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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.
11
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EXECUTIVE SUMMARY
r
Propylene glycol (CAS Registry number 57-55-6) Is a colorless, viscous,
hygroscopic liquid at room temperature (Brown et al., 1980). It Is mlscible
In many organic solvents and 1n water. The compound 1s expected to undergo
reactions typical of monohydrlc alcohols forming esters, acetals, ethers and
similar products (Brown et al., 1980). Propylene glycol 1s produced commer-
cially by the hydrolysis of propylene oxide (Brown et al., 1980). Current
domestic manufacturers are as follows (CMR, 1987): Arco 1n Bayport, TX, Dow
Chemical 1n Freeport and Plaquemlne, TX, Ol1n In Brandenburg, KY, and Union
Carbide In South Charleston, WV. In addition, Texaco has a plant on
stand-by 1n Port Neches, TX (CMR, 1987). During 1985, 499.529 million
pounds of propylene glycol were produced 1n the United States (USITC, 1986).
The use pattern for this compound 1s as follows (CMR, 1987): unsaturated
polyester resins, 46X; exports, 18%; Pharmaceuticals and food, 8%; semi-
moist pet food, 7X; humectant for tobacco, 5X; po\'mer1c plastldzer, 5%;
paint and coatings, 4%; functional fluids, 3%; cellophane, 2%; miscella-
neous, 2%.
If released to air, propylene glycol 1s expected to exist almost
entirely 1n the vapor phase. Reaction with photochemkally generated
hydroxyl radicals In the atmosphere 1s expected to be an Important fate
process. The half-life for this reaction has been estimated to be 20 hours
(see Section 2.1.1.). The complete water solubility of propylene glycol
(Rlddlck et al., 1986) suggests that significant amounts of this compound
may also be removed from the atmosphere by wet deposition. Propylene glycol
Is not susceptible to reaction with ozone (U.S. EPA, 1987). If released to
water, propylene glycol Is expected to blodegrade readily under both aerobic
1v
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and anaerobic conditions. Results of several biodegradatlon screening
studies suggest that the biodegradatlon half-life under aerobic conditions
typically ranges between 1 and 4 days, and the biodegradatlon half-life
under anaerobic conditions typically ranges between 3 and 5 days. Lactalde-
hyde, pyruvate and acetol have been Identified as Intermediates in the
metabolism of propylene glycol under aerobic conditions (Kersters and DeLey,
1963; Miller, 1979; Wllletts, 1979). Chemical hydrolysis, oxidation by
reaction with hydroxyl radicals, bloaccumulatlon In aquatic organisms,
adsorption to suspended solids and sediments and volatilization are not
expected to be Important fate processes. If released to soil, propylene
glycol 1s predicted to blodegrade readily under both aerobic and anaerobic
conditions. The biodegradatlon half-life in soil 1s expected to be com-
parable with or slightly lower than that In water. Rapid blodegradation Is
expected to limit the extent of leaching through soil. The relatively high
vapor pressure of propylene glycol suggests that volatilization from dry
soil surfaces may occur. Volatilization from moist soil Is predicted to be
Insignificant.
Propylene glycol could potentially be released to the environment In the
effluent and, to a lesser extent, emissions from manufacturing and use
facilities, and as a result of spillage or Improper disposal of consumer and
Industrial products that contain this compound. Propylene glycol may also
form 1n the environment as a metabolite of propylene glycol dlnltrate, a
military propellant that may be found 1n the wastewater streams from
munitions plants and loading operations (Kaplan et al., 1982). Considering
the extensive use of propylene glycol In a wide variety of consumer products
such as food, Pharmaceuticals, cosmetics and functional fluids, the most
probable routes of human exposure are likely to be Ingestlon and dermal
-------
contact. The National Occupational Hazard Survey estimates that >2.5
million people may be exposed to propylene glycol in occupational settings
(NIOSH, 1984). During August 1974, propylene glycol was qualitatively
identified In the effluent from a chemical manufacturing plant In Memphis,
TN (Shackelford and Keith, 1976). Propylene glycol has been detected in
emissions from an industrial source (Graedel, 1978).
The few available data Indicate that propylene glycol is relatively
nontoxlc to aquatic biota. The lowest concentration reported to have an
effect was 3850 mg/i, which slightly increased the ventilation rate of
adult rainbow trout, Salmo gairdnerl (Majewskl et a!., 1978). Reported
lethal concentrations were all in the g/l range.
Data on mice (Salter et al., 1935) and dogs (Lehman and Newman, 1937)
suggest that small oral doses of propylene glycol are absorbed rapidly and
virtually completely. Rapid and extensive gastrointestinal absorption 1s
also suggested for humans (Yu et al., 1985), but the rate of absorption In
dogs and humans appears to become rate-saturated at higher doses (Hanzllk et
al., 1939). In humans, estimated apparent volume of distribution studies
suggest that propylene glycol distributes throughout the body water com-
partment.
Propylene glycol appears to undergo blotransformatlon primarily by
oxldative pathways to lactic acid and pyruvlc acid, which can enter the tri-
carboxylic add cycle, contributing to the body's energy sources and even-
tually become degraded to 1- or 2-carbon units that may become assimilated
Into the endogenous carbon pool. Excretion of unchanged compound appears to
be primarily through the urine (Hanzllk et al., 1939). Plasma elimination
half-time In humans is -3.8-4.1 hours, with total body clearance estimated
at 0.08-0.1 l/hour/kg when normalized for body weight (Yu et al., 1985).
vi
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Gaunt et al. (1972) evaluated the carclnogenlcHy of propylene glycol in
male and female Charles RWer CO rats fed 0, 6250, 12,500, 25,000 or 50,000
ppm of the compound 1n the diet for 2 years. In both treated and control
groups, there was a high but similar Incidence of mammary fIbroadenomas,
pituitary adenomas ar>d subcutaneous fIbrosarcomas. Mammary fIbroadenomas
have been shown to occur spontaneously In a high proportion of 2-year-old
rats of the Charles River CD strain. No carcinogenic effects could be
attributed to propylene glycol when administered 1n the diet of rats at
doses <50,000 ppm for 2 years.
Subchronlc and chronic studies suggest that propylene glycol has a very
low order of toxldty. Gaunt et al. (1972) evaluated several parameters of
toxldty 1n rats fed diets containing <50,000 ppm for 2 years. There were
no statistically significant differences between treated and control rats In
cumulative death rate, body weight gain, food consumption, hematology,
urinary cell excretion or renal clearance. A wide range of hlstologlcal
abnormalities was reported In the kidney, liver and lung, but the Incidence
was similar In both test and control groups. These changes were also
consistent with those expected 1n aging rats.
Well et al. (1971) reported no effects on the parameters of toxldty
evaluated 1n male and female beagle dogs receiving 2 g/kg bw/day propylene
glycol 1n the diet for 2 years. Dogs receiving 5 g/kg/day for 2 years had
lower total erythrocyte counts, lower hemoglobin and hematocrlt values,
Increased total blUrubln, and Increases 1n anlsocytosls, polkllocytes and
retlculocytes. These changes were Indicative of some erythrocyte destruc-
tion with replacement from the bone marrow. There was no evidence of damage
to bone marrow or spleen, and no hlstopathologlcal or biochemical evidence
of hepatic damage was observed at any dose.
-------
Morris et al. (1942) reported slight hepatic damage In albino rats fed
2.45 or 4.9% propylene glycol for 2 years. No other details were provided.
Okumura et al. (1986) reported some differences In hematologlcal and serum
biochemical effects In F-344 rats fed 2.5 or 5% propylene glycol 1n the diet
for 2 years; however, the effects may not have differed significantly from
the normal state.
Subchronlc administration of propylene glycol at 1-10% 1n drinking water
caused no gross or microscopic lesions In rats (Kesten et al., 1939;
Seldenfeld and Hanzllk, 1932; Weatherby and Haag, 1938). Administration to
rats for 20 weeks at >40% of the diet resulted 1n deaths, at >30% resulted
In growth depression, and at >10% resulted 1n kidney lesions. There were no
effects at <6% (Guerrant et al., 1947).
Continuous Inhalation exposure of rats to 170-350 mg/m3 for 3-18
months had no effects on appearance, growth, reproduction or hlstopatho-
loglcal appearance of tissues 1n rats (Robertson et al., 1947).
