Public Notice

AMMONIA A-1
APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS
The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C.
9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99–
499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with
the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most
commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological
profiles for each substance included on the priority list of hazardous substances; and assure the initiation
of a research program to fill identified data needs associated with the substances.
The toxicological profiles include an examination, summary, and interpretation of available toxicological
information and epidemiologic evaluations of a hazardous substance. During the development of
toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to
identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a
given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance
that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration
of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of
cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are
used by ATSDR health assessors to identify contaminants and potential health effects that may be of
concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or
action levels.
MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor
approach. They are below levels that might cause adverse health effects in the people most sensitive to
such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and
chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,
MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method
suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end
point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the
liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level
above the MRL does not mean that adverse health effects will occur.
Appendix – 001
AMMONIA A-2
APPENDIX A
MRLs are intended only to serve as a screening tool to help public health professionals decide where to
look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that
are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of
the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,
elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR
uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health
principle of prevention. Although human data are preferred, MRLs often must be based on animal studies
because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes
that humans are more sensitive to the effects of hazardous substance than animals and that certain persons
may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that
have been shown to be nontoxic in laboratory animals.
Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the
Division of Toxicology, expert panel peer reviews, and agency-wide MRL Workgroup reviews, with
participation from other federal agencies and comments from the public. They are subject to change as
new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in
the most recent toxicological profiles supersede previously published levels. For additional information
regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease
Registry, 1600 Clifton Road NE, Mailstop F-32, Atlanta, Georgia 30333.
Appendix – 002
AMMONIA A-3
APPENDIX A
MINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name: Ammonia
CAS Number: 7664-41-7
Date: July 2004
Profile Status: Third Draft Post-Public
Route: [ X ] Inhalation [ ] Oral
Duration: [ X ] Acute [ ] Intermediate [ ] Chronic
Graph Key: 14
Species: Human
Minimal Risk Level: 1.7 [ ] mg/kg/day [ X ] ppm
Reference: Verberk MM. 1977. Effects of ammonia in volunteers. Int Arch Occup Environ Health
39:73-81.
Experimental design: The study examined the effects of exposure to ammonia in a group of
16 volunteers. Eight of them (experts) knew the effects of ammonia from the literature, but had had no
personal contact, whereas the remaining eight subjects (non-experts) were students from a non-science
faculty and were not familiar with ammonia or experiments in laboratory situations. All members of a
group were exposed on the same day to one of the concentrations tested (50, 80, 110, or 140 ppm). The
testing was repeated with a 1-week interval. Immediately before and after exposure, vital capacity, forced
expiratory volume, and forced inspiratory volume were measured. During exposure, each subject
recorded subjective feelings every 15 minutes as no sensation (0), just perceptible (1), distinctly
perceptible (2), nuisance (3), offensive (4), or unbearable (5). No statistical analysis was performed and
there was no group exposed to air only. A few weeks after the experiments, the subjects were tested to
measure (pre-existing) non-specific reactivity of the airways to exogenous stimuli.
Effects noted in study and corresponding doses: None of the participants was hypersusceptible to nonspecific irritants. Results of the pulmonary function tests after exposure were not statistically
significantly different from pre-exposure values. For the non-experts, there was a clear increase in the
number of reported symptoms for smell, eye irritation, throat irritation, cough, and general discomfort as
the exposure concentration increased. The latter was not as clear for the experts. The number of
symptoms recorded with a score>3 (nuisance) for smell, eye irritation, nose, throat, and urge to cough for
the 50, 80, 110, and 140 ppm exposure groups was 2, 2, 7, and 11 , respectively, for the experts and 6, 12,
18, and 29, respectively, for the non-experts. It should also be mentioned that the subjective responses
appeared more pronounced in the non-expert group than in the expert group.
Dose and end point used for MRL derivation: 50 ppm for mild irritation to the eyes, nose, and throat in
humans exposed to ammonia gas for 2 hours.
