FIRST DRAFF
Un.-ed Stales ECAO-CI.N-G116
Environment Proteclion JulV
Agency ''
s>EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR PROPIONIC ACID
Prepared for
OFFICE OF SOLTD HASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: 00 NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy and policy Implications.
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DISCLAIMER
This report is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PRE F ACE
Health and Environmental Effects Documents (HEEDS) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
is intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for
emergency and remedial actions under the Comprehensive Environmental
Response. Compensation and Liability Act (CERCLA). Both published
literature and information obtained for Agency Program Office files are
evaluated as they pertain to potential human health, aquatic life and
environmental effects of hazardous waste constituents. The literature
searched for in this document and the dates searched are included in
Appendix: Literature Searched.” Literature search material is current up
to 8 months previous to the final draft date listed on the front cover.
Final draft document dates (front cover) reflect the date the document is
sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. for systemic toxicants, trese include: Reference doses
(RfOs) for chronic and subchronic exposures for both the inhalation and oral
exposures. The subchronic or partial lifetime RfD, is an estimate of an
exposure level which would not be expected to cause adverse effects when
exposure occurs during a limited time interval i.e., for an interval which
does not constitute a significant portion of the lifespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronic estimates generally reflect
exposure durations of 30—90 days. The general methodology for estimating
subchronic RfDs is the same as traditionally employed for chronic estimates,
except that subchronic data are utilized when available.
In the case of suspected carcinogens, a carcinogenic potency factor, or
q 1 * (U.S. EPA, 1960), is provided. These potency estimates are derived
for both oral and inhalation exposures where possible. In addition, unit
risk estimates for air and drinking water are presented based on inhalation
and oral data, respectively. An RfD may also be derived for the noncarcino-
genic health effects of compounds that are also carcinogenic.
Reportable quantities (RQ5) based on both chronic toxicity and
carcinogenicity are derived. The RQ is used to determine the quantity of a
hazardous substance for which notification is required in the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQ5 (chronic toxicity
and carcinogenicity) represent two of six scores developed (the remaining
four reflect ignitability, reactivity, aquatic toxicity, and acute maniTialian
toxicity). Chemical—specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxicity and cancer based RQs are
defined in U.S. EPA . 1984 and 198bb, respectively.
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EXECUTIVE SUMMARY
Propionic acid is an oily liquid with a pungent, disagreeable, rancid
odor (Windholz et al., 1983). It is miscible with water (Windholz et al.,
1983). Production data for propionic acid were not available; however, the
total capacity of U.S. industry to manufacture propionic acid was <225
million pounds in 1988 (SRI, 1989). Demand is expected to increase to 145
million pounds by 1992. This is equivalent to an annual growth of 2-3%
(CMR, 1988). Proplonic acid is used primarily as a grain and feed preserva-
tlve and in the formation of cellulose plastics. The current use pattern
for propionic acid has been reported as follows (CMR, 1988): grain and feed
preservativec %), cellulose plastics (20%), calcium and sodium propion—
ates (18%), nerbicide manufacture (18%), exports (15%) and miscellaneous
uses, including butyl and pentyl propionates (4%). Butyl and pentyl
propionates may have a growing market in the paint and coating industries in
the future (CMR, 1988).
The environmental fate of propionic acid can be predicted with some
accuracy since some of the major fate processes have been experimentally
examined. When propionic acid is released to the atmosphere, it will
degrade by reactions with photochemically produced hydroxyl radicals. The
average half—life for propionic acid degradation in the atmosphere is —13
days; however, physical removal from air by wet deposition may also be
important. The dominant degradation process for propionic acid in soil and
water is biodegradation. Many biological screening studies have examined
the biodegradability of propionic acid and have found that it is readily
biodegradable (Dawson and Jenkins, 1950; Dias and Alexander, 1971; Gaffney
and Heukelekian, l958a,b, 1961; Heukelekian and Rand, 1955; Malaney and
iv
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Gerhold, 1969; McKinney et al., 1956; Takemoto et al, 1981; Urano and Kato,
1986; Yonezawa et al. 1 1982). VolatilizatIon of propionic acid from the
aquatic environment (where it would mostly exist in the ionic form) should
not be a significant transport process. Proplonic acid is a relatively
volatile compound and may evaporate from dry surfaces. It should not adsorb
to most soils. In the presence of other chemicals that are toxic to
microbes (such as leactiates from landfills and waste sites), leaching has
occurred.
Monitoring data regarding the presence and release of propionic acid in
air and water were scarce in the available literature cited tn P ppendIx A.
Propionic acid may be released to the aquatic environment in wastewater
discharges from industry and sewage treatment facilities; it can also be
released to groundwater supplies by leachates from municipal and industrial
landfills and industrial sites (Albalges et. al., 1986; Burrows and Rowe,
1975; Lema et al., 1988). Propionic acid has been identified as a component
of exhaust from gasoline and diesel-fueled engines (Kawamura et dl., 1985);
therefore, the lack of monitoring data does not necessarily Indicate that
propionic acid Is not present in ambient air, especially if proplonic acid
is emitted to the air during the combustion of hydrocarbon fuels and has a
moderate persistence In air.
The National Occupational Exposure Survey has statistically estimated
that 23,161 U.S. workers are potentiafly exposed to propionic acid
occupationally (NIOSH, 1989). No other data on occupational exposure to
proplonic acid were available in the literature cited in Appendix A.
Insufficient data are available to estimate average daily intakes from
the air and food and drinking water.
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Very little data are available on the environmental effects of propionic
acid. Acute toxicity studies with the bluegill, Lepomis macrochirus,
Oaphnia magna and the mosquito larva, Culex sp., resulted in median toler-
ance limits of 188 mg/2. (24-hour), 50 mg/ I (48-hour) and >1000 mg/I
(24- and 48-hour) (Dowden and Bennett, 1965). Median tolerance limits of 96
mg/I (24—hour) and 73 mg/t (48-hour) were reported for the carp.
Cyprinus carpio .
Mold growth and aflatoxin production were halted when Aspergillus flavus
was exposed to the test article for 9 days at 0.2% v/v; growth retardation
and other effects were observed at >0.05% v/v (Ghosh and Haggblom, 1965).
The chitin ntent of the system (an indicator of mold growth) was reduced
when propionic acid was added at 0.05% v/w along with Aspergillus flavus for
up to 20 days (Ghosh and Haggblom, 1985). There was slight growth of the
Penicilliurn sp. mold in control corn with 10% added moisture and in corn
treated with 0.025% propionic acid; however, no mold appeared at treatment
levels of 0.05 and 0.1% propionic acid. Corn with 15% added moisture had
mold growth at all levels except for the highest treatment level (Smith et
al., 1983). The corn and mold were incubated for 8 weeks.
The effects of propionic acid on oxygen uptake in the fungus Microsporum
canis were reported in an abstract (Melton, 1951). The test substance at
0.027 M inhibited oxygen uptake by 32% when incubated with the fungus for
5—1 days.
An abstract of a Japanese paper revealed that propionic acid decreased
the respiratory rate of rice roots in a culture solution (Yamada and Ota,
1958). Further information was not reported.
The rate of absorption of a mixture of seven short—chain fatty acids in
human jejunum fell in the range of 0.2-1 1 M/minute/30 cm jejunum (Oawson
et al., 1964). Propionic acid was absorbed at a slower rate than
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longer-chain fatty acids (Dawson et al . , 1964). No other studies reqarding
the absorption of proplonic acid in humans were located. Data from LU 50
studies in rats and rabbits indicate that proplonic acid Is absorbed by the
oral and dermal route, respectively, (Smyth et al., 1962), but quantitative
data were not available. Small amounts of propionic acid, found normally in
food, are metabolized by a series of enzymatic reactions to acetyl-CoA,
which enters the citric acid cycle (Metzler, 1977). Data regarding
distribution and excretion of propionic acid were not located.
Rats fed diets that provided 0.2 or 2 g propionic acid/kg/day for 20—101
weeks developed proliferative alterations (such as hyperplasia) in the
stomach mucosa (Griem, 1985). Similar alterations occurred In rats fed
diets providing 2.5 g/kg/day for 110 days (Mori, 1953) and in weanling rats
fed diets providing 4 g/kg/day for up to 21 days (Rodrigues et a]., 1986).
Although these findings might indicate that the stomach is a target for
propionic acid, the dietary levels of proplonic acid used in these studies
are several orders of magnitude higher than those used for proplonic acid as
a food preservative (see Chapter 3). Data were not available regarding the
subchrofliC or chronic toxicity of propionic acid from inhalation exposure.
Oral and dermal LD 50 s of 4262 and 497 mg/kg have been determined for
proplonic acid in rats and rabbits, respectively (Smyth et al.. 1962).
ID 50 data for other species were not available. There was no mortality in
rats exposed to unspecified concentrated vapors of propionic acid for up to
8 hours (Smyth et al., 1962).
Preliminary data suggested that precancerous lesions occurred in the
stomach mucosa of rats fed dietary doses of 2 g/kg/day of propionic acid for
>20 weeks (Griem, 1985). PropionIc acid induced a slight increase in the
lung-colonizing ability of Lewis lung carcinoma P—29 cells when Injected
into mice (Takenaga, 1986).
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Evidence from two studies (Bas ler et al . 1 1961; Litton Bionetics, 19761
indicates that proplonic acid is not strongly genotoxic. Propionic acid
induced DNA damage in • coil , but did not induce gene mutations in
bacteria, gene conversion in yeast , sister chromatid exchanges in hamster
cells in vitro or micronuclet in hamsters in vivo . Studies regarding
developmental toxicity or reproductive effects of propionic acid were not
available.