Acute + -»x1c1ty data Indicate that propylene glycol has a low order of
toxlclty, with oral LD5Q values ranging from 21.8-45.9 g/kg In rats and
22.8-31.87 In mice (Laug et al., 1939; Weatherby and Haag, 1938; Smyth et
al., 1941; Bornmann, 1955).
Propylene glycol was found to be nonmutagenlc when tested 1n Salmonella
typhlmurlum TA1535, TA1537 and TA1538 and Saccharomyces cerevlslae 04, with
or without metabolic activation (LHton Blonetlcs Inc., 1976). Results of
cytogenetlc testing in vivo 1n the bone marrow of rats and _1_n vitro with
human embryonic lung culture cells WI-38 were negative. Propylene glycol
was also nonmutagenlc In the dominant lethal assay In rats (Utton Blonetlcs
Inc., 1974). In a host-mediated assay using ICR mice, negative results were
obtained with Salmonella TA1530, and questionably positive results were
-------
obtained at the high dose only in Salmonella strain G 46. The results with
the Saccharomyces 03 tester strain appeared weakly mutagenic in the host-
mediated assay, but were difficult to Interpret because propylene glycol may
have been selectively toxic for mutants of this organism (LHton Blonetlcs
Inc., 1974).
Food and Drug Research Labs. (1973) evaluated propylene glycol for
teratogenlclty In mice, rats, hamsters and rabbits. No adverse maternal or
fetal effects were attributed to propylene glycol administration In any
species. Male and female white rats exposed continuously to a super-
saturated atmosphere of propylene glycol <18 months bred as regularly and
produced litters as large as did the control animals (Robertson et a!.,
1947). No differences In appearance or weight gain between the offspring of
treated and control groups were reported. However, maternal toxldty was
not achieved In any of these experiments and there Is concern about adequacy
of dose-response range at upper limits.
Propylene glycol 1s classified In EPA Group D, not classifiable as to
carclnogenlclty to humans. An RfD of 2 mg/kg/day or 116 mg/day for a human
with an Inhalation rate of 20 mVday for subchronlc or chronic Inhalation
exposure to propylene glycol was based on no effects In an 18-month study In
which rats were exposed continuously to 170-350 mg/m3 (mean: 260 mg/m3)
(Robertson et al., 1947). An RfO of 0.03 g/kg/day or 2 g/day for a 70 kg
human for subchronlc oral exposure to propylene glycol 1s based on a NOEL of
6X of the diet (3 g/kg/day) 1n a 20-week dietary study using rats (Guerrant
et al., 1947). Kidney lesions were observed at 10/4 of the diet, the next
higher concentration. The chronic oral RfO, 0.02 g/kg/day or 1 g/day for a
70 kg human was derived from the NOEL of 2.1 g/kg/day In female rats fed a
1x
-------
diet containing 50,000 ppm for 2 years(Gaunt et al., 1972). An RQ of 1000
was based on the observatlan of kidney lesions in rats fed a diet containing
10% (5 g/kg/day) for 20 weeks (Guerrant et al., 1947).
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Reaction with Hydroxyl Radicals 5
2.1.2. Reaction with Ozone 5
2.1.3. Photolysis 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. M1crob1al Degradation 6
2.2.4. Bloconcentratlon 7
2.2.5. Adsorption 7
2.2.6. Volatilization 7
2.3. SOIL 8
2.3.1. Hydrolysis 8
2.3.2. M1crob1al Degradation 8
2.3.3. Adsorption 8
2.3.4. Volatilization 9
2.4. SUMMARY 9
3. EXPOSURE 11
4. AQUATIC TOXICITY 12
4.1. ACUTE TOXICITY 12
4.2. CHRONIC EFFECTS 12
4.3. PLANT EFFECTS 12
4.4. SUMMARY 14
5. PHARMACOKINETCS 15
5.1. ABSORPTION 15
5.2. DISTRIBUTION 16
5.3. METABOLISM 17
5.4. EXCRETION 17
5.5. SUMMARY 19
x1
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TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 21
6.1. SYSTEMIC TOXICITY 21
6.1.1. Inhalation Exposures 21
6.1.2. Oral Exposures 22
6.1.3. Other Relevant Information 26
6.2. CARCINOGENICITY 28
6.2.1. Inhalation 28
6.2.2. Oral 28
6.2.3. Other Relevant Information 29
6.3. MUTAGENICITY 29
6.4. TERATOGENICITY 32
6.5. OTHER REPRODUCTIVE EFFECTS 33
6.6. SUMMARY 33
7. EXISTING GUIDELINES AND STANDARDS 37
7.1. HUMAN 37
7.2. AQUATIC 37
8. RISK ASSESSMENT 38
8.1. CARCINOGENICITY 38
8.1.1. Inhalation 38
8.1.2. Oral 38
8.1.3. Other Routes 38
8.1.4. Weight of Evidence 39
8.1.5. Quantitative Risk Estimates 39
8.2. SYSTEMIC TOXICITY 39
8.2.1. Inhalation Exposure 39
8.2.2. Oral Exposure 40
9. REPORTABLE QUANTITIES 44
9.1. BASED ON SYSTEMIC TOXICITY 44
9.2. BASED ON CARCINOGENICITY 44
10. REFERENCES 48
APPENDIX A: LITERATURE SEARCHED 60
APPENDIX B: SUMMARY TABLE FOR PROPYLENE GLYCOL 63
xll
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LIST OF TABLES
No. , TUIe Page
1-1 Current Domestic Producers, of Propylene Glycol 3
4-1 Acute ToxIcHy of Propylene Glycol to Aquatic Organisms ... 13
6-1 Acute Effects of Propylene Glycol 27
6-2 Mutagenldty Testing of Propylene Glycol 30
9-1 Oral ToxIcHy Summary for Propylene Glycol 45
9-2 Oral Composite Scores for Propylene Glycol 46
9-3 Propylene Glycol: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 47
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LIST OF ABBREVIATIONS
t-
BCF B1oconcentrat1on factor
BOOT Biochemical oxygen demand, theoretical
bw Body weight
CS Composite score
DNA DeoxyMbonuclelc add
ECso Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Koc Son soprtlon coefficient standardized
with respect to soil organic water
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
1050 Dose lethal to 5054 of recipients
MED Minimum effective dose
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
RVj Dose-rating value
RVe Effect-rating value
x1v
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUflBER
Propylene glycol is also known as 1,2-propanedlol, 1,2-dlhydroxypropane,
methylethylene glycol and methyl glycol (SANSS, 1987). The structure,
empirical formula, molecular weight and CAS Registry number are as follows:
CH3
I
HO-CH-CH2-OH
Empirical formula: C,jHg02
Molecular weight: 76.1
CAS Registry number: 57-55-6
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Propylene glycol Is a colorless, viscous, hygroscopic liquid at room
temperature. It 1s practically odorless and has a slight characteristic
taste (Brown et al., 1980). Propylene glycol 1s expected to undergo
chemical -reactions typical of monohydrlc alcohols form'ng esters, acetals,
ethers and similar products (Brown et al., 1980). Glycol Is mlsclble with
alcohols, acetone, chloroform and many other organic solvents (Hawley, 1981;
Wlndholz, 1983). Relevant physical properties are as follows:
Melting point, °C: -60 Brown et al., 1980
Boiling point, eC: 187.3 Brown et al., 1980
Vapor pressure
at 25°C: 0.22 mm Hg Miller, 1979
at 20°C: 0.08 mm Hg Weber et al., 1981
Water solubility: complete R1dd1ck et al., 1986
Log Kow: -0.92 Hansch and Leo, 1985
Specific gravity: 1.038 (20/20°C) Brown et al., 1980
0073d -1- 06/26/87
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RefractWeMndex, njj°: 1.4326 Brown et a"!., 1980
Flashpoint: - 101°C Brown et a!., 1980
(Tag closed cup)
Conversion factors (25°C): 1 mg/m3 = 0.322 ppm Verschueren, 1983
1 ppm = 3.11 mg/m3
1.3. PRODUCTION DATA
Propylene glycol 1s prepared by the hydrolysis of propylene oxide under
pressure and at high temperature without a catalyst (Brown et al., 1980).
The X yield of propylene glycol 1s controlled by the mo! ratio of water to
propylene oxide. Higher hydrolysis ratios Increase the yield of propylene
glycol but also result 1n Increased purification costs (Brown et al. 1980).