Because the effects observed were local irritation effects, they were not time-dependent (but rather
concentration-dependent), an adjustment to 24-hour exposure was not necessary.
[ ] NOAEL [ X ] LOAEL
Appendix – 003
AMMONIA A-4
APPENDIX A
Uncertainty Factors used in MRL derivation:
[ X ] 3 for use of a minimal LOAEL
[ ] 10 for extrapolation from animals to humans
[ X ] 10 for human variability
Was a conversion used from ppm in food or water to a mg/body weight dose?
N/A
If an inhalation study in animals, list the conversion factors used in determining human equivalent dose:
N/A
Other additional studies or pertinent information which lend support to this MRL: Although the Verberk
et al. (1977) study has limitations (no statistical analysis, subjective end points, no control group), it
demonstrates that concentrations of 50 ppm ammonia can produce minimal discomfort in healthy
members of the general population and therefore, should be avoided. Additional relevant information is
provided by a study by Ferguson et al. (1977). In that study, a group of six healthy volunteers, not
previously accustomed to working in an ammonia environment, were exposed 5 days/week to 25 ppm
(2 hours/day), 50 ppm (4 hours/day), or 100 ppm (6 hours/day) of ammonia, or to 50 ppm of ammonia
6 hours/day for 6 weeks. End points monitored included subjective and objective measures of eye and
throat irritation as well as pulse rate, respiration rate, pulmonary function (FVC, FEV), assessment of
neurological function (reflex, balance, and coordination), and body weight. The exposure protocol
consisted of a pre-exposure evaluation by a physician, 3 hours of exposure (this conflicts with exposure
data on table 2 of the study and mentioned above), a mid-point physician’s observation, lunch break,
3 additional hours of exposure, and a third physician’s observation 30 minutes after exposure ceased. The
conjunctiva and mucosa of the nose and throat were examined by a physician before and after each daily
exposure and the degree of irritation noted was described as mild, moderate, or marked. Exposure to
ammonia had no significant effect on the measures of respiratory function or in the neurological tests
conducted. The results of the evaluations of irritation conducted by the physician showed no significant
differences between the exposure groups, including the 0 ppm exposure group (pre-exposure). All
subjects experienced some watering of the eyes and a sensation of dryness in the nose and throat and there
was one observation of definite redness in the mucosa of the nose after a 6-hour exposure to 100 ppm
during which time, there was an excursion to 200 ppm ammonia. No redness was observed in this subject
the following morning. Throughout the study, the physician observed 6 cases of eye irritation, 20 of nose
irritation, and 9 of throat irritation, and most cases appeared to have occurred the first week of the study
during exposure to 50 ppm. It is difficult to determine in this study a NOAEL or LOAEL for irritation
due to the different exposure durations experienced by the subjects, but it would appear that an exposure
concentration of 100 ppm ammonia for 6 hours caused no significant changes in the vital functions
measured and that 50 ppm can cause eye, nose, and throat irritation.
NIOSH (1974) reviewed 15 studies of case reports in which subjects were exposed to very high, but
unquantified, concentrations of ammonia. The 15 reports provided a representative array of documented
clinical findings including death, permanent eye lesions, and chronic respiratory symptoms, as well as
acute lower and upper respiratory symptoms. The only quantitative information available was that a
worker died 6 hours after estimated exposure to 10,000 ppm ammonia for an unspecified time (Mulder
and Van der Zalm 1967). Studies with volunteers, also reviewed by NIOSH (1974), generally used
concentrations of ammonia much higher than those in the studies by Verberk et al. (1977) or Ferguson et
al. (1977) and/or exposure durations of only minutes. For example, exposure to a concentration of
500 ppm for 30 minutes caused respiratory irritation graded as severe by 2 out 7 subjects (Silverman et al.
1949). Four out of 6 volunteers exposed to 50 ppm ammonia for 10 minutes graded the irritation as
"moderate" and none described it as "discomforting" or "painful" (MacEwen et al. 1970). All of the
Appendix – 004
AMMONIA A-5
APPENDIX A
subjects rated the odor as "highly penetrating" at 50 ppm and 3 subjects gave the same rating to 30 ppm.