RfDs of 0.2 and 0.02 mg/kg/day were derived for subctironic and chronic
oral exposure to propionic acid, respectively 1 based on the LOAEL for fore-
stomach hyperplasia in rats in the 20-week dietary study by Griem (1985).
The RfD values are well below the estimated daily average consumption of
propionic acid by the general population. An RQ of 1000 was calculated
based on the same effect level used to derive the RfDs. Because of the
inadequate evidence of carcinogenicity in animals, propionic acid is
classified in U.S. EPA weight-of-evidence Group D (not classifiable as to
human carcinogenicity). Assignment to Group 0 precludes calculation of a
carcinogenic potency factor or cancer—based RQ for propionic acid.
viii
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TABLE OF CONTENTS
1. INTRODUC1ION
1.1.
1.2.
1.3.
1.4.
1.5.
Page
I
1
2
2
2
2. ENVIRONMENTAL FATE AND TRANSPORT.
2.1. AIR
S
S
2.1.1. Degradation
2.1.2. Physical Removal.
5
S
2.2. WATER.
6
2.2.1.
2.2.2.
2.2.3.
2.2.4.
2.2.5.
2.3. SOIL
2.3.1.
2.3.2.
2.3.3.
Hydrolysis
Oxidation
Microbial Degradation
Volatilization.
Adsorpt ‘ion
Degradation
Adsorption/Leaching
Evaporation
6
6
6
7
7
7
8
8
2.4. SUMMARY.
3.1.1. Environmental Monitoring Data
3.1.2. Human Sources of Emission
9
3.2. FOOD .
3.3. INHALATION
3.3.1. Environmental Monitoring Data
3.3.2. Human Sources of Emission
3.4. DERMAL
3.5. SUMMARY
11
11
11
11
12
12
STRUCIURE AND CAS NUMBER
PHYSICAL AND CHEMICAL PROPERTIES
PRODUCTION DATA
USE DATA
SUMMARY
3. EXPOSURE 10
3.1. WATER 10
10
10
ix
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TABLE OF CONTENTS (cont.)
4.1.1. Acute Toxic Effects on Fauna.
4.1.2. Chronic Effects on Fauna.
Effects on Flora
Effects on Bacteria
Page
13
13
13
13
13
14
14
4.2.1. Effects on Fauna.
4.2.2. Effects on Flora.
14
15
6. EFFECTS
6.1. SYSTEMIC TOXICITY
21
6.1.1.
6.1 .2.
6.1 .3.
Inhalation Exposure .
Oral Exposure
Other Relevant Information.
21
21
23
6.2. CARCINOGENICITY.
24
7. EXISTING GUIDELINES AND STANDARDS 28
7.1. HUMAN
7.2. AQUATIC
4. ENVIRONMENTAL TOXICOLOGY.
4.1. AQUATIC TOXICOLOGY
4.1 .3.
4.1.4.
4.2. TERRESTRIAL TOXICOLOGY
4.3. FIELD STUDIES
4.4. AQUATIC RISK ASSESSMENT.
4.5. SUMMARY
5. PHARMACOKINEICS
5.1. ABSORPTION
5.2. DISTRIBUTION
5.3. METABOLISM
5.4. EXCRETION
5.5. SUMMARY
15
15
16
18
18
18
18
20
20
6.2.1. Inhalation
6.2.2. Oral
24
6.2.3. Other Relevant
Information
25
6.3.
GENOTOXICITY
25
6.4.
DEVELOPMENTAL TOXICITY
25
6.5.
OTHER REPRODUCTIVE EFFECTS
25
28
28
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TABLE OF CONTENTS (cont.)
8. RISK ASSESSMENT
8.1.1.
8.1 .2.
8.1.3.
8.1.4.
8.1 .5.
Inhalation
Oral
Other Routes
Weight of Evidence
Quantitative Risk Estimates
Page
29
8.2. SYS1EMIC TOXICITY 30
8.2.1. Inhalation Exposure
8.2.2. Oral Exposure
9. REPORTABLE QUANTITIES 33
9.1. BASED ON SYSTEMIC TOXICITY
9.2. 8AS D ON CARCINOGENICIIY
10. REFERENCES 38
APPENDIX A: LITERATURE SEARCHED
APPENDIX B: SUMMARY TABLE FOR PROPIONIC ACID
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
PROPIONIC ACID
49
52
53
8.1. CARCINOGENICI1Y
29
29
29
29
29
30
30
30
33
33
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LIST OF TABL.(S
_____ Title PaQe
1 -1 Current Domestic Manufacturers of Propionic Acid 3
6-1 Genotoxicity Testing of Propionic Acid 26
9 -1 Oral Toxicity Summary for Propionic Acid Using the
Wistar Rat 34
9-2 Oral Composite Scores For Propionic Acid Using the Rat. . . . 35
9-3 Propionic Acid: Minimum Effective Dose (NED) and
Reportable Quantity (RQ) 36
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LIST OF ABBREVIATIONS
AEL Adverse-effect level
ATP Adenosine triphosphate
bw Body weight
CAS Chemical Abstract Service
CoA Coenzyme A
CS Composite score
DNA Deoxyribonucleic acki
FEL Frank effect level
GRAS Generally recognized as safe
HID Highest Ineffective dose
K Octanol/water partition coefficient
ow
LD 50 Dose lethal to 50% of recipients
LOU Log dose units
L O Lowest effective dose
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEI.. No-observed-adverse-effect level
PEL Permissible exposure level
PKa Negative log 10 of dissociation constant
ppm Parts per million
ROW Reference dilution water
RfD Reference dose
RQ Reportable quantity
RVd Dose-rating value
RV Effect—rating value
e
SCE Sister chromatid exchange
SRW Standard reference water
TIV Threshold limit value
TWA Time—weighted average
v/v Volume per volume
v/w Volume per weight
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Proplonic acid is the common name for the chemical known as propanoic
acid by the 9th Collective Indices of the CAS. Other synonyms of propionic
acid include carboxyethane, ethanecarboxylic acid, ethylformic acid.
Luprosil, metacetonic acid and pseudoacetic acid (Chemline, 1989). The
structure 1 molecular weight, empirical formula and CAS number for propionic
acid are listed below;
a
,\
HO CH 2 CH 3
Molecular weight.: 74.08
Empirical formula: C 3 H 6 0 2
CAS Registry number: 79-09-4
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Propionic acid is an oily liquid with a pungent, disagreeable 1 rancid
odor (Wlndholz et al., 1983). It Is miscible with water (Windholz et al. ,
1983) and is soluble with organic solvents such as alcohol 1 chloroform and
ether (Sax and Lewis, 1987). Selected physical properties for proplonic acid
are listed below:
Melting point: -20.8°C Sax and Lewis, 1987
Boiling point: 140.7°C Sax and Lewis, 1987
Density (g/cm 3 ): 0.9942 (20°C) Sax and Lewis, 1981
Vapor pressure: 3.53 mm Hg Daubert and Danner, 1985
at 25°C
Water solubiuity miscible Windholz et al., 1983
at 25°C:
Log K 0 : 0.33 Hansch and Leo, 1985
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Henry’s Law constant: 4.45xl0 7 Nirmalakhandan and
atm-m 3 /mol at 25°C Speece, 1988
PKa 4.87 Riddick et al., 1986
Flash point: 54.4°C (open cup) Sax and Lewis, 1987
Air odor threshold: 0.16 ppm (v/v) Amoore and Hautala, 1983
Water odor threshold: 28 ppm (w/v) Amoore and Hautala, 1983
Conversion factor: 1 mg/rn 3 = 0.325 ppm
(air at 20°C) 1 ppm = 3.80 mg/ni 3
1.3. PRODUCTION DATA
Production data for propionic acid were not available; however, the
total capacity of U.S. industry to manufacture propionic acid was <225
million pounds In 1988 (SRI, 1989). Demand was 130 million pounds In 1988
and ‘is expected to increase to 145 million pounds by 1992. This ‘is equiva-
lent to an annual growth of 2-3% (CMR, 1968). Table 1-1 lists the current
U.S. manufacturers of propionic acid with their respective locations and
annual capacities.
1.4. USE DATA
Proplonic acid is used primarily as a grain and feed preservative (25%)
and as an intermediate in the formation of cellulose plastics (20%).
Calcium and sodium propionates and herbicide production each consume —18% of
the total propionic acid produced. Miscellaneous uses, including the
manufacture of butyl’ and pentyl propionate, account for 4% of the propionic
acid production; —15% is exported. Buty1 and pentyl propionates may have an
increasing role in the paint and coating markets in the future (CMR, 1988).
1.5. SUMMARY
Propionic acid is an oily liquid with a pungent, disagreeable, rancid
odor (Windholz et al., 1983). It is miscible with water (Windholz et aL,
1983). Production data for propionic aUd were not available; however, the
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1A LE 1—1
Current Domesflc Manufacturers of Proplonic Acid*
Manufacturer
Locaflon
Annual Capacity
(millions of pounds}
Eastman Kodak Co.
Klngsport,
TN
55
Hoechst Celanese Corp.
Pampa, TX
20
Union Carb de Corp.
Texas City,
TX
<150
Total
<225
*Source: SRI, 1989
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total capacity of U.S. industry to manufacture propionic acid was <225
million pounds in 1988 (SRI, 1989). Demand is expected to increase to 145
million pounds by 1992. This is equivalent to an annual growth of 2-3%
(CMR, 1988). Propionic acid is used primarily as a grain and feed preserva-
tive and in the formation of cellulose plastics. [ he current use pattern
for propionic acid has been reported as follows: grain and feed preserva-
tives (25%), cellulose plastics (20%), calcium and sodium propionates (18%),
herbicide manufacture (18%), exports (15%) and miscellaneous uses, including
butyl and pentyl propionates (4%). Butyl and pentyl propionates may have a
growing market in the paint and coating industries in the future (CMR, 1988).