Current domestic manufacturers are listed In Table 1-1. Texaco has a 50
million pounds/year propylene glycol facility on stand-by In Porte Neches,
TX. Also, Texaco markets material produced by Arco through a toll arrange-
ment (CMR, 1987). During 1985, 499.5 million pounds of propylene glycol was
produced 1n the United States (USITC, 1986).
1.4. USE DATA
The use pattern for propylene glycol Is as follows (CMR, 1987): unsatu-
rated polyester resins, 46%; exports, 18%; Pharmaceuticals and food, 8%;
sem1-mo1st pet food, 7%; humectant for tobacco, 5X; polymeric plastldzer,
5%; paint and coatings, 4%; functional fluids, 3%; cellophane, 2%; miscella-
neous, 2%. In the food Industry propylene glycol 1s used as a solvent,
humectant and preservative. It Is also used In the manufacture of products
that come Into contact with food such as cork seals, bottle cap linings and
plastldzers for food wraps, as a solvent for flavoring materials, extract
preparations and food colors, and as a lubricant for food machinery (Brown
et al., 1980; Miller, 1979). This compound Is also used as a softening
agent, spreader, emollient, Intermediate, drug vehicle and preservative 1n
0073d -2- 11/17/87
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TABLE 1-1
Current Domestic Producers of Propylene Glycol3
Company
Arco Chemical
Dow Chemical
Dow Chemical
Ol1n Corp.
Union Carbide
Location
Bayport, TX
Freeport, TX
Plaquemlne, LA
Brandenburg, KY
South Charleston, WV
Annual Capac1tyb
(millions of pounds)
250
250
150
70
100
aSource: CMR, 1987
bCapacH1es at some locations can be supplemented by using hydratlon
equipment normally used for ethylene glycol production (CMR, 1987; SRI,
1986).
0073d
-3-
06/26/87
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the preparation of cosmetics and Pharmaceuticals (Brown et a"!., 1980). As a
functional fluid, 1t is used In brake and hydraulic fluids as a solvent,
lubricant and coupling agent (MUler, 1979). Aqueous solutions of propylene
glycol are used effectively as antifreeze mixtures and are preferred in
refrigeration units found in breweries, dairies and packing houses (Brown et
al., 1980).
1.5. SUMMARY
Propylene glycol (CAS Registry number 57-55-6) Is a colorless, viscous,
hygroscopic liquid at room temperature (Brown et al., 1980). It 1s mlsdble
In many organic solvents and In water. The compound is expected to undergo
reactions typical of monohydrlc alcohols forming esters, acetals, ethers and
similar products (Brown et al., 1980). Propylene glycol 1s produced commer-
cially by the hydrolysis of propylene oxide (Brown et al., 1980). Current
domestic manufacturer are as follows (CMR, 1987): Arco 1n Bayport, TX, Dow
Chemical In Freeport and Plaquemlne, TX, OUn 1n Brandenburg, KY, and Union
Carbide 1n South Charleston, WV. In addition, Texaco has a plant on
stand-by 1n Port Neches, TX (CMR, 1987). During 1985, 499.529 million
pounds of propylene glycol was produced In the United States (USITC, 1986).
The use pattern for this compound 1s as follows (CMR, 1987): unsaturated
polyester resins, 4654; exports, 18%; Pharmaceuticals and food, 8%; semi-
moist pet food, 754; humectant for tobacco, 554; polymeric plastldzer, 5%;
paint and coatings, 454; functional fluids, 3%; cellophane, 2)4; miscella-
neous, 2%.
0073d -4- 09/29/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2,1. AIR
Based on the vapor pressure of propylene glycol (see Section 1.2.), this
compound Is expected to exist almost entirely 1n the vapor phase In the
atmosphere (Elsenrekh et a!., 1981).
2.1.1. Reaction with Hydroxyl Radicals. The rate constant for the reac-
tion of propylene glycol with photochemlcally generated hydroxyl radicals 1n
the atmosphere has been measured to be (12^1)x!0"12 cm3-molecule-sec at
22°C (Atkinson, 1985). Assuming a typical ambient hydroxyl radical concen-
tration of 8.0xlOs molecules/cm3 (U.S. EPA, 1987), the hydroxyl reaction
half-life has been estimated to be 20 hours. Thus, the reaction of
propylene glycol with hydroxyl radicals 1n the atmosphere Is expected to be
an Important fate process.
2.1.2. Reaction with Ozone. Propylene glycol 1s not susceptible to
reaction with ozone In the atmosphere (U.S. EPA, 1987).
2.1.3. Photolysis. Because of the complete water solubility of propylene
glycol (R1dd1ck et al., 1986), significant amounts of this compound may be
removed from the atmosphere by wet deposition.
2.2. WATER
2.2.1. Hydrolysis. Propylene glycol 1s expected to be resistant to
chemical hydrolysis under environmental conditions (Lyman et al., 1982).
2.2.2. Oxidation. The half-life for propylene glycol reacting with
photochemlcally generated hydroxyl has been determined to range from 1.3-2.3
years, based on measured reaction rate constants ranging between 0.94xl09
and 1.68xl09 i/mol-sec (Anbar and Neta, 1967; Dorfman and Adams, 1973) and
an ambient hydroxyl radical concentration of 10~17 mol/i In natural
waters (Mill et al., 1980). Pertinent data regarding the reaction of
0073d -5- 09/29/87
-------
propylene glycol with singlet oxygen or alky! peroxy radicals could not be
located In the available literature as dted In Appendix A.
2.2.3. M1crob1al Degradation. Propylene glycol was readily degradable In
blodegradatlon screening studies using activated sludge, sewage seed and
wastewater Inoculum (Price et al., 1974; Bridle et a!., 1979a; KapJ^in et
al., 1982; Lamb and Jenkins, 1952; Takemoto et al., 1981; Grunwald et al.,
1984). According to Price et al. (1974), the typical blodegradatlon half-
life for 3-10 mg/i propylene glycol In unaccllmated freshwater samples
seeded with settled domestic wastewater Is ~4 days. When Incubated In
mineralized dilution water seeded with settled domestic sewage, 2.5 ppm
propylene glycol contained oxygen equivalent to 2.2, 56.7, 77.8 and 80% of
BOOT after 5, 10, 20 and 50 days, respectively (Lamb and Jenkins, 1952).
When Incubated In a nutrient broth seeded with activated sludge, 100 ppm
propylene glycol underwent 50% loss In -1 day (Kaplan et al., 1982). In
synthetic seawater samples Inoculated with settled domestic wastewater,
propyU.ie glycol consumed oxygen equivalent to 55, 72, 73 and 83% BOOT after
5, 10, 15 and 20 days of Incubation, respectively (Price et al., 1974).
Under strongly aerobic conditions, metabolism of propylene glycol by a
\
FlavobacteMum sp. proceeded by catabollsm to lactaldehyde followed by
metabolizing to pyruvate and then oxidation to CO- (Wnietts, 1979).
Resting cells of both Gluconobacter oxydans (suboxydans) and the yeast,
asenula mlso IfO 0146. oxidized propylene glycol to acetol (hydroxy-2-propa-
none) (Kersters and OeLey, 1963; MUler, 1979). Propylene glycol Is also
amenable to blodegradatlon under anaerobic conditions (Speece, 1983; Chou et
al., 1979). The half-life for 100 ppm propylene glycol Incubated under
anaerobic conditions In a nutrient broth containing digester sludge and a
basal salt medium was -3-5 days (Kaplan et al., 1982).
0073d -6- 06/26/87
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2.2.4. Bloaccumulatlon. Experimental data regarding bloaccumulation of
propylene. glycol In aquatic organisms could not be located In the available
literature as cited 1n Appendix A.
A BCF of <1 was estimated for propylene glycol using a measured log
KQW of -0.92 (Hansch and Leo, 1985) and the following linear regression
equation: log BCF = 0.76 log KQW - 0.23 (Lyman et a!., 1982). This BCF
value and the complete water solubility of propylene glycol Indicate that
bloaccumulatlon 1n aquatic organisms should not be significant.
2.2.5. Adsorption. Experimental data regarding adsorption of propylene
glycol to suspended solids and sediments In water could not be located In
the available literature as cited In Appendix A. Considering the complete
water solubility of this compound and Its estimated K value of 8
(Section 2.3.3.), physical adsorption to suspended solids and sedlmeRts Is
not expected to be significant.