IBT (1973) exposed 10 subjects to 32, 50, 72, and 134 ppm for 5 minutes and the frequency of positive
findings was as follows: at 32 ppm, 1 subject complained of dryness of the nose; at 50 ppm, 2 subjects
complained of dryness of the nose; at 72 ppm, 3 subjects experienced eye irritation, 2 had nasal irritation,
and 3 had throat irritation; and at 134 ppm, 5 subjects had signs of lacrimation, 5 had eye irritation, 7 had
nasal irritation, 8 had throat irritation, and 1 had chest irritation.
Collectively, the available information from studies in humans supports the 50 ppm exposure level from
the Verberk et al. (1977) study as a minimal LOAEL for irritation in acute studies. In general, studies in
animals have used higher exposure concentrations. For ammonia, a corrosive irritant gas that affects the
portal of entry and produces irritation of the eyes and respiratory tract, use of human data should be
preferred over animal studies.
Agency Contact (Chemical Manager): Nickolette Roney, MPH
Appendix – 005
HYDROGEN SULFIDE AND CARBONYL SULFIDE A-1
APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS
The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C.
9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99–
499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with
the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most
commonly found at facilities on the CERCLA National Priorities List (NPL), prepare toxicological
profiles for each substance included on the priority list of hazardous substances, and assure the initiation
of a research program to fill identified data needs associated with the substances.
The toxicological profiles include an examination, summary, and interpretation of available toxicological
information and epidemiologic evaluations of a hazardous substance. During the development of
toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to
identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a
given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance
that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration
of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of
cancer effects. These substance-specific estimates (which are intended to serve as screening levels) are
used by ATSDR health assessors to identify contaminants and potential health effects that may be of
concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or
action levels.
MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor
approach. They are below levels that might cause adverse health effects in the people most sensitive to
such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and
chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,
MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method
suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end
point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the
liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level
above the MRL does not mean that adverse health effects will occur.
MRLs are intended only to serve as a screening tool to help public health professionals decide where to
look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that
Appendix – 006
HYDROGEN SULFIDE AND CARBONYL SULFIDE A-2
APPENDIX A
are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of
the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,
elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR
uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health
principle of prevention. Although human data are preferred, MRLs often must be based on animal studies
because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes
that humans are more sensitive to the effects of hazardous substance than animals and that certain persons
may be particularly sensitive. Thus, the resulting MRL may be greater than 100-fold below levels that
have been shown to be nontoxic in laboratory animals.
Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the
Division of Toxicology and Human Health Sciences, expert panel peer reviews, and agency-wide MRL
Workgroup reviews, with participation from other federal agencies and comments from the public. They
are subject to change as new information becomes available concomitant with updating the toxicological
profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels.
For additional information regarding MRLs, please contact the Division of Toxicology and Human
Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, Mailstop
F-57, Atlanta, Georgia 30329-4027.
Appendix – 007
HYDROGEN SULFIDE AND CARBONYL SULFIDE A-3
APPENDIX A
MINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name: Hydrogen Sulfide
CAS Number: 7783-06-4
Date: November 2016
Profile Status: Final
Route: Inhalation [ ] Oral
Duration: Acute [ ] Intermediate [ ] Chronic
Graph Key: 17
Species: Human
Minimal Risk Level: 0.07 [ ] mg/kg/day ppm
Reference: Jäppinen P, Vikka V, Marttila O, et al. 1990. Exposure to hydrogen sulphide and respiratory
function. Br J Intern Med 47:824-828.
Experimental design: This study evaluated lung function in three male and seven female subjects with
bronchial asthma requiring medication for 1–13 years; none of the subjects had severe asthma. The
subjects were exposed to 2 ppm hydrogen sulfide for 30 minutes. Respiratory function in response to a
histamine challenge was assessed prior to exposure and after exposure.