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
2.Ll. Degradation. Based upon a vapor pressure of 3.53 sin Hg at 25°C
(Daubert and Danner, 1985), propionic acid is expected to exist predomi-
nantly in the vapor phase in the atmosphere (Elsenreich et al., 1981). The
dominant environmental fate process in the air is probably the vapor phase
reaction with photochemically produced hydroxyl radicals. The rate constant
for the reaction of propionic acid with hydroxyl radicals has been experi-
mentally determined to be l.22xl0’ 2 cm 3 /molecule-sec at 25°C (Daugaut
et al., 1988). Based upon an average yearly atmospheric hydroxyl radical
concentration of 5.Ox1O’ molecules/cm 3 in a typical atmosphere
(Atkinson, 1985), the corresponding half-life for propionic acid would be
—13 days. For highly polluted atmospheres, the hydroxyl radical concen-
tration may increase by an order of magnitude and this would lower the
half-life by an order of magnitude. Since organic acids of low molecular
weight have absorption bands at wavelengths well below the environmentally
significant range (>290 nm), photochemical reaction in the air is not
expected to be significant (Calvert and Pitts, 1966).
2.1.2. Physical Removal. The complete miscibility of propionic acid in
water (Windholz et al., 1983) suggests that physical removal from air by wet
deposition (rainfall, dissolution in clouds, etc.) is possible. The
propionate ion has been detected in precipitation collected in Wisconsin at
concentrations up to 2.1 1 zmol/t and Upton, NV, at trace concentrations
(Chapman et al., 1986). Therefore, physical removal from air by wet
deposition may have some environmental significance, especially in the
absence of any fast degradation rate in air.
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2.2. WATER
With a PKa of 4.87 (Riddick et al., 1986), proplonic acid is expected
to exist n equal proportions as the associated form and the propionate ion
in environmental waters at a pH of 4.87 (Harris and Hayes, 1982). Under
almost neutral and alkaline conditions (pH >6.87), over 99% of the proplonic
acid that occurs in aqueous media will dissociate to the proplonate ion
(Harris and Hayes, 1982). At pHs of 5.87 and 3.87, —90 and 10% of the total
propionic acid will be dissociated, respectively (Harris and Hayes, 1982).
2.2.1. Hydrolysis. Experimental data regarding the hydrolysis of
propionic acid were not available In the literature cited in Appendix A.
Carboxylic acids are generally resistant to aqueous environmental hydrolysis
(Harris, 1982). Therefore, hydrolysis of proplonic acid is not expected to
be significant in the environment.
2.2.2. OxIdation. The rate constant for the reaction of the propionate
ion with hydroxyl radicals in water at a pH of 9 is 4.lxlO° t/mol-sec
(Anbar and Neta, 1967). Assuming the hydroxyl radical concentration in full
intensity sunlit natural water is l.OxlO’ 7 mol/t (Mill et al., 1980),
the half-life for the photochemical reaction of proplonic acid with hydroxyl
radicals in water under conditions of continuous full intensity sunlight
would be —4.65 years. Therefore, this photooxfdation reaction in natural
waters is not expected to be significant.
2.2.3. MicrobIal Degradation. Grab sample data regarding the biodegrada-
tion of proplonic acid in natural waters were not available in the litera-
ture; however, a number of aerobic biological screening studies, which used
settled wastewater, sewage or activated sludge for inocula, have demon-
strated that proplonic acid Is readily biodegradable (Dawson and Jenkins,
1950; DIas and Alexander, 1971; Gaffney and Heukelekian, 1958a,b;
0452d -6- 07/24/90
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Heukelekian and Rand, 1955; Malaney and Gerhold, 1969; McKinney et al.,
1956; Takemoto et at., 1981; tirano and Kato, 1986; Yonezawa et al., 1982).
These studies indicate that propionic acid should rapidly degrade in most
environmental waters.
2.2.4. Volatilization. Under almost neutral and alkaline conditions (pH
>6.81), over 99% of the propionic acid that occurs In aqueous media will
dissociate to the propionate ion (Harris and Hayes . 1982). Ions are not
expected to volatilize from water. For acidic waters, the relative concen-
trations of associated and dissociated propionic acid will depend upon pH.
Neverth2less, a Henry’s Law constant of 4.45xlO atrn-m 3 /mol at 25°C
(Nirmalakhandan and Speece, 1988) indicates that volatilization of
associated propionic acid from environmental waters will be extremely slow
(Thomas, 1982). Using the method of Thomas (1982), the volatilization
half-life of propionic acid from a model river 1 in deep, flowing 1 rn/sec
with a wind velocity of 3 rn/sec is estimated to be 10 days. This half-life
suggests that volatilization is not a significant fate process for propionic
acid.
2.2.5. Adsorption. The relative concentrations of associated and
dissociated propionic acid will depend upon PH; however, neither propionic
acid nor the propionate ion are expected to undergo adsorption. Ions do not
usually adsorb to organic carbon as strongly as their associated counter-
!at.ts (Harris and Hayes, 1982) and proplonic acid is completely miscible in
water (Windholz et al., 1983). This suggests that partitioning from the
water column to aquatic sediments or suspended material is unlikely to have
environmental significance.
2.3. SOIL
2.3.1. Degradation. Grab sample data regarding the biodegradation of
propionic acid/propionate In soil were not available in the literature.
0452d -1 - 03/26/90
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A number of aerobic biological screening studies, which utilized settled
wastewater, sewage or activated sludge for inocula, have demonstrated that
propionic acid/propionate is readily biodegradable (Dawson and Jenkins,
1950; Dias and Alexander, 1911; Gaffney and Heukelekian, 1958a,b, 1961;
Heukelekian and Rand, 1955; Malaney and Gerhold, 1969; McKinney et al.,
1956; Takemoto et al., 1981; Urano and Kato, 1986; Yonezawa et al., 1982).
These studies indicate propionic acid/propionate should degrade rapidly in
most soils. No data are available to suggest that any degradation process
in soil, other than biodegradation, is significant.
2.3.2. Adsorption/Leaching. Propionic acid is completely miscible in
water (Windholz et al., 1983), suggesting that adsorption should not be
significant and that propionic acid should be very mobile in soil. Under
most soil conditions, propionic acid can be expected to leach. Concurrent
biodegradation may diminish the general significance of leaching, especially
if biodegradation can occur fast enough to utilize available propionic acid
concentrations.
Propionic acid has been detected in leachates from municipal and indus-
trial landfills (Albaiges et al., 1986; Lema et al., 1988) at concentrations
up to 4.5 g/t (Burrows and Rowe, 1975), demonstrating that leaching can
occur. It has been reported that the presence of other constituents in the
leachate can adversely affect the biodegradation efficiency of microbes to
utilize propionic acid (Abrams et al., 1975). Under these conditions,
propionic acid may not biodegrade rapidly and could leach into groundwaters.
2.3.3. EvaporatIon. Propionic acid has a relatively high vapor pressure
of 3.53 nn Hg at 25°C (Daubert and Danner, 1985), and a moderate amount of
evaporation from dry surfaces can be expected. A Henry’s Law constant of
0452d -8- 03/26/90
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4..45x10 7 atm-m 3 /mol at 25°C (Nirmalakhandan and Speece, 1966) ‘indicates
that volatilization of propionic acid from moist soil surfaces should not be
significant (Thomas 1 1982).
2.4. SUMMARY
The environmental fate of propionic acid can be predicted with some
accuracy since some of the ma3or fate processes have been experimentally
examined. When propionic acid is released to the atmosphere, it will
degrade by reactions with photochemically produced hydroxyl radicals. The
average half-life for propionic acid degradation in the atmosphere is —13
days; however, physical removal from air by wet deposition may also be
important. The dominant degradation process for propionic acid in soil and
water is biodegradation. Many biological screening studies have examined
the biodegradability of propionic acid and have found that it is readily
biodegradable (Dawson and Jenkins, 1950; Dias and Alexander, 1911; Gaffney
and Heukelekian, 1958a,b, 1961; Heukelekian and Rand, 1955; Malaney and
Gerhold, 1969; Mckinney et al., 1956; Takemoto et al., 1981; Urano and Kato,
1986; Yonezawa et al., 1982). Volatilization of propionic acid from the
aquatic environment (where it would mostly exist in the ionic form) should
not be a significant transport process. Propionic acid is a relatively
volatile compound and may evaporate from dry surfaces. It should not adsorb
to most soils. In the presence of other chemicals that are toxic to
microbes (such as leachates from landfills and waste sites), leaching has
occurred.
0452d -9- 01/24/90
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3. EXPOSURE
The National Occupational Exposure Survey has statistically estimated
that 23,161 U.S. workers are potentially exposed to proplonic acid occupa-
flonally (N1OSHI 1989). This estimate is based upon NIOSH surveys of U.S.
industry that were conducted between 1981 and 1983. No other data on
occupational exposure to proplonic acid were available in the literature
cited In Appendix A.
3.1. WATER
3.1.1. Envlronmei ta1 Monitoring Data. Monitoring data regarding the
presence of propionic acid ‘in water were scarce in the literature cited in
Appendix A. Waters from the Ohio River, the Little Miami River and Tanners
Creek contained proplonic acid at. concentrations from 0.1-0.8 g/t
(Murtaugh and Bunch, 1965). The propionate ion was also detected In the
sediments of Loch (11, Scotland (Miller et al., 1979).
Proplonic acid has been detected in groundwaters contaminated with
leachates from municipal and industrial landfills and hazardous waste sites
(Albalges et dl., 1986; Burrows and Rowe, 1975; Lema et al., 1988).