2.2.6. Volatilization. Pertinent data regarding the volatilization of
propylene glycol from-water could not be located 1n the available IH^rature
as dted In Appendix A. Henry's Law constant for ethylene glycol has been
measured to be 5.9x10"* atm-mVmol at 25°C (H1ne and Mookerjee, 1975).
Considering the structural similarity of ethylene and propylene glycol,
Henry's Law constant for propylene glycol Is expected to be on the same
order of magnitude or slightly higher (Brown et al., 1980). Volatilization
can be considered unimportant as an Intermedia transfer mechanism for
organic compounds with a Henry's Law constant <3xlO~7 atm-mVmol (Lyman
et al., 1982). Therefore, volatilization of propylene glycol from water
surfaces 1s not expected to be significant.
0073d -7- 06/26/87
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2.3. SOIL
2.3.1. Hydrolysis. Propylene glycol Is not expected to undergo hydroly-
sis In the environment because 1t contains no hydrolyzable functional groups
(Lyman et al., 1982).
2.3.2. M1crob1al Degradation. Limited data regarding the blodegradatlon
of propylene glycol In soils were located 1n the available literature as
cited 1n Appendix A. A variety of microorganisms capable of degrading
propylene glycol under aerobic conditions has been Isolated from soil,
Including Alcallqenes strains MC11 and TE8, Corynebacterlum OEH8 and a
bacterium strain, SA-1 (Harada and Nagashlma, 1975; Tanaka et al., 1975;
Flncher and Payne, 1962). Acetol, lactaldehyde, lactic acid and pyruvlc
add have been produced as metabolites of propylene glycol by the bacterium
strain, SA-1 (Tanaka et al., 1975). Based on results from blodegradatlon
studies In aqueous media (see Section 2.2.3.), blodegradatlon of propylene
glycol 1n soil under aerobic and anaerobic conditions 1s an Important
removal mechanism. The blodegradatlon half-life In so1l_ ^s expected to be
comparable with or slightly lower than that In water.
2.3.3. Adsorption. The complete water solubility and the relatively low
log K of propylene glycol suggest that H would leach readily through
soil. The soil adsorption coefficient for this compound has been estimated
using the following linear regression equation (Lyman et al., 1982): log
K » 0.544 log K * 1.377, where the log K value 1s -0.92 (Hansch
oc ow ow
and Leo, 1985). A K value of 8 also suggests that this compound would
to be very highly mobile 1n soil (Swann et al., 1983); however, blodegrada-
tlon should limit the extent of leaching Into groundwater.
0073d -8- 09/29/87
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2.3.4. Volatilization. Pertinent data regarding volatilization of
propylene glycol from soil trould not be located In the available literature
as cited 1n Appendix A. The vapor .pressure of propylene glycol [0.22 mm Hg
at 25°C (Miller, 1979)] suggests that volatilization from dry soil surfaces
may occur. Evaporation from moist soil surfaces 1s expected to be Insignif-
icant because this compound should blodegrade fairly rapidly, may have a
tendency to leach through soil and does not appear to evaporate signifi-
cantly from water.
2.4. SUMMARY
If released to air, propylene glycol 1s expected to exist almost
entirely 1n the vapor phase. Reaction with photochemlcally generated
hydroxyl radicals In the atmosphere Is expected to be an Important fate
process. The half-life for this reaction has been estimated to be 20 hours
(see Section 2.1.1.). The complete water solubility of propylene glycol
(R1dd1ck et al., 1986) suggests that significant amounts of this compound
may also be removed from the atmosphere by wet deposition. Propylene glycol
Is not susceptible to reaction with ozone (U.S. EPA, 1987). If released to
water, propylene glycol 1s expected to blodegrade readily under both aerobic
and anaerobic conditions. Results of several blodegradatlon screening
studies suggest that the blodegradatlon half-life under aerobic conditions
typically ranges between 1 and 4 days, and the blodegradatlon half-life
under anaerobic conditions typically ranges between 3 and 5 days. Lactalde-
hyde, pyruvate and acetol have been Identified as Intermediates 1n the
metabolism of propylene glycol under aerobic conditions (Kersters and OeLey,
1963; MUler, 1979; Hllletts, 1979). Chemical hydrolysis, oxidation by
reaction with hydroxyl radicals, bloaccumulatlon In aquatic organisms,
adsorption to suspended solids and sediments and volatilization are not
0073d -9- 10/02/87
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expected to be Important fate processes. If released to soil, propylene
glycol 1s predicted to blcrdegrade readily under both aerobic and anaerobic
conditions. The blodegradatlon half-life 1n soil 1s expected to be
comparable with or slightly lower than that In water. Rapid blodegradatlon
is expected to limit the extent of leaching through soil. The relatively
high vapor pressure of propylene glycol suggests that volatilization from
dry soil surfaces may occur. Volatilization from moist soil 1s predicted to
be Insignificant.
0073d -10- 09/29/87
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3. EXPOSURE
r
Propylene glycol could potentially be released to the environment 1n the
effluent and, to a lesser extent, emissions from manufacturing and use
facilities, and as a result of spillage or Improper disposal of consumer and
Industrial products that contain this compound. Propylene glycol may also
form In the environment as a metabolite of propylene glycol dlnHrate, a
military propellant that may be found 1n the wastewater streams from
munitions plants and loading operations (Kaplan et al., 1982). Considering
the extensive use of propylene glycol 1n a wide variety of consumer products
such as food, Pharmaceuticals, cosmetics and functional fluids, the most
probable routes of human exposure are likely to be Ingestlon and dermal
contact. The National Occupational Hazard Survey estimates that >2.5
million people may be exposed to propylene glycol In occupational settings
(NIOSH* 1984). During August 1974, propylene glycol was qualitatively
Identified In the effluent frir; a chemical manufacturing plant 1n Memphis,
TN (Shackelford and Keith, 1976). Propylene glycol has been detected 1n
emissions from an Industrial source (Graedel, 1978).
0073d -11- 09/29/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The available Information regarding the toxkHy of propylene glycol to
aquatic organisms Is presented In Table 4-1. The few available data
Indicate that propylene glycol Is relatively nontoxlc to aquatic biota. The
lowest concentration reported to have an effect was 3850 mg/l, which
slightly Increased the ventilation rate of adult rainbow trout, Sal mo galrd-
nerl (Majewskl et a!., 1978). Reported lethal concentrations for propylene
glycol were all In the g/l range (see Table 4-1).
Majewskl et al. (1978) compared propylene glycol with ethanol .and
acetone In terms of their toxldty and effect on cardiovascular/respiratory
parameters. They concluded that propylene glycol was the least toxic of the
three and recommended that 1t be used as a solvent for other compounds In
aquatic toxldty studies.
4.2. CHRONIC EFFECTS
Pertinent data regarding the chronic toxldty of propylene glycol to
aquatic organisms could not be located 1n the available literature as dted
1n Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding effects of propylene glycol on aquatic plants
could not be located 1n the available literature as dted In Appendix A.
Tarkpea et al. (1986) reported a 30-m1nute EC5Q of 26,800 mg/l for
Inhibition of luminescence In the Mlcrotox assay with the bacteria. Photo-
bacterium phosphoreum.
0073d ' -12- 06/26/87
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o
o
to
o.
TABLE 4-1
Acute Toxicity of Propylene Glycol to Aquatic Organisms
Species
Concentration Exposure Conditions
(rag/t)
Effect
Reference
FISH
Rainbow trout
Sal mo ijalrdner I
I
CO
Goldfish
Carasslus auratus
50,000
3,850
42.476
>5,000
static, aerated
flowthrough. aerated
static
static, aerated
no mortalIty,
ftngcrlings,
24 hours;
slight (18X)
Increase In
ventilation
rate, adults,
9-24 hours
96-hour LC5Q
24-hour LC5Q
Majewski
et al.. 19/0
Mayer and
Ellersleek, 1906
Bridle et al..
1979h
INVERTEBRATES
Copepod
Nitocra spinlpes
>10.000
static, not aerated
salinity - 0.7X
96-hour
Tarkpea et al.,
1906
CO
-------
4.4. SUMMARY
The few available dat-a Indicate that propylene glycol Is relatively
nontoxlc to aquatic biota. The lowest concentration reported to have an
effect was 3850 mg/l, which slightly Increased the ventilation rate of
adult rainbow trout, Salmo galrdneM (Majewskl et al., 1978). Reported
lethal concentrations were all In the g/l range.
