyg 2:188-199.
Lippmann M, Thurston GD. 1996. Sulfate concentrations as an indicator of ambient particulate
matter air pollution for health risk evaluations. J. Expo. Anal. Environ. Epidemiol. 6(2):123-146.
OEHHA. 2000. Office of Environmental Health Hazard Assessment. Staff report. Adequacy of
California Ambient Air Quality Standards: Senate Bill No. 25 - Children's Environmental Health
Protection.
Ostro B, Lipsett M, Wiener M, and Selner JC. 1989. A panel study of the effect of acid aerosols
on asthmatics. J. Air Waste Management Assoc. 89-94.1:1-15.
Determination of Noncancer Chronic Reference Exposure Levels Batch 2B December 2001
A - 108
Sulfuric acid
Raizenne M, Neas LM, Damokosh AI, Dockery DW, Spengler JD, Koutrakis P, Ware JH, and
Speizer FE. 1996. Health effects of acid aerosols on North American children: pulmonary
function. Environ Health Perspect 104: 506-514.
Schlesinger RB, Chen LC, Finkelstein I, and Zelikoff JT. 1990. Comparative potency of inhaled
acidic sulfates: speciation and the role of hydrogenion. Environ Res 52:210-224.
Silbaugh SA, Mauderly JL, Macken CA. 1981. Effects of sulfuric acid and nitrogen dioxide on
airway responsiveness of the guinea pig. J. Toxicol. Environ. Health 8(1-2):31-45.
Stern B, Jones L, Raizenne M, Burnett R, Meranger JC, Franklin CA. 1989. Respiratory health
effects associated with ambient sulfates and ozone in two rural Canadian communities. Environ.
Res. 49(1):20-39.
Thurston GD, Lippmann M, Scott MB, Fine JM. 1997. Summertime haze air pollution and
children with asthma. Am. J. Respir. Crit. Care Med. 155(2):654-660.
U.S. EPA. 1989. U.S.Environmental Protection Agency. An Acid Aerosols Issue Paper: Health
Effects and Aerometrics. EPA/600/8-88/00SF. OHEA/ORD. Research Triangle Park, NC: U.S.
EPA.
Utell MJ, Morrow PE, Speers DM, Darling J, Hyde RW. 1983. Airway responses to sulfate and
sulfuric acid aerosols in asthmatics: an exposure-response relationship. Am Rev Resp Dis
128:444-450.