3.1.2. Human Sources of Emission. Proplonic acid may be released to the
aquatic environment in wastewater discharges from industry and sewage treat-
ment facilities. Primary effluents from three sewage treatment facilities
contained propionic acid at concentrations from 16-3800 pg/i (Murtaugh
and Bunch, 1965). Secondary effluents from four sewage treatment facilities
contained proplonic acid at concentrations from 1.2-68 g/9. (Murtaugh
and Bunch, 1965). Propionic acid was detected in the wastewater effluent of
a coal gasification plant (Giabbai et al., 1985).
0452d -10- 03/26/90
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Propionic acid can be released to groundwater supplies by leachates From
municipal and industrial landfills and hazardous waste sites (Albaiges et
alit 1986; Burrows and Rowe, 1975; Lema et al., 1988).
3.2. FOOD
Propionic acid has been qualitatively detected as a volatile component
of baked potatoes (Coleman et al., 1981) and cooked meats (Shibamoto et al.,
1981). Dalieb fruit, Borassus aethiopum L., contained propionic acid at an
average concentration of 84 mg/kg (Harper et al., 1986).
Insufficient data are available to estimate an average daily intake of
propionic acid from food.
3.3. INHALATION
3.3.1. Environmental Monitoring Data. Monitoring data regarding the
presence of propionic acid in the atmosphere are scarce in the literature
cited in Appendix A. The average and maximum propionic acid concentrations
for the ambient air over the Netherlands in 1980 were 0.15 and 2.0 ppb,
respectively (Guicherit and Schulting 1 1985).
The average daily inhalation by a human adult was not computed because
information regarding the presence of propionic acid in U.S. ambient air was
lacking; however, the lack of monitoring data does not necessarily indicate
that propionic acid is not present in ambient air, especially if proplonic
acid is emitted to air during the combustion of hydrocarbon fuels.
3.3.2. Human Sources of Emission. Propionic acid has been identified as
a component of exhaust from gasoline and diesel-fueled engines (Kawamura et
al., 1985). No other information regardthg the release of propionic acid to
air was available In the literature cited in Appendix A.
0452d 07/24/90
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3.4. DERMAL
Pertinent data regarding the environmental dermal monitoring of
propionic acid were not located in the available literature cited in
Appendix A.
3.5. SUMMARY
Monitoring data regarding the presence and release of propionic acid in
air and water were scarce in the available literature cited in Appendix A.
Proplonic acid may be released to the aquatic environment in wastewater
discharges from industry and sewage treatment facilities. Propion’lc acid
can be released to groundwater supplies by leachates from municipal and
industrial landfills and hazardous waste sites (Albalges et al., 1986;
burrows and Rowe, 1975; lema et al. 1988). Proplonic acid has been
identified as a component of exhaust from gasoline and diesel-fueled engines
(Kawamura et al. , 1985); therefore, the lack of monitoring data does not
necessarily indicate that proplonic acid is not present in ambient air.
especially if propionic acid is emitted to the air during the combustion of
hydrocarbon fuels and has a moderate persistence in air.
The National Occupational Exposure Survey has statistically estimated
that 23,167 U.S. workers are potentially exposed to propionic acid occupa-
tionally (NIOSHI 1989). No other data on occupational exposure to propionic
acid were available in the literature cited in Appendix A.
Insufficient data are available to estimate average daily intakes from
.the air and food and drinking water.
0452d -12- 07/24/90
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects of Fauna. Acute toxicity studies were
performed on the bluegill, Lepom is macrochirus, Daphnia magna and the
mosquito larva, Culex sp. (Dowden and Bennett, 1965). The bluegills were
tested in ROW For 24 hours and the median tolerance limit was 188 mg/I.
Daphnia magna were tested in SRW for 48 hours and the median tolerance limit
was SO mg/I. Finally, Culex sp. were tested For 24 and 48 hours in ROW
and the limits were both >1000 mg/I. Water quality parameters were not
reported.
An abstract of a Japanese study with carp, Qyprinus carpio , reported
24- and 48-hour median tolerance limits of 96 and 13 mg/t, respectively
(Funasaka et al., 1916). Further information was not available.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY — — Pertinent data regarding the effects of chronic
exposure of aquatic fauna to propionic acid were not located in the
available literature cited in Appendix A.
4.1.2.2. BIOACCUMLJLATION/BIOCONCENTRATION - — Pertinent data regarding
the bioaccumulation/bioconcentration potential of propionic acid in aquatic
fauna were not located in the available literature cited in Appendix A.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY — — Pertinent data regarding the toxic effects of
exposure of aquatic flora to propionic acid were not located in the
available literature cited in Appendix A.
4.1.3.2. BIOCONCENTRATION - - Pertinent data regarding the bioconcen-
tration potential of propionic acid in aquatic flora were not located in the
available literature cited in Appendix A.
O452d -13- 03/26/90
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4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to prop’ionic acid were not located in the
available literature cited in Appendix A.
4.2. TERRESTRiAL TOXICOLOGY
4.2.1. Effects on Fauna. Several fungi were tested with proplonic acid,
a fungicide. The mold Aspergillus flavus was exposed In a liquid medium to
proplonic acid at 0.01, 0.05. 0.1 and 0.2% v/v for 9 days (Ghosh and
Haggblom, 1985). At the highest concen rat.ion, there was no mold growth or
aflatoxin production. Mold exposed to the 0.1% level had growth and afla-
toxin production lower than control levels. Also, the 0.05% level caused a
retardation of Initial mycelial growth and conidial germination. Proplonic
acid was also added to rice at 0.05% v/u for up to 20 days and the chitin
content of the system (an indicator of mold growth) and aflatoxin production
of the mold were measured. The chitin content was consistently lower in the
rice Inoculated simultaneously with mold and propionic acid. The chitin
content was also reduced, though to a lesser degree, when proplonic acid was
added at 3 and 9 days after mold inoculation. Aflatoxin content was also
much lower when mold and propionic acid were added at the same time. This
decrease was much less pronounced when the acid was added 3 or 9 days after
mold Inoculation.
Smith et al. (1983) also tested propion’ic acid with molds. Proplonic
acid was added to corn at 0.025. 0.05 arid 0.1% and then Inoculated with
Penicillium sp. and Incubated for 8 weeks. ihe corn had varying amounts of
moisture added. There was slight mold growth n the control corn with 10%
added moisture and in corn treated wIth 0 025% proplonic acid; however, no
mold appeared at the other treatment levels. Corn with 15% added moisture
had mold growth at all levels except for the highest treatment level.
0452d -14- 03/26/90
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The effects of propionic acid on oxygen uptake in the fungus Microsporum
canis were reported in an abstract (Melton . 1951). The test substance at
0.021 M inhibited oxygen uptake by 32% when incubated with the fungus for
5 -1 days.
4.2.2. Effects on flora. An abstract of a Japanese paper revealed that
propionic acid decreased the respiratory rate of rice roots in a culture
solution (Yamada and Ota, 1958). Further information was not reported.
4.3. FIELD STUDIES
Pertinent data regarding the effects of propionic acid on flora and
fauna in the field were not located in the available literature cited In
Appendix A.
4.4. AQUATIC RISK ASSESSMENT
The lack of an adequate quantity of pertinent data regarding the effects
of exposure of aquatic fauna and flora to propionic acid prevented the
development of a freshwater criterion by the method of U.S. EPA IOWRS fl9Bb).
Additional data required for the development of a freshwater criterion
include the results of acute assays with a salmonid fish species, a warm
water fish species, a third fish species or an amphibian, planktonic and
benthic crustaceans, an insect, a nonarthropod and nonchordate species, and
an insect or species from a phylum not previously represented. The fish and
invertebrate studies available did not contain sufficient information for
risk assessment. The development of a freshwater criterion also requires
data from chronic toxicity tests with two species of fauna and one species
of algae or vascular plant and at least one bioconcentration study.
The lack of an adequate quantity of pertinent data regarding the effects
of exposure of aquatic fauna and flora to propionic acid prevented the
development of a saltwater criterion by the method of U.S. EPA/OWRS (l98b).
0452d -15- 03/26 ’90
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Additional data required for the development of a saltwater cr1ter ori
include the results of acute assays with two chordate species, a nonarthro-
pod and nonchordate species, a mysid orpanaeid crustacean, two additional
nonchordate species, and one other species of marine fauna. The development
of a saltwater criterion also requires data from chronic toxicity tests with
two species of fauna and one species of algae or vascular plant and at least
one bioconcentratlOn study.
4.5. SUMMARY
Very little data are available on the environmental effects of proplon%c
acid. Acute toxicity studies with the bluegill, j pomls macrochirus,
Daphnia ma na and the mosquito larva, Culex sp. resulted in median toler-
ance limits of 188 mg/a. (24-hour), 50 mg/9. (48-hour) and >1000 mg/I
(24- and 48-hour) (Dowden and Bennett, 1965). Median tolerance limits of 96
mg/a. (24-hour) and 73 mg/I (48-hour) were reported for the carp
( Cyprinus carpio )
Mold growth and aflatoxin production were halted when Aspergillus flavus
was exposed to the test article for 9 days at 0.2% v/v; growth retardation
and other effects were observed at >0.05% v/v (Ghosh and Haggblom, 1965).
The chitin content of the system (an indicator of mold growth) was reduced
when propionic acid was added at 0.05% v/u along with Aspergillus flavus for
up to 20 days (Ghosh and Haggblom, 1985). There was slight growth of the
Penicillium sp. mold in control corn with 10% added moisture and In corn
treated with 0.025% propionlc acid; however, no mold appeared at treatment
levels of 0.05 and 0.1% propion’tc acid. Corn with 15% added moisture had
mold growth at all levels except for the highest treatment level (Smith et
al.. 1983). The corn and mold were incubated for 8 weeks.