0073d -14- 06/26/87
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5. PHARMACOKINETICS
5.1. ABSORPTION
Absorption of propylene glycol from the gastrointestinal tract appears
to be rapid and virtually complete. Salter et al. (1935) reported that
Intestinal absorption in mice was 77.8% complete In 30 minutes and 93.7%
complete In 5 hours. Small dosages administered to dogs are rapidly and
nearly completely absorbed. Lehman and Newman (1937) administered propylene
glycol at 2 ml/kg bw by stomach tube or Intravenously by Injection and
compared the concentration of propylene glycol 1n the blood at several time
points from 0.5-9 or 10 hours after treatment. The concentration-time
curves obtained from the two routes of administration were nearly Identical;
peak levels of propylene glycol 1n the blood were measured at 0.5 hours.
Oral administration of larger doses (8-12 cc/kg bw) resulted In higher and
later peaks 1n blood concentrations, which suggested that gastrointestinal
absorption Is a saturable process. Low blood levels were obtained after
administration Into the Isolated stomach of the dog, which suggested that
absorption from this organ 1s slight.
Hanzllk et al. (1939) administered propylene glycol at 1 ml/kg bw to
humans and measured the concentration In blood at 0.5-10 hours after treat-
ment. Blood concentrations of propylene glycol reached a maximum 1n 0.5
hour and remained at that level for -4 hours before decreasing, which
suggested that gastrointestinal absorption was delayed but able to keep pace
with elimination. Within 10 hours of Ingestlon, 20-25% of the dose was
excreted unchanged 1n the urine.
In two separate studies, Yu et al. (1985) examined the pharmacoklnetlcs
of propylene glycol 1n humans during multiple oral dosing regimens. In
study I, 16 patients received 20 mi (20.7 g) propylene glycol every 8
0073d -15- 09/29/87
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hours as a solvent In a sodium phenytoln oral solution. In study II, six
additional patients received 40 ml (41.4 g) of propylene glycol every 12
hours in the same oral formulation. Subjects were maintained on the formu-
lation for a minimum of 3 days to allow establishment of steady-state, after
which serial blood sampling was performed at 0, 1, 2, 3, 4, 6 and 8 hours
postdoslng in study I and II; an additional sample was drawn at 12 hours In
study II. In both studies, propylene glycol was found to be absorbed
rapidly, with plasma concentrations peaking within 1 hour after administra-
tion of the dose. Data to analyze the absorption rate of propylene glycol
were insufficient, and the authors suggested that although H is likely that
propylene glycol 1s absorbed completely Into the systemic circulation, no
direct evidence of this was available.
5.2. DISTRIBUTION
Yu et al. (1985) estimated apparent volumes of distribution from the
pharmacoklnetlc study with humans discussed In Section 5.1. The average
apparent volumes of distribution were 0.58 and 0.52 I/kg In study I and
II, respectively, and were not statistically different from one another.
The value of 0.5 l/kg approximates total body water and may Indicate that
propylene glycol distributes uniformly Into total body water without
preferential distribution to specific tissues. Considerable Individual
variation was noted, however, In the plasma concentrations of subjects In
both studies. The Investigators suggested that these differences resulted
from Individual differences In clearance rate and can result In an Increased
accumulation of propylene glycol In Individuals with unusually low clearance
rates.
0073d -16- 09/29/87
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5.3. METABOLISM ..
Ruddlck (1972) reviewed the biochemistry of propylene glycol and Us
metabolism in the body. The metabolic pathways are depicted in Figure 5-1.
Propylene glycol Is oxidized to lactic add or pyruvlc acid by one of two
pathways, depending on whether the substrate Is the free glycol or phos-
phorylated glycol. Free propylene glycol 1s metabolized through lactalde-
hyde, methylglyoxal and lactic add. The phosphorylated glycol 1s metabo-
lized through acetol phosphate, lactaldehyde phosphate, lactyl phosphate and
lactic add. Once pyruvate or lactate 1s formed, energy can be provided by
further oxidation through the tMcarboxyllc add cycle or through the
glycolytlc pathway, the latter contributing to glycogen formation. Other
Information presented 1n the review by Ruddlck (1972) suggests that the
oxidation of propylene glycol 1s not just restricted to the formation of
lactate or pyruvate, but the corresponding deoxyaldehyde, as well as
proplonaldehyde, lactaldehyde and 1- and 2-carbon units that may enter the
endogenous carbon pool. In ruminants, the primary metabolite 1s proplonate,
which 1s formed In the rumen by the mlcroblal population. In the chick,
propylene glycol 1s metabolized by the bacteria In the cecum to proplon-
aldehyde.
5.4. EXCRETION
Hanzllk et al. (1939) reported that 20-25% of an oral dose to humans of
1 mi/kg propylene glycol was excreted unchanged In the urine within 10
hours of Ingestlon. Browning (1965) stated that approximately one-third of
a dose of propylene glycol 1s excreted through the kidneys as a conjugate
with glucuronlc add, and the rest Vs metabolized or excreted unchanged in
the urine.
0073d -17- 09/29/87
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CHaCHOHCHgOH
•cctol
CHCHOHCH(OH)OP0H
3£
CH,CHOHCOOPO,H2
Lactyl pko«phat«
CHjCHOHCOOH
L«ctt< vld
CH,CHOHCHO
CHjCOCHO
HcUyl |lyoK«l
CH,CHOHCOOH
Lactic
CH3COCOOH
,Pyru?ic Kid
FIGURE 5-1
Metabolic Pathways of Propylene Glycol
Source: Rowe and Wolf, 1982
0073d
-18-
06/26/87
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Yu et al. (1985) studied the elimination of propylene glycol In the
plasma of humans given oral doses of 20 ml (20.7 g) every 8 hours (study
I) or 40 mi (41.4 g) every 12 hours (study II) In a steady-state situa-
tion. Plasma concentrations peaked within 1 hour and declined In a mono-
exponential manner. Elimination half-times were -3.8 hours for study I and
4.1 hours for study II. Total body clearance of propylene glycol varied
considerably between Individuals. When normalized for body weight, mean
total body clearance rates of 0.106 and 0.109 l/hour/kg bw were estimated
for subjects 1n study I using steady-state assumptions and nonsteady-state
assumptions, respectively. At the higher doses of study II, mean total body
clearances, normalized for body weight, were -0.079 and 0.086 l/hour/kg
using steady-state and non sleady-state assumptions, respectively.
5.5. SUMMARY
Data on mice (Salter et al., 1935) and dogs (Lehman and Newman, 1937)
suggest that small oral doses of propylene glycol are absorbed rapidly and
virtually completely. Rapid and extensive gastrointestinal absorption Is
also suggested for humans (Yu et al., 1985), but the rate of absorption 1n
dogs and humans appears to become rate-saturated at higher doses (Hanzllk et
al., 1939). In humans, estimated apparent volume of distribution studies
suggest that propylene glycol distributes throughout the body water com-
partment.
Propylene glycol appears to undergo blotransformatlon primarily by
oxldatlve pathways to lactic add and pyruvlc add, which can enter the tr1-
carboxyllc add cycle, contributing to the body's energy sources and even-
tually become degraded to 1- or 2-carbon units that may become assimilated
Into the endogenous carbon pool. Excretion of unchanged compound appears to
0073d -19- 09/29/87
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be primarily through the urine (Hanzllk et al., 1939). Plasma elimination
half-time in humans is -3."8-4.1 hours, with total body clearance estimated
at 0.08-0.1 i/hour/kg when normalized for body weight (Yu et al.. 1985).
0073d -20- 09/29/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY -
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC — Pertinent data regarding the systemic toxlclty
of propylene glycol as a result of subchronk Inhalation exposures could not
be located In the available literature as cited In Appendix A.
6.1.1.2. CHRONIC — A group of twenty, 7-week-old male and female
white rats were exposed continuously to a supersaturated atmosphere
calculated to contain 170-350 mg/m3 propylene glycol vapor for 3-18 months
(Robertson et al., 1947). A control group of 10 rats was maintained.
Weight gain was substantially higher In the treated males than 1n the
controls. Female weight data were not plotted; they varied because of the
birth of young. No difference was noted In the general condition between
the treated or control rats, and the treated rats bred as regularly and
produced Utters as large as did the controls. No differences were noted In
general appearance and weight gain between pups of treated and control
groups. Sacrifices were scheduled at Intervals from 3-18 months, and
urlnalysls and gross and hlsto- logical examinations of the kidneys, liver,
spleen and lung were conducted. Pathological effects related to exposure
were not observed In any of the tissues examined. Some changes occurred In
the cells of the lungs, commonly a perlvascular and perlbronchlal
accumulation of round cells. This change began to appear at the end of 5
months of exposure 1n the treated groups, but occurred with equal frequency
1n both control and test animals.