Effect noted in study and corresponding doses: No statistically significant changes in forced vital
capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow were noted.
Airway resistance (Raw) and specific airway conductance (SGaw) did not show statistically significant
changes when examined as a group. In two subjects, there were changes of over 30% in both Raw and
SGaw; these changes were suggestive of bronchial obstruction. Additionally, 3 of 10 subjects
complained of headaches after exposure.
Dose and end point used for MRL derivation:
[ ] NOAEL LOAEL
Uncertainty Factors used in MRL derivation:
3 for use of a minimal LOAEL
[ ] 10 for extrapolation from animals to humans
3 for human variability
3 for database deficiencies
The 2 ppm concentration was considered a minimally adverse effect level because the changes in airway
resistance and specific airway conductance were only observed in 2 of 10 subjects. Because the study
was conducted using asthmatics (who are likely to be a sensitive subpopulation) a partial uncertainty
factor of 3 was used to account for human variability. An additional uncertainty factor of 3 was used for
database deficiencies due to concern for the short (30-minute) exposure duration in the principal study.
Was a conversion factor used from ppm in food or water to a mg/body weight dose? No.
If an inhalation study in animals, list conversion factors used in determining human equivalent dose: No.
Was a conversion used from intermittent to continuous exposure? Not applicable.
Appendix – 008
HYDROGEN SULFIDE AND CARBONYL SULFIDE A-4
APPENDIX A
Other additional studies or pertinent information that lend support to this MRL: Bhambhani et al. (1996b)
evaluated the acute effects of hydrogen sulfide on the physiological and hematological health of male and
female volunteers exposed to 5 ppm during two 30-minute sessions of submaximal exercise (50% of
maximum aerobic power). No significant changes in any parameter were noted in the women, whereas
the men showed a significant decrease in muscle citrate synthetase as well as nonsignificant changes in
lactate, lactate dehydrogenase, and cytochrome oxidase. Together, these changes were considered
indicative of compromise of aerobic metabolism.
No respiratory or cardiovascular effects were observed in 16 male volunteers exposed by oral inhalation
to hydrogen sulfide at 0.5, 2, or 5 ppm for>16 minutes while exercising (Bhambhani and Singh 1991).
The end points examined included heart rate, oxygen uptake, carbon dioxide output, and blood gases.
Airway resistance and conductance were not measured in this study. No significant changes in
pulmonary function parameters were noted in individuals exposed to 10 ppm hydrogen sulfide for
15 minutes during exercise (Bhambhani et al. 1996a).
Respiratory distress was noted in two workers exposed to>40 ppm hydrogen sulfide for under 25 minutes
(Spolyar 1951). In animals, impacts on the respiratory system such as increases in the cellularity and
lactate dehydrogenase and alkaline phosphatase activity in bronchial lavage fluids have been seen at
exposures as low as 10 ppm for 4 hours (Lopez et al. 1987), although without a dose-related trend.
Moderate to massive pulmonary edema was observed in rats exposed to 375 or 399 ppm for 4 hours
(Prior et al. 1990). A significant dose-related decrease in lung microsomal cytochrome c oxidase activity
was seen in rats following a 4 hour exposure to 50, 200, or 400 ppm hydrogen sulfide (Khan et al. 1990).
Similarly, succinate oxidase activity also decreased in a dose-related fashion; although no affect was
observed at the lowest dose. Cytochrome oxidase levels returned to normal by 24 hours postexposure in
animals in the 200 ppm group, but not the 400 ppm group. Exposure at the two higher dose levels was
also associated with complete abolition of the zymosan-induced stimulation of respiratory rates of
pulmonary alveolar macrophages and there were significant decreases in the number of viable
macrophages in lung lavage fluids at the highest dose (Khan et al. 1991).
Agency Contact (Chemical Manager): Selene Chou
Appendix – 009
Appendix – 010
Appendix – 011
Appendix – 012
Appendix – 013