0452d -16- 07/24/90
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The effects of propIontc ac d on oxygen uptake n the fungus M crosporum
canis were reported n an abstract (Melton, 1951). The test substance at
0.027 M nh1b1ted oxygen uptake by 32% when thcubated w’ith the fungus for
5—7 days.
An abstract of a Japanese paper revealed that proplon c acid decreased
the respiratory rate of rice roots ‘in a culture solution (Yamada and Ota,
1958). Further ‘information was not reported.
0452d -17- 03/2b/90
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5. PHARMACOKINETICS
5.1. ABSORPTION
Indirect evidence from ID 50 studies indicates that propionic acid is
absorbed by rats after oral administration and by rabbits after dermal
application (Smyth et al., 1962). The only quantitative data regarding the
rate of oral absorption of propionic acid are from a study by Dawson et 81.
(1964) using humans. Of a mixture of seven short-chain fatty acids (concen-
tration not specified) introduced into the Jejunum of seven patients by oral
intubation, propionic acid was absorbed 2 times slower than valeric and
caproic acids, but 1.5 times faster than acetic acid. The average rate of
absorption for the mixture was 0.59 pM/minute/30 cm Jejunum (range
0.2-1.1). These results indicated that the absorption rate increased with
increasing fatty acid chain length (i.e., greater lipid solubility). Data
regarding absorption following inhalation exposure were not available.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of propionic acid were not
located in the available literature cited in Appendix A.
5.3. METABOLISM
Studies examining the metabolism of propionic acid after inhalation,
oral or dermal administration to humans or experimental animals were not
available. In higher animals, propionate (ingested as a food preservative
or derived from the metabolism of odd—carbon number fatty acids) is
converted into pyruvate, and eventually into acetyl-C0A, by a series of
enzymatic reactions. A schematic representation, adapted from Metzler
(1977), is shown in Figure 5-1. The pathway begins with the formation of
propionyl-C0A followed by carboxylation (a biotin— and AlP—dependent
reaction) to yield (S)-methylmalonyl-C0A, which is in turn isomerized to
O452d -18- 01/24/90
-------
pi i yI.CoA (S ) y &o I-CoA
pf pionate 0 H,C
AT? II AT?
H 3 C01.C00 H 3 C—01 2 -C—S—CoA HCCSCOA
CoA•SH /
ra ma e
H 3 C
(R)-methytm&Ionyl-C0A OOCCC-S—Co
/
14
j vuarnir. a
0
II
uc uIyI.CoA OOCCH 2 — Q4 - C — S — Co;
1 IGTP
ca.bov. linor Bcca.o jd.s non
Co 2 . pyrlivEe oLaJoa a!e
1
sc ryI-CoA
FIGURL 5-1
Schematic Presentation of the Metabolic Transformation
of Propionic Acid
Source: Metzler, 1917
0452d -19.- 03/26/90
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(R)-methylmalonyl-C0A. The latter is then converted into succinyl-CoA in a
vitamin ]2 coenzyme-requiring step. In subsequent steps, succlnyl-CoA is
converted into oxaloacetate, pyruvate, and finally acetyl-CoA, which can
enter the citric acid cycle.
5.4. EXCRETION
Pertinent data regarding the excretion of proplonic acid were not
located in the available literature cited in Appendix A.
5.5. SUMMARY
The rate of absorption of a mixture of seven short-chain fatty acids in
human jejunum Fell in the range of 0.2-1.1 pM/minute/3D cm jejunum (Dawson
et al., 1964). Propionic acid was absorbed at a slower rate than longer-
chain fatty acids (Dawson et al., 1964). No other studies regarding the
absorption of propionic acid in humans were located. Data from LD 50
studies in rats and rabbits indicate that propionic acid is absorbed by the
oral and dermal route, respectively, (Smyth et al., 1962), but quantitative
data were not available. Small amounts of propionic acid, found normally in
food, are metabolized by a series of enzymatic reactions to acety l-CoA,
which enters the citric acid cycle (Metzler, 1971). Data regarding
distribution and excretion of propionic acid were not located.
0452d -20- 03/26/90
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Pertinent data regarding the subchronic and
chronic toxicity of propionic acid from inhalation exposure were not located
in the available literature cited in Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SLJBCHRON IC - — Only two subchronic oral studies were located
in the available literature. In a study by Mon (1953), five weanling
albino rats (both sexes, but distribution/sex was not specified) were fed a
diet of rice supplemented with 5% propionIc acid For 110 days. Assuming a
reference food factor of 0.05 for rats (U.S. EPA, 1980), this diet provided
an estimated daily dose of 2500 mg of propionIc acid/kg bw. The body weiaht
of the rats was monitored every 2 weeks. One rat died early In the course
of the experiment, but the cause of death was not reported. The stomachs of
the remaining four rats were examined for gross lesions at the end of treat-
ment. Three of these rats had abnormalities and were subjected to gastric
histological examinations that showed “umbilicate or warty lesions” in the
forestomach. No other endpoints were examined. Data regarding untreated
controls were not provided.
In a study conducted by Gniem (1955), groups of 30 male weanling Wistar
rats were fed diets containing 0 (control). 0.4 or 4% propionic acid. These
diets provided estimated doses of 0, 200 or 2000 ing propionic acid/kg lday,
assuming a reference food factor for rats of 0.05 (U.S. EPA, 1980). Histo-
logical examinations (stomach, intestine, esophagus, liver, kidneys, spleen,
heart, lungs, adrenals, pancreas, thyroid and brain) were performed on 10
rats/group after 20 weeks of treatment, and on the remaining rats, following
death or sacrifice if clinically perceptible disease symptoms appeared
0452d -21- 01/24/90
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(Section 6.1.2.2.). Rats receiving 2000 mg/kg/day propionic acid showed
changes in the forestomach mucosa, including grossly observable elevations
in six animals and hyperkeratosis and hyperplasia, including hyperplastic
degeneration of the limiting ridge, in all animals. Squamous epidermis
hyperplasia with incipient ulceration and papillomatosis was particularly
marked in 6/10 rats. No gross changes were observed in the fore- and
glandular stomach of rats receiving 200 mg/kg/day doses of propionic acid
other than slightly swollen limiting ridges. Histological examination of
this region demonstrated hyperplasia and hyperkeratotic changes. No patho-
logical changes were observed in the stomach mucosa of rats receiving the
control diet. Pathological effects in tissues other than the stomach were
not reported.
6.1.2.2. CHRONIC -- Groups of 20 male rats were administered
estimated propionic acid doses of 0, 200 or 2000 mg/kg/day until death or
sacrifice when moribund (Griem, 1955). Information regarding this phase of
the study is incomplete because the study was still ongoing at the time of
the report. Survival in the control, low- and high-dose groups by age 2
years (after 101 weeks of treatment) was 16/20, 13/20 and 12/20, respec-
tively. Many of the high-dose rats appear to have been examined after 50-94
weeks of treatment, but information on duration of treatment In the examined
low-dose rats is not available. Histological alterations in the rats that
died or were sacrificed were more severe and extensive than those observed
at 20 weeks and apparently were still limited to the gastric region.
Effects in the 2000 mg/kg/day group included vast areas of squamous hyper-
plasia with dyskeratosis and hyperplastic ulcers in the forestomach. The
margins of the hyperplasia frequently showed papillomatous proliferation
(Section 6.2.2.). Erosive changes occurred In the glandular region of the
0452d -22- 03/26/90
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stomach in all examined high-dose group animals. Effects in the 200
mg/kg/day group included changes in the forestomach mucosa that were similar
to but apparently more frequent (“demonstrated increasingly”) than those
occurring at 20 weeks. Histological examinations of the glandular stomach
mucosa were unremarkable in the 200 mg/kg group.
6.1.3. Other Relevant Informat%on. In a study conducted by Rodrigues et
al. (1986), male weanling F344 rats (6/group) were fed diets containing 0 or
4% propionic acid for up to 27 days. This diet provided a dose of 4
g/kg/day assuming a food factor of 0.1 for weanling rats (Arrington, 1972).
The experimental treatment resulted in a 5.6% increase (p<0.001) in the
[ methyl- 3 Hjthymidine labelling index (indicating proliferative changes) in
the mid-region of the forestomach. This effect, which was not noticeable
before 21 days of treatment, was not observed in the prefundic region. The
increase in labelling correlated positively with thickening of the mucosa
along the lesser curvature of the stomach and also with nodular thickening
of the anterior wall of the forestomach (Rodrigues et al., 1986). The
effect of propionic acid, according to Rodrigues et a]. (1986), could be due
to changes in stomach pH. No attempt was made to investigate the revers-
ibility of the histological change observed.
Single-dose oral and dermal LD 50 values of 4262 and 497 mg/kg were
determined for propionic acid in male Carworth-Wistar rats and male New
Zealand rabbits, respectively (Smyth et al., 1962); the animals were
observed for 14 days, but the vehicles were not specified. Smyth et al.
(1962) also reported that exposure to concentrated vapors (concentration not
specified) of propionic acid for up to 8 hours was not lethal in rats within
14 days. Ord and Wretlind (1961) reported an intravenous LD 50 In mice of
625 mg/kg for propionic acid in aqueous solution. Doses near the L0 50
produced convulsions and respiratory arrest (Oro and Wretlind, 1961).