Robertson et al. (1947) also exposed 29 rhesus monkeys continuously to
propylene glycol for <13 months. One exposure chamber held 15 monkeys and
the other, 14. Concentrations of propylene glycol were -100-220 mg/m3 In
one chamber and 230-350 mg/m3 In the other. A control group of 16
0073d -21- 09/29/87
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unexposed monkeys was maintained. The results In exposed monkeys were
reported without specifying to which concentration they had been exposed.
Mortality and moribund sacrificed claimed 13 exposed and 10 control monkeys,
primarily associated with parasitism or Infection. Weight gains In control
and treated monkeys appeared to be normal except In treated monkeys on
months 5-8 when insufficient food was given. Comparisons between treated
and control monkeys were not possible beyond 5 months because of the small
number of surviving controls. Urine concentrating ability, a measure of
kidney function, microscopic appearance of the urine, blood cell counts and
hemoglobin determinations were similar in treated and control animals.
Discoloration of the facial skin was observed In treated monkeys, which was
attributed to the drying effect of the glycol and disappeared upon removal
from the vapor chambers. Gross appearance on necropsy and histopathologic
appearance of lung, liver, kidney, spleen, mesenterk lymph glands, adrenals
and sometimes stomach, Intestines and testes were not different between
exposed and control monkeys. The Investigators concluded that there were no
adverse effects from exposure to propylene glycol.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC -- Gaunt et al. (1972) conducted a short-term
study, concurrent wHh a long-term study, on groups of 15 male and 15 female
Charles River CD rats. In the short-term study, the rats were fed diets
containing 0 or 50,000 ppm propylene glycol for 15 weeks. No compound-
related effects were reported on hematologlcal Indices, serum and urine
analysis or organ weights. No hlstopathology was performed.
Guerrant et al. (1947) reported a 20-week study in which groups of five
male and five female young growing rats were fed diets containing propylene
glycol at 0, 1, 3, 6, 10, 15, 20, 30, 40, 50 or 60%. At >40% of the diet,
0073d -22- 09/29/87
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mortality occurred within a few days. At >30%, there was a depression In
growth rate. Hemoglobin * determination revealed no adverse effects on
hemoglobin formation. At >10%, the Incidence and severity of pathological
lesions Increased. Lesions of the kidney consisting of degeneration, Inter-
stitial hemorrhage and edema, glomerular nephritis and calcification of the
cortex predominated. No adverse effects were observed at <6% (60,000 ppm).
Hanzllk et al. (1939) provided diets In which propylene glycol was
substituted for 25, 50, 75 or 100% of the carbohydrate (12.1, 24.2, 36.4 or
48.5% of the diet) for up to 24 months to groups of five rats. Retarded
growth was observed at all dietary levels; the first death at 36.4% occurred
at -20 weeks and all rats at 48.5% died In -1 month. In another part of
this study, Increased body weight gain compared with controls was observed
In a group of six rats fed a diet containing 25% less carbohydrate than
controls and intubated with propylene glycol equivalent to 12.8% of the diet
consumed the previous day. The controls consisted of six llttermates, and
treatment continued for 5 months. Van Winkle and Newman (1941) performed a
pair-feeding experiment using two groups of 10 young rats. One group
received a control diet and the other received the same diet but with 25% of
the carbohydrate replaced wHh an equlcalorlc amount of propylene glycol.
After 163 days of feeding, body weights of propylene glycol-treated rats
exceeded those of controls, liver glycogen levels In treated rats were 2-7
times the levels In controls.
Oral administration of 1-10% solutions of propylene glycol 1n the
drinking water of rats for periods of 100-234 days produced no gross or
microscopic evidence of pathologic effects from propylene glycol treatment
(Kesten et al., 1939; Seldenfeld and Hanzllk, 1932; Weatherby and Haag,
1938; Auerbach Associates, 1977).
0073d -23- 09/29/87
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Braun and Cartland (1936) performed a 50-day gavage study in which
groups of one to three rabbits received dosages of 1050, 2100, 3150, 4200 or
8400 mg/kg/day for 50 days. There were no effects on gross appearance at
necropsy. Anorexia and retarded growth occurred at >4200 mg/kg/day.
Van Winkle and Newman (1941) provided drinking water containing 5 or 10%
propylene glycol to groups of four dogs for 5-9 months. Propylene glycol
Intakes were -5.1 and 4.5 ml/kg/day (5.3 and 4.7 g/kg/day) (Informatics
Inc., 1973). Clinical pathology tests and hlstopathologlc examination of
the kidney and liver Indicated no lesions or functional Impairment of these
organs.
6.1.2.2. CHRONIC -- In the long-term portion of the study reported by
Gaunt et al. (1972), 30 male and 30 female Charles River CD rats were fed
diets containing 0, 6250, 12,500, 25,000 or 50,000 ppm propylene glycol for
2 years. The mean dally Intakes of propylene glycol were reported to be 0,
0.2, 0.4, 0.9 and 1.7 g/kg 1n males and 0, 0.3, 0.5, 1.0 and 2.1 g/kg In
females. No statistically significant differences were reported between
treated and control rats In cumulative death rate, body weight gain, food
consumption, hematology, urinary cell excretion or urine concentration
tests. A wide range of nonneoplastlc hlstologkal abnormalities was
observed In the kidneys, liver and lungs; however, the Incidence was similar
in both test and control animals and the changes were consistent with those
expected In aging rats. Therefore, no toxic symptoms were reported 1n rats
fed diets containing <50,000 ppm propylene glycol for 2 years.
Morris et al. (1942) fed groups of six male and four female albino rats
diets containing 0, 2.45 or 4.9% propylene glycol for 24 months. There were
no effects on food consumption, body weight gain or survival. Slight
hepatic damage was reported in a table, but It was not clear at which dose
0073d -24- 06/26/87
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this was found, how many animals were involved or what the nature of the
damage was. The discussion in the text only stated that the group of
animals receiving propylene glycol differed very slightly from the controls.
Well et al. (1971) fed groups of five male and five female beagle dogs
diets that provided dcrsages of 2.0 and 5.0 g/kg bw/day propylene glycol for
2 years. The concentration of proplyene glycol In the diet at the low dose
was -8% and at the high dose, -20%. Controls received diets containing
comparable caloric amounts of dextrose or no treatment. The concentrations
of propylene glycol and dextrose In the diets were adjusted weekly for each
group to approximate the predetermined dosage levels by using the mean body
weights and mean diet consumptions for the group. The dogs were evaluated
for mortality, organ and body weights, hematology, blood chemistry and
urlnalysls. Gross and hlstopathologlcal evaluations were performed on a
comprehensive set of organs and tissues. No effects were observed In any of
the parameters evaluated 1n dogs receiving 2 g/kg/day for 2 years. Dogs
receiving the high dose of propylene glycol had lower hemoglobin and hemato-
crlt values, and the total erythrocyte counts were lower than the controls,
while Increases were seen 1n anlsocytosls, polkllocytes and retlculocytes.
These changes were Indicative of some erythrocyte destruction with replace-
ment from the bone marrow; the changes did not appear to be Irreversible,
and there was no evidence of damage to bone marrow or spleen. An Increase
\r\ total blUrubln values was also reported 1n the dogs receiving the high
dose of propylene glycol. No hlstopathologlcal or biochemical evidence of
hepatic damage was observed at any dose level.
Okumura et al. (1986) reported on the effects of the administration of
0, 2.5 or 5% propylene glycol in the diets of groups of 50 male and 50
female F-344 rats for 2 years. No significant differences were noted in
0073d -25- 09/29/87
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food Intake, growth, appearance or behavior between treated and control
animals. In male rats, the- average erythrocyte and leukocyte counts and the
mean corpuscular hemoglobin concentration values of both treated groups were
significantly elevated compared with controls. In both groups of treated
females, the mean corpuscular volume was significantly elevated. Although
some differences existed 1n the hematology of treated and control groups,
some of the values may not have differed from the normal state and may not
represent compound-related adverse effects. In males, some serum biochemi-
cal data differed from the controls, suggesting slight liver damage, but may
not have differed significantly from the normal state. Apparently, hlsto-
pathologlc examination was not performed.