0452d -23- 03/26/90
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Intravenous injection of 1.2 mg/kg sodium propionate (0.93 mg/kg
proplonic acid equivalents) Induced a biphasic contraction in rat ileum in
situ (Yajima, 1984). The initial phasic response was attributed to release
of the neurotransmitter acetyicholine by propionic acid, whereas the tonic
contraction was presumably due to a direct effect of proptonic acid on the
muscle (Yajima, 1984). PropIonic acid at a concentration of 0.1 M did not
induce contractions in the isolated small intestine of guinea pigs and did
not abolish the contraction Induced by histamine (Oró and Wretlind, 1961).
The investigators did not elaborate on the relevance of this finding.
Accumulation of propionic acid or its metabolite propIonyl-C0A resulted In
inhibition of oxidative metabolism in Intact rat hepatocytes (Brass et al.,
1986; Brass and Beyerlnck, 1988).
6.2. CARCINOGENICITY
6.2.1. InhalatIon. Pertinent data regarding the inhalation carcinogen-
Icity of propionic acid were not located in the available literature cited
in Appendix A.
6.2.2. Oral. In a study conducted by Grlem (1985), male Wistar rats
(20/group) were fed a diet that provided estimated doses of 0, 200 or 2000
mg propionic acid/kg/day for >20 weeks (details regarding the protocol are
provided in Section 6.1.2.2.). Rats n the high-dose group had papilloma-
tous processes In the forestomach mucosa, and one animal (examined after 94
weeks of treatment) had a papillomatuuc tumor in the vicinity of the
limiting ridge. This tumor exhibited regional carcinomatous degeneration.
Proliferation of germinal cells was also observed in this group. According
to Griem (1985), the changes observed in the high-dose group could be
described as small, local carcinomatous degeneration or as precancerous
0452d -24- 03/2&/90
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stages. Rats in the low-dose group showed hyperplast’ic changes in the
forestomach mucosa, whereas no pathological effects were notlced in Control
animals (see SectIon 6.1.2.2.1.
6.2.3. Other Relevant Information. Treatment of cultured low—metastatic
Lewis lung carcinoma P-29 cells with 1 mM propionic acid for 5 days
increased the lung-colonizing ability of the cells when 1n ected into male
C5161/6 mice (Takenaga, 1986). This increase (l3 -43 lung nodules/mouse) was
considered slight compared with that induced by butyric acid (150-191 lung
nodules/mouse); untreated cells induced -5 nodules/mouse. According to
Takenaga (1986), the increased colonizing activity may result from
epigenetic alterations induced by propionic acid.
6.3. GENOTOXICITY
Data from genotoxicity tests with propionic acid are presented In
Table 6-1. Proplonic acid induced DNA damage in Escherlchia coil in a dose-
related manner (Basler et al., 1987), but was negative in the SOS chromotest
in E. coil , reverse mutation tests in Salmonella typhimurium , a test for
mitotic gene conversion in Saccharomyces cerevislae , the SCE test in Chinese
hamster V79 cells, and in the micronucleus test in Chinese hamsters (Basler
et al., 1987; Litton Bionetics, 1976).
6.4. DEVELOPMENTAL TOXICITY
Pertinent data regarding the developmental toxicity of propionic acid
were not located in the available literature cited in Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Data regarding other reproductive effects of proplonic acid were not
located In the available literature cited in Appendix A.
6.6. SUMMARY
Rats fed diets that provided 0.2 or 2 g proplonic acid/kg/day for 20-101
weeks developed proliferative alterations (such as hyperplasia) in the
0452d -25- 08/20/90
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TABLE 6-1
Genotoxicity Testing of Propiunic Acid
Assa t
Indicator Organism
Application
Purity
(%)
Concentration
or Dose
Activating
System
Response
Co4lvnent
Reference
DNA damage
(scherichia c .]j.
polA and polA;
rec-and rec’
spot test
99
1, 5 or 25 at
—
•
Dose-related Increase in the
differences in growth inhibl-
tion in both polA’- and
rec” tests
Basler et
1987
al.,
SOS chromatid
F. coil PQ31
tube test
99
0.01-10.0 n*I
.S9
S9 not described
Basler et
1987
al.,
Reverse
mutation
Salmonella typhi—
murium TA9B, TA100,
1A153S. TA1531
plate
incorporation
99
0.01-10
aI/plate
±S9
Activated with Aroclor—
induced rat S9
Basler et
1981
al.,
Reverse
mutation
S. typhimurium
TA100, 1A98, TA1535,
TA1537. TA1538
liquid
suspension
NR
0.02315-
0.09500%
•S9
-
Act vated with rat, mouse or
monkey S9 from various organs
Litton
Bionetics.
1976
Reverse
mutation
S. typhimurium
TA100, TA98. TA1535.
TA1S31, TA1538
plate
incorporation
NR
0.02315-
0.09500%
in top agar
•S9
Activated with rat, mouse or
monkey S9 from various organs
Litton
Bionetics,
1916
Mitotic gene
conversion
Saccharomyces
cerevlsiae D4
liquid
suspensIon
NR
0.02315-
0.09500%
•S9
Activated with rat, mouse or
monkey S9 from various organs
Litton
Bionetics.
1976
SCE test
Chinese hamster
V19 cells
cell culture
99
0.1-33.3 n
±S9
S9 not described
Basler et
1981
al
Micronucleus
test
Chinese hamster
polychromatic
erythrocytes
single i.p.
dose
99
5 mt/kg of
2.5% solution
in saline
(125 mg/kg)
NA
-
Examined 12—48 hours after
treatment
Basler et
1987
al.,
i.p. = Intraperitoneal ; NA not applicable; NR not reported
I ’. ,
Q
‘.0
-------
stomach mucosa (Griem, 1985). SimIlar alterations occurred in rats fed
diets providing 2.5 g/kg/day for 110 days (Mor’i, 1953) and in weanling rats
fed diets providing 4 g/kg/day for up to 27 days (Rodrigues et al., 1986).
Although these findings might indicate that the stomach is a target for
propion’ic acid, the dietary levels of propionic acid used in these studies
are several orders of magnitude higher than those used for propion’ic acid as
a food preservative (see Chapter 3). Data were not available regarding the
subchronic or chronic toxicity of propionic acid from inhalation exposure.
Oral and dermal LD s of 4262 and 497 mg/kg have been determined for
proplonic acid in rats and rabbits, respectively (Smyth et al., 1962).
ID data for other species were not available. There was no mortality in
rats exposed to unspecified concentrated vapors of propionic acid for up to
B hours (Smyth et al., 1962).
Preliminary data suggested that precancerous lesions occurred in the
stomach mucosa of rats fed dietary doses of 2 g/kg/day of propionic acid for
>20 weeks (Griem, 1985). Proplonlc acid induced a slight increase in the
lung-colonizing ability of Lewis lung carcinoma P-29 cells when injected
Into mice (Takenaga, 1986).
Evidence from two studies (Basler et al., 1987; Litton Bionetics, 1976)
indicates that propionic acid is not strongly genotoxic. Propionic acid
induced DNA damage in E. coil , but did not induce gene mutations in
bacteria, gene conversion in yeast, sister chromatid exchanges in hamster
cells vitro or micronuciei in hamsters jj vivo . Studies regarding
developmental toxicity or reproductive effects of propionic acid, were not
available.
0452d -27- 08/20/90
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7. EXISTING GUIDELINES AND STANDARDS
Li. HUMAN
ACGIH (1989) recommended a TLV-TWA of 10 ppm (—30 mg/rn 3 ) for propionic
acid. This recommendation is based largely on analogy with acetic acid, and
is designed to prevent significant irritation of eyes or respiratory
passages (ACGIHI 1986). OSHA (1989) established a PEL for propionic acid of
10 ppm (—30 mg/ma) TWA. U.S. EPA (1985) has proposed an RQ of 5000 for
proplonic acid. Propionic acid is exempt from the requirement of a
tolerance for several agricultural commodities when used as a fungicide
(U.S. EPA, 1998).
7.2. AQUATIC
Guidelines and standards to protect aquatic life from exposure to
propionic acid were not located in the available literature cited in
Appendix A.
0452d -28- 08/20/90
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the inhalation carcinogen-
icity of prop’ionic acid were not located in the available literature cited
in Appendix A.
8.1.2. Oral. In a study conducted by Griem (1985), male Wistar rats
(20/dose) were fed propionic acid in the diet at estimated doses of 0. 200
or 2000 mg/kg/day. Treatment continued until death ‘or sacrifice when
moribund, but 16, 13 and 12 rats In the control, low- and high-dose groups,
respectively, were alive after 101 weeks of treatment and were not examined
because the study was ongoing at the time of the report. Animals in the
high-dose group developed proliferative changes in the forestomach mucosa,
which were interpreted by Griem (1985) as precancerous. Rats in the
low-dose group developed hyperplastic changes, whereas control animals were
not affected. Because this report is preliminary, the results must be
interpreted with caution until the completed study can be evaluated fully.
Histological effects were not reported in tissues other than the stomach.
8.1.3. Other Routes. Treatment of cultured low—metastatic Lewis lung
carcinoma P-29 cells with 1 n l propionic acid for 5 days increased the
lung-colonizing ability of the cells when injected into male C57BL/6 mice
(Takenaga, 1986).
8.1.4. Weight of Evidence. No data were available regarding the carcino-
genicity of proplonic acid In humans. Carcinogenicity data in animals are
limited to suggestive but preliminary results in male Wistar rats (Griem,
1985). Propionic acid was not genotoxic in assays conducted in bacterial or
manmialian systems (Basler et al., 19BL Litton Bionetics, 1976). Based on
0452d -29- 08/20/90
-------
the evidence discussed previously, and according to U.S. EPA (1986a) guide-
lines, propionic acid is placed in U.S. EPA weight—of-evidence Group U - -
not classifiable as to carcinogenicity to humans. further testing may be
desired to establish the likelihood that propionic acid may be carcinogenic
with prolonged exposure.