6.1.3. Other Relevant Information. Acute toxlclty data for propylene
glycol are summarized In Table 6-1; the compound has a low order of
toxkUy. Several Investigators reported that administration of lethal and
sublethal doses of propylene glycol to rats, mice, rabbits, guinea pigs and
dogs resulted In central nervous system depression (Bornmann, 1955; Hlckman,
1965; Laug et al., 1939; Seldenfeld and Hanzllk, 1932; Zarosllnskl et al.,
1971; Braun and Cartland, 1936). Propylene glycol produced lack of muscular
coordination (Hlckman, 1965), loss of equilibrium (Latven and MolHor, 1939;
Laug et al, 1939; Seldenfeld and Hanzllk, 1932), analgesia (Laug et al.,
1939; Braun and Cartland, 1936; Seldenfeld and Hanzllk, 1932), muscle
tremors (Weatherby and Haag, 1938; Braun and Cartland, 1936; Seldenfeld and
Hanzllk, 1932) and occasionally convulsions (Hkkman, 1965; Weatherby and
Haag, 1938). Other effects of acute polslonlng with propylene glycol were
an Increase 1n the respiratory rate .(Braun and Cartland, 1936), depression
of the respiratory rate and heartbeat, hypotension, Irritation of the
digestive tract, hemolysls and diuresis (Al-KhudhalM and Whltwam, 1986;
Bornmann, 1955; Smyth et al., 1941; Seldenfeld and Hanzllk, 1932).
0073d -26- 06/26/87
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TABLE 6-1
Acute Effects of Propylene Glycol
Route Species
Oral rats
rats
rats
rats
rats
rats
rats
rats
mice
mice
mice
guinea pigs
guinea pigs
IntraperHoneal rats
rats
rats
mice
mice
mice
mice
mice
L050
(g/kg)
33.5
21.8
29
26.35
45.9
44.4
25.9
35.8
24.8
22.8
31.87
19.6
18.35
14.7
13.5
13.5
13.5
12.8
9.73
17.2
11.2
Reference
Weatherby and Haag, 1938
Laug et a!., 1939
Thomas et al . , 1949
Smyth et al., 1941
Smyth et al., 1969
Smyth et al., 1970
Bartsch et al., 1976
Union Carbide
Corporation, 1978
Laug et al., 1939
Latven and MolHor, 1939
Bornmann, 1955
Laug et al., 1939
Smyth et al., 1941
Hlckman, 1965
Thomas et al . , 1949
Bartsch et al., 1976
Holman et al., 1979
Holman et al., 1979
Karel et al., 1947
Zarosllnskl et al., 1971
Budden et al., 1978
0073d
-27-
06/26/87
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Pathological changes after acute oral administration of propylene glycol
to rats, mice and guinea* pigs were minimal, producing slight hydropic
degeneration of the kidney, with debris and casts In a few cortical tubules,
slight congestion of the liver and hemorrhaglc areas In the small Intestine
(Laug et al., 1939).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled propylene glycol could not be located In the available literature as
cited 1n Appendix A.
6.2.2. Oral. Gaunt et al. (1972) studied the potential carclnogenldty
of propylene glycol In 30 male and 30 female Charles River CD rats fed 0,
6250, 12,500, 25,000 or 50,000 ppm of the compound In the diet for 2 years.
The authors reported the mean dally Intakes of propylene glycol to be 0,
0.2, 0.4, 0.9 and 1.7 gm/kg/day 1n male rats and 0, 0.3, 0.5, 1.0 and 2.1
g/kg/day 1n females. There were no statistically significant differences
between treated and control rats 1n cumulative death rate, body weight gain,
food consumption, hematology, urinary cell excretion or renal concentration
tests. A wide range of hlstologlcal abnormalities were reported, particu-
larly In the kidneys, liver and lung; however, the Incidence was similar In
both test and control groups. The hlstopathologlcal changes were consistent
with those expected In aging rats. Among both treated and control rats,
there was a high Incidence of mammary Hbroadenomas, pituitary adenomas and
subcutaneous Mbrosarcomas. The authors reported that mammary fIbroadenomas
have been shown to occur spontaneously In a high proportion of 2-year-old
rats of Charles River CD strain. The results of this study Indicate that no
carcinogenic effects could be attributed to propylene glycol when adminis-
tered In the diets of rats at doses <50,000 ppm for 2 years.
0073d -28- 06/26/87
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6.2.3. Other Relevant Information. Several carclnogenkity studies \n
which propylene glycol was administered to rats and mice as a vehicle
control were reviewed by Miller (1979). In these reports, the compound was
Injected subcutaneously or applied topically to the oral mucosa repeatedly
for >8 months. No Increase In tumor incidence was observed.
Stenbach and Shublck (1974) tested the effect on tumor Incidence of
twice weekly applications of 0.02 mi solutions of 10, 50 and 100%
propylene glycol to the shaved skin of groups of 50 female Swiss mice.
Treatment was conducted for the llfespan of the animals and no statistically
significant differences 1n Incidence of skin or other tumors were reported.
Farsund (1978, 1981) reported that subcutaneous Injection of 0.2 ml
propylene glycol to 12 hairless mice, 3 times/week for 3 months, slightly
Increased the proportion of dlplold cells, slightly reduced the proportion
of tetraplold cells and virtually eliminated the octaplold class of cells in
the bladder mucosa. DNA synthesis in the tetraplold cells ceased. The
author stated that the changes observed 1n bladder mucosa cells that were
due to propylene glycol treatment were qualitatively similar to but less
severe than those observed after administration of the bladder carcinogen,
d1butyln1trosam1ne, and the alkylatlng agent, cyclophosphamlde.
6.3. MUTAGENICITY
LHton Blonetlcs, Inc. (1974, 1976) tested propylene glycol for
mutagenlc response 1n a variety of assays. The results are summarized 1n
Table 6-2.
Negative results were obtained when propylene glycol was tested for
genetic activity In a series of Uj. vitro mlcroblal assays with and without
metabolic activation. The indicator organisms used were Salmonella typhl-
murium strains TA1535, TA1537 and TA1538 and Saccharomyces cerevlsiae D4
(Litton Blonetlcs Inc., 1976).
0073d -29- 09/29/87
-------
o
o
-J
OJ
CX
1ABLE 6-2
Nutagenlctty Testing of Propylene Glycol
i
CJ
o
i
Assay
Reverse
mulatton
Nilotic
Reverse
mutation
Nttotlc
recomblnat Ion
Cytogenetlc
chromosome
damage
Chromosome
aburrat Ion
Dominant
lethal
Indicator
Organism
Salmonella
lyujilmur turn
1A1535. TA1537.
1A1638
Saccharuniyces
recombination
S. iyjililniur lun
Gib. 1A1530*
S. cerevlslae
D3
bone marrow
cells
human embryonic
limy cells Ml 38
random-bred
rats
Application
plate
Incorporation
suspension
cerevlslae D4
host-mediated In
1CR Mice: single
dose or S dally
doses (gavaye)
host-mediated In
1CR mice: single
dose or S dally
doses (gavage)
\n vivo male
albino rats
culture
In vivo random-
bred rats
Concentration
or Dose
1.25-5X
1.25-5X
30. 2600 or
SOOO «g/kg
30. 2SOO or
SOOO mg/kg
30. 2500 and
SOOO mg/kg
0.1 to >0.001
Mg/ml
30. 2600 and
SOOO mg/kg
Activating
System
• S-9
iS-9
NA
NA
NA
NA
NA
Hesponse Comments
- NC
- NC
-. •_ weak or questionable
positive result with
Salmonella G46 at high
acute dose only
» results difficult to
Interpret due to low
recoveries of organisms
NC
NC
NC
Reference
Ulton Blonetlcs
Inc.. 19/b
t Itton Blonetlcs
Inc.. 1976
III ton Blunetlcs
Inc.. 1974
llllon Blonetlcs
Inc.. 1974
Mllon Blonellcs
Inc.. 1974
lllton Blonetlcs
Inc.. 1974
Lit Ion Blonellcs
Inc.. 19/4
NA - Not applicable; NC - no comment
U5
-------
Propylene glycol was tested for mutagenic response in a host-mediated
assay using male ICR mice as hosts and Salmonella typhimurlum G46 and TA1530
and Saccharomyces cerevisiae 03 as the Indicator organisms (Litton Bionetics
Inc., 1974). In both an acute and subacute study, the mice received one or
five dally oral doses, respectively, of 30, 2500 or 5000 mg/kg propylene
glycol and then were Inoculated with the Indicator organism. The mice were
sacrificed 3 hours after treatment with the test organism. The results were
negative with Salmonella TA1530, weak or questionably positive at the high
acute dose only with Salmonella G 46 and difficult to Interpret wHh
Saccharomyces D3. The yeast showed Increased recomblnant frequencies at all
dose levels except the acute high dose, which resulted 1n low recomblnant
frequency, which was possibly due to selective killing of the mutants.