8.1.5. Quantitative Risk Estimates. The lack of suitable positive inha-
lation or oral carcinogenic data precludes the derivation of carcinogenic
potency slope factors for propionic acid.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding inhalation exposure
to propionic acid were not located in the available literature cited in
Appendix A.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME (SUBCHRONIC) — — Only two subchronic
studies with propionic acid were identified in the available literature, and
both were performed in rats. In the study by Mon (1953), weanling albino
rats were fed a rice diet that provided an estimated dose of 2.5 g of
propionic acid/kg/day for 110 days (Rec. #3, Appendix C.2.2.). Three out of
four rats that survived until the end of the treatment period showed gross
lesions in the stomach; histological examinations of these rats showed
“umbilicate or warty lesions” in the forestomach. Inadequacies of this
study, particularly the small number of animals, use of an unbalanced diet
and no information regarding untreated controls, preclude its direct use for
risk assessment.
In the study by Gniem (1985), male weanling Wistar rats were adminis-
tered estimated doses of 0, 200 or 2000 mg propionic acid/kg/day for 20
weeks. Rats at 200 mg/kg/day (Rec. #1, Appendix C.2.2.) had hyperplastic
O452d -30- 08/20/90
-------
and hyperkeratotic changes in the forestomach mucosa, with slightly swollen
limiting ridges. No gross changes were observed at this dose level. Rats
at 2000 mg/kg/day (Rec. #2, Appendix C.2.2.) had hyperplastic degeneration
and Incipient ulceration and papillomatosis of the forestomach mucosa. No
histological effects were reported in tissues other than the stomach. No
I’4OAEI can be identified from the study by Griem (1985); however, the dose of
200 mg/kg/day is a LOAEL. Other studies (Mori, 1953; Rodrigues et dl.,
1986) support the LOAEL of 200 mg/kg/day.
The Griern (1985) study, however, is a very tenuous basis for an RfO.
Only one sex of one species was tested, small numbers of rats were examined
at 20 weeks and few parameters of toxicity were evaluated. Furthermore, the
distinction between preneoplastic and nonneoplastic lesions is not entirely
clear. It is possible that the nonneoplastic lesions observed at 200
mg/kg/day at 20 weeks may progress to preneoplastic or neoplastic with
prolonged exposure.
Nevertheless, the LOAEL of 200 mg/kg/day is the only possible basis for
an RfD for subchronic oral exposure to propionic acid. If it Is desirable
to derive an RfD, an uncertainty factor of 1000 (10 to estimate a NOAEL from
a LOAEI, 10 for inter— and 10 for intraspecies variability) should be
applied, and the resulting RIO for subchronic oral exposure would be 0.2
mg/kg/day. For the reasons discussed above, the RfD should be considered
provisional. As discussed above, confidence In the key study is low;
confidence in the data base and the RfD are low (Section 8.2.2.2.).
8.2.2.2. CHRONIC —— Preliminary data indicated that dietary exposure
to estimated doses of 200 or 2000 mg/ky/day for durations >20 weeks produced
dose-related gastric alterations in rats (Griem, 1985). Examinations were
performed following death or when the animals were moribund; 4/20, 7/20 and
0452d -31- 08/20/90
-------
6/20 rats were examined in the control, low- and high-dose groups, respec-
tively, by week 101. Many of the high-dose rats appear to have been
examined after 50—94 weeks of treatment, but specific information on
durations of treatment in the low—dose group were not reported. The gastric
changes were more severe and extensive than those occurring after 20 weeks
(see Section 8.2.2.1.), particularly at the high dose. Effects included
forestomach hyperplasia and hyperkeratosis at the low dose and hyperplastic
ulcers in the forestomach and erosive changes in the glandular stomach at
the high doses. It is inappropriate to use the chronic data from this study
as the basis for a chronic RfD because they are preliminary and incomplete
(durations of treatment in the examined low-dose group rats could be
subchronic and over half of the exposed rats in both dosed groups were still
being treated at the time of the report). A provisional chronic oral RFD,
however, can be calculated from the subchronic oral RFD of 0.2 mg/kg/day,
which is based on the same study. Applying an uncertainty factor of 10 to
the subchronic RfD of 0.2 mg/kg/day results in an RfD for chronic oral
exposure of 0.02 mg/kg/day. Confidence in the key study is low for the
reasons discussed In Section 8.2.2.1. Confidence in the data base is low
because additional chronic data are not available. Confidence in the RFD is
low. The RfD is approximately an order of magnitude below the estimated
daily consumption of propionic acid by the general population (FASEB, 1979).
Furthermore, propionic acid has been designated a GRAS substance regarding
its use as a food preservative (FASLB, 1979). It is likely that the
provisional chronic oral RfD is unnecessarily conservative to protect
against the nonneoplastic effects of propionic acid.
0452d -32- 08/20/90
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxicity of propionic acid was discussed ‘in Chapter 6 and data
suitable for RQ derivation are summarized in Table 9—1. The chronic data
from the Griem (1985) study are not included In Table 9-1 because the data
are preliminary and incomplete. The subchronlc rat study of Mon (1953) is
not presented in Table 9-1 because of inadequacies such as the small number
of animals and lack of control data.
Effects attributed to subchnon’ic oral exposure to prop’ionic acid are
limited to the forestomach mucosa of rats and Included hyperplasia at the
low dose and hyperplastic degeneration with incipient ulceration at the high
dose (see lable 9-1). Derivations of CSs, based on the lowest equivalent
human dose associated with these effects, are presented in Table 9-2. The
human MEDs were divided by an uncertainty factor of 10 to approximate
chronic exposure because the preliminary chronic data from the same study
indicate that the gastric effects increase in severity with increased dura-
tion of exposure. The most appropriate e for hyperplasia accompanied by
hyperkeratosis is 4, and gastric mucosal degeneration with unknown func-
tional significance warrants an RVe of 6. The highest CS of 7.73, which
corresponds to an RQ of 1000, Is chosen to represent the hazard associated
with chronic (noncancer) toxicity resulting from exposure to propionic acid
(Table 9-3).
9.2. BASED ON CARCINOGENICITY
Preliminary carcinogenicity data, sun nar1zed in Section 6.2.. suggested
that male Wistar rats given an estimated 2 g/kg/day dose of proplonic acid
in the diet for >20 weeks exhibited histopathological changes in the fore-
stomach mucosa that were characterized by the investigator as precarcino-
genic (Griem, 1985). Takenaga (1986) showed that treatment of cultured
0452d -33- 08/20/90
-------
TABLE 9 1
Oral Toxicity Summary for Proplonic Acid Using the Wistar Rata,b
Sex No.
Sta
at
rt
Average Transformed
WelghtC Exposure Animal Dosed
(kg) (mg/kg/day)
Equivalent
Human Dosee Response
(mg/kg/day)
M 10 0.35 0.4% in the diet 200 34.20 HyperpIasla and hyper-
(20 weeks) keratosis of the fore-
stomach mucosa
P 1 10 0.35 4% in the diet 2000 342.00 Hyperplastic degenera-
(20 weeks) tion and incipient
ulceration of the fore-
stomach mucosa
àSource: GrIem, 1985
bThe vehicle/physical state was diet and the purity of the compound was not reported.
Ckeference body weight (U.S. [ PA, 1980)
dAnh,p41 dose Is scaled to the human dose by a surface area scaling factor (body weight) 2 / 3 (Mantel and
Schneiderman. 1975).
ecalculated using rat reference food factor of 0.05 (U.S. EPA, 1980)
I ’. )
0
D
U,
I ’ ,
-------
TABLE 9-2
Oral Composite Scores for Proplonic Acid Using the Rata
Animal Dose
(mg/kg/day)
Chronic
Human MEOb
(mg/day)
RVd
Effect
RVe
CS
RQ
200
239.40
1.93
Hyperplasla and
hyperkeratosis of
forestomach mucosa
4
7.13
1000
2000
2393.97
1.0
Hyperplastic
degeneration and
incipient ulcera-
tion of the fore-
stomach mucosa
6
6.00
1000
aSource: Griem, 1985
bHuman equivalent dose (mg/kg/day) from Table 9-1 multIplied by 70 kg to
express MED in mg/day for a 70 kg human. The dose was divided by an
uncertainty factor of 10 to approximate chronic exposure.
0452d -35- 08/20/90
-------
TABLE 9-3
Propionic Acid
(CAS No. 19-09-4)
Minimum Effective Dose (NED) and Reportable Quantity (RQ)
Route: oral (diet)
Species/sex: rat/male
Dose*: 239.40 mg/day
Duration: 20 weeks
Effect: hyperplasla and hyperkeratosis of forestomach mucosa
RVd: 1.93
RVe: 4
CS: 1.72
RQ: 1000
Reference: Griem, 1985
*Equ%valent human dose
0452d -36- 08/20/90
-------
low-metastatic Lewis lung carcinoma P-29 cells with 1 m M propionic acid for
5 days increased the lung-colonizing ability of the cells when injected into
male CS7BL/6 mice. Data regarding the carcinogenicity of propionic acid in
other species of animals or humans are lacking, and propionic acid is
classified in U.S. EPA weight-of-evidence Group D -- not classifiable as to
human carcinogenicity. Hazard ranking is not possible for EPA Group D
chemicals (U.S. (PA, l986b); hence, a cancer-based RQ cannot be derived.
0452d -37- 08/20/90
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u.s. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic loxicity Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Superfund Programs: Notification Regu’irements; Reportable
Quantity Adjustments; Final Rule and Proposed Rule. Federal Register.
50(65): 13495.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185 ): 33992-34003.
U.S. EPA. 1986b. Methodology For Evaluating Reportable Quantity Adjust-
ments Pursuant to CERCLPI Section 102. Prepared by the Carcinogen Assessment
Group, Office of Health and Environmental Assessment for the Office of
Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1988. Proplonic Acid: Exemption from the Requirement of a
Tolerance. 40 CFR 180.1023.
U.S. EPA/OWRS. 1986. Guidelines for Deriving Numerical National Water
Quality for the Protection of Aquatic Organisms and their Uses. U.S. EPA,
Washington. DC. 6RA18522.
0452d -47- 08/20/90
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Windholz, M.. S. Budavarl, R.F.Blumettl and 1.5. Otterbein. 1983. The
Merck Index. Merck and Co., Inc., Rahway, NJ. p. 1121.
Yajima, 1. 1984. Effect of sodium propionate on the contractile response
of the rat ileum in situ . Jap. J. Pharmacol. 35(3): 265 —271.
Vaniada , N. and V. Ota. 1958. Respiration of crop plants. VIII. Effect of
hydrogen sulfide and lower fatty acids on root respiration of rice. Nippon
Sakumotsu. Gakkai Kiji. 27: 155-160. CFCA 52, 14967e.
Yonezawa, V., V. irushigawa, S. Masunaga, H. Masunaga, M. Hirai and M.
Tanaka. 1982. Biodegradation of organic compounds by activated sludge. 3.
Biodegradability of linear fatty acids by non-acclimated activated sludge.
Kogai Shigen Kenkyusho Iho. 12: 85-91.
0452d -48- 08/20/90
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APPENDIX A
LITERATURE SEARCHED
This HEED is based on data identified by computerized literature
searches of:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
IOXL I 1
TOXLIT 65
R1ECS
OHM TAOS
STORE 1
SRC Environmental fate Data Bases
SANSS
AQUIRE
I SC AP P
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
H SOB
SCISEARCH
Federal Research In Progress
These searches were conducted in January, 1990, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hygienists).
1986. DocumentatIon of the lhreshold Limit Values and Biological
Exposure indices, 5th ed. Cincinnati, OH.
ACSIH (American Conference of Governmental Industrial Hygienists).
1987. TLVs: Threshold Limit Values for Chemical Substances in the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p
Clayton, G.D. and F.E. Clayton, Ed 1981. Patty’s Industrial
Hygiene and Toxicology, 3rd rev ed , Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and f.E. Clayton, Ed. 1981. Patty’s Industrial
Hygiene and loxicology, 3rd rev ed , Vol. 26. John Wiley and
Sons, NY. p. 2879-3816.
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty’s Industrial
Hygiene and loxlcology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3811—5112.
Grayson, M. and D. Eckroth, Ed. 1918-1984. Kirk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
hamilton, A. and H.L. Hardy. 1974. Industrial ToxIcology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 515 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, LW. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screenIng for compounds of interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS P884-243906. SRI International,, Menlo
Park, CA.
NIP (National loxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1971. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Reinhold Co., NY.
SRI (Stanford Research Institute). 1981. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report in the Special Review
Program, Registration Standards Program and the Data Call in
Programs. Registration Standards and the Data Call in Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Pubi.
1892, Washington, DC.
Verschueren. K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Reinhold Co., NY.
Windholz, M.,, Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.8. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
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In addition, approximately 30 compendia of aquatic toxicity data were
reviewed, including the following:
Battelle’s Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects or Chemicals o c t Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.1. finley. 1980. Handbook of Acute loxicity
of Chemicals to Hsh and Aquatic Invertebrates. Summaries of
Toxicity Tests Conducted at Columbia National fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Pubi. No. 3-A.
Pimental, 0. 1971. Ecological Effects of Pesticides on Non—larget
Species. Prepared for the U.S. EPA, Washington, DC. PB—269605.
Schneider, B.A. 1979. Toxicology Handbook. Manmialian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-136876.
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“I
0.
U i
0
APPENDIX B
Sumary Table for Propionic Acid
Species
Exposure
Effect
RID or
Reference
Inhalation Exposure
ID
ID
ID
ID
NA
Subchronic
Chronic
ID
ID
ID
ID
NA
Carcinogenicity
ID
ID
ID
ID
NA
Oral Exposure
Subchron ic
rat
0.45
(200
for
in the diet
mg/kg/day)
20 weeks
hyperplasia and hyper-
keratosis of fore-
stomach mucosa
0.2
mg/kg/day
Griem,
1985
Chronic
rat
0.4%
(200
for
in the diet
mg/kg/day)
20 weeks
hyperplasia and hyper-
keratosis of fore-
stomach mucosa
0.02
mg/kg/day
Griem,
1985
Carcinogenicity
ID
ID
ID
ID
NA
REPORTABLE QUANTITIES
1000
Griem,
1985
Based on chronic toxicity:
Based on carcinogenicity:
ID
NA
ID = Insufficient data; NA = not applicable
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO PROPIONIC ACID
C.]. DISCUSSION
A dose/duration response graph for oral exposure to propionic acid
generated by the method of Crocket et al. (1985) using the computer software
by Durkth and Meylan (1989) developed under contract to ECAO-Cinclnnatl is
presented in Figure C-i. Data used to generate this graph are presented in
Section C.2. in the generation of this figure, all responses are classified
as adverse (EEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for plotting.
For oral exposure, the ordinate expresses dose as human equivalent dose.
The animal dose in rug/kg/day is multiplied by the cube root of the ratio of
the animal:human body weight to adjust for species differences in basal
metabolic rate (Mantel and Schnelderman, 1975). The result is then
multiplied by 70 kg, the reference human body weight, to express the human
equivalent dose as mg/kg for a 70 kg human.
When sufficient data are available, an adverse effects boundary (solid
line) is drawn by identifying the lowest adverse effect dose or concen-
tration at the shortest duration of exposure at which an adverse effect
occurred. From this starting point, an infinite line is extended upward,
parallel to the dose axis. The starting point is then connected to the
lowest adverse effect dose or concentration at the next longer duration of
exposure that has an adverse effect dose or concentration equal to or lower
than the previous one. This process is continued to the lowest adverse
effect dose or concentration. From this point, a line parallel to the
duration axis is extended infinitely to the right. The adverse effects
region lies above the adverse effects boundary.
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(Oral Exposure)
A AEL
F • FEL
L • LOAEL
FIGURE c-i
Dose/Duration-Response Graph for Oral Exposure
to Propthnic Acid
108800
Propionic acid
I I T 1
-I— i i i i
A
t
V
F5
4 I i I ii;
R4
p.’
C
R2
R3
U
I
V
z
I
LI
ieeo
8.001
LI
HUNRM EQUIU DURRHOH (fraction lifespan)
1
0452d
-54-
08/20/90
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Using the envelope method, when sufficient data are available, a no
adverse effects boundary (dashed line) is drawn starting with the point
representing the highest no-adverse-effects dose or concentration. From
this point, a line parallel to the duration axis is extended to the dose or
concentration axis. The starting point is then connected to the next equal
or lower no adverse effect dose or concentration at a longer duration of
exposure. When this process can no longer be continued, a line parallel to
the dose or concentration axis is dropped to the duration axis. The no
adverse effects region lies below the no adverse effects boundary. At both
ends of the graph between the adverse effects and no adverse effects
boundaries are regions of ambiguity. The area (if any) resulting from the
intersections of the adverse effects and no adverse effects boundaries is
defined as the region of contradiction.
In the censored data method, when sufficient data are available, all no
adverse effect points located in the region of contradiction are dropped
from consideration and the no adverse effects boundary is redrawn so that it
does not intersect the adverse effects boundary and no region of contradic-
tion is generated. This method results in the most conservative definition
of the no adverse effects region.
Figure C-l illustrates the paucity of data for oral exposure to
propionic acid. Data suitable for presentation in Figure C—l are limited to
an LD 50 value in rats (Rec. #5, Section C.2.2.), a subchronic LOAEL for
forestomach hyperplasia and hyperkeratosis in rats (Rec. #1, Section C.2.2.)
and AEL 5 for hyperplasia and other forestomach mucosal alterations in rats
(Recs. #2, 3 and 4, Section C.2.2.). These data are insufficient to define
adverse effects or no adverse effects boundaries. Chronic toxicity data
reported by Griem (1985) are not summarized in Section C.2.2 or plotted in
0452d _55 - 08/20/90
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Figure c-i because treatment durations are inadequately reported and the
data are preliminary. The LOAEL (Rec. #1, Section C.2.2.) is used as the
basis For the subchronic and chronic oral RfDs For proplonic acid.
C .2. DATA USED TO GENERA IE THE DOSE/DURATION—RESPONSE GRAPH
C.2.l. Inhalation Exposure. Data were insufficIent for generating dose/
duration-response graphs for inhalation exposure to propionic acid.
C.2.2. Oral Exposure.
chemical Name: Propionic acid
CAS Number: 19-09-4
Document Title: Health and Environmental Effects Document on Propionic Acid
Document Number: pending
Document Date: pending
Document Type: HEED
RECORD #1: Species: Rats Body Weight: 0.35 kg
Sex: Male Reported Dose: 0.4%
Effect: IOAE I Converted Dose: 200 mg/kg/day
Route: Food Exposure Period: 20 weeks
Duration Observation: 20 weeks
Number Exposed: 10
Number Responses: 10
Type of Effect: HYPRP
Site of Effect: 61 1R
Severity Effect: 4
Co n i T ient: Concentrations tested: 0.4 and 4%. Wistar rats were used.
Hyperplasia and hyperkeratosis in the forestomach. Effects
on 11 other tissues not reported. See next record for effects
at the higher dose.
Citation: Griem, 1985
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