Propylene glycol was tested In an hi vivo cytogenetlc assay to assess
chromosomal damage 1n somatic cells (LHton Bionetics Inc., 1974). Groups
of 15 random-bred male albino rats, 10-12 weeks old, received acute doses of
propylene glycol at 30, 2500 or 5000 mg/kg. The animals were sacrificed
after 6, 24 or 48 hours, and bone marrow metaphase chromosomes were
examined. No significant aberrations of the bone marrow metaphase chromo-
somes were reported In propylene glycol treated animals. No significant
aberrations 1n anaphase chromosomes were reported In human embryonic lung
culture cells WI-38 exposed to doses of 0.1, 0.01 or 0.001 yg/ml (LHton
Bionetics Inc., 1974).
In a dominant lethal assay, groups of ten, 10- to 12-week-old
random-bred male rats were administered either one dose or one dose each day
for 5 days of 30, 2500 or 5000 mg/kg propylene glycol (LUton Bionetics
Inc., 1974). The males were subsequently mated to two females/week for 7-8
0073d -31- 09/29/87
-------
weeks. Fourteen days after exposure, the females were sacrificed and
examined for early deaths,- late fetal deaths and total Implantations. No
significant effects were reported, and propylene glycol was considered
nonmutagenlc 1n the dominant lethal assay at the dosages tested. However,
the test was not carried out long enough (10 weeks postexposure) to fully
evaluate Impact on spermatogonla.
6.4. TERATOGENICITY
Food and Drug Research Labs. (1973) evaluated propylene glycol for
teratogenldty 1n mice, rats, hamsters and rabbits. No adverse maternal or
fetal effects were attributed to propylene glycol administration In any
species. The results are summarized below.
Groups of 25-28 female albino CD-I outbred mice and groups of 25-28
female Wlstar rats were administered oral doses of 0, 16.0, 74.3, 345 and
1600 mg/kg propylene glycol on days 6-15 of gestation. The mice were sacri-
ficed on day 17, the rats on day 20; no compound-related effects were
observed In either species on the number of Implantation sites, resorptlon
sites, live and dead fetuses, pup body weight and presence of abnormalities
1n fetal soft or skeletal tissues.
Groups of 24-27 adult female Golden hamsters were administered oral
doses of 15.5, 72.0, 334.5 and 1550 mg/kg propylene glycol on days 6-10 of
gestation. The animals were sacrificed on day 14, and no compound-related
effects were reported on the numbers of Implantation sites, resorptlon
sites, live and dead fetuses, pup body weight or anatomical abnormalities.
Groups of 15-20 Dutch-belted rabbits were administered oral doses of
12.3, 57.1, 267 or 1230 mg/kg propylene glycol on days 6-18 of gestation.
0073d -32- 11/17/87
-------
The animals were sacrificed on day 29, and no effects were reported on the
numbers of corpora lutea,- Implantation sites, resorptlon sites, live and
dead fetuses, fetal weight or visceral or skeletal abronmalltles of the
fetuses.
Since maternal tox-lclty was not achieved In any of the studies, there 1s
concern about adequacy of dose-response range at upper limits.
6.5. OTHER REPRODUCTIVE EFFECTS
A group of twenty, 7-week-old male and female white rats were exposed
continuously to an atmosphere of 170-350 mg/m3 propylene glycol vapor for
3-18 months (Robertson et a!., 1947). Height gain was higher 1n the treated
males than In the controls. Female weight data were not plotted; they
varied because of the birth of young. No difference was noted In the
general condition between the treated or control rats, and the treated rats
bred as regularly and produced litters as large as did the controls. No
differences were noted 1n general appearance and weight gain between pups of
treated and control groups.
6.6. SUMMARY
Gaunt et al. (1972) evaluated the cardnogenlclty of propylene glycol 1n
male and female Charles River CO rats fed 0, 6250, 12,500, 25,000 or 50,000
ppm of the compound In the diet for 2 years. In both treated and control
groups, there was a high but similar Incidence of mammary fIbroadenomas,
pituitary adenomas and subcutaneous fIbrosarcomas. Mammary fIbroadenomas
have been shown to occur spontaneously 1n a high proportion of 2-year-old
rats of the Charles River CO strain. No carcinogenic effects could be
attributed to propylene glycol when administered In the diet of rats at
doses <50,000 ppm for 2 years.
0073d -33- 11/17/87
-------
Subchronic and chronic studies suggest that propylene glycol has a very
low order of toxlcity. Gaunt et al. (1972) evaluated several parameters of
toxIcHy in rats fed diets containing <50,000 ppm for 2 years. There were
no statistically significant differences between treated and control rats in
cumulative death rate, body weight gain, food consumption, hematology,
urinary cell excretion or renal clearance. A wide range of hlstologlcal
abnormalities was reported 1n the kidney, liver and lung, but the Incidence
was similar In both test and control groups. These changes were also
consistent with those expected In aging rats.
Well et al. (1971) reported no effects on the parameters of toxldty
evaluated 1n male and female beagle dogs receiving 2 g/kg bw/day propylene
glycol In the diet for 2 years. Dogs receiving 5 g/kg/day for 2 years had
lower total erythrocyte counts, lower hemoglobin and hematocrU values,
Increased total b1Hrub1n, and Increases In anlsocytosls, polkllocytes and
retlculocytes. These changes were Indicative of some erythrocyte destruc-
tion with replacement from the bone marrow. There was no evidence of damage
to bone marrow or spleen, and no hlstopathologUal or biochemical evidence
of hepatic damage was observed at any dose.
Morris et al. (1942) reported slight hepatic damage 1n albino rats fed
2.45 or 4.9X propylene glycol for 2 years. No other details were provided.
Okumura et al. (1986) reported some differences In hematologlcal and serum
biochemical effects 1n F-344 rats fed 2.5 or 5% propylene glycol In the diet
for 2 years; however, the effects may not have differed significantly from
the normal state.
Subchronic administration of propylene glycol at 1-10% In drinking water
caused no gross or microscopic lesions In rats (Kesten et al., 1939;
Seldenfeld and Hanzllk, 1932; Weatherby and Haag, 1938). Administration to
0073d -34- 11/17/87
-------
rats for 20 weeks at >40% of the diet resulted In death, at >30% resulted In
growth depression, and at->10% resulted In kidney lesions. There were no
effects at <6% (Guerrant et a!., 1947).
Continuous Inhalation exposure of rats to 170-350 mg/m3 for 3-18
months had no effects' on appearance, growth, reproduction or histopatho-
loglcal appearance of tissues In rats (Robertson et al., 1947).
Acute toxldty data Indicate that propylene glycol has a low order of
toxlclty, with oral LD5Q values ranging from 21.8-45.9 g/kg In rats and
22.8-31.87 In mice (Laug et al., 1939; Weatherby and Haag, 1938; Smyth et
al., 1941; Bornmann, 1955).
Propylene glycol was found to be nonmutagenlc when tested 1n Salmonella
typhlmurlum TA1535, TA1537 and TA1538 and Saccharomyces cerevlslae D4, with
or without metabolic activation (LUton Blonetlcs Inc., 1976). Results of
cytogenetlc testing UT_ vivo In the bone marrow of rats and j_n vitro with
human embryonic lung culture cells WI-38 were negative. Propylene glycol
was also nonmutagenlc In the dominant lethal assay In rats (Litton Blonetlcs
Inc., 1974). In a host-mediated assay using ICR mice, negative results were
obtained with Salmonella TA1530, and questionably positive results were
obtained at the high dose only In Salmonella strain G 46. The results with
the Saccharomyces 03 tester strain appeared weakly mutagenlc In the host-
mediated assay, but were difficult to Interpret because propylene glycol may
have been selectively toxic for mutants of this organism (LHton Blonetlcs
Inc., 1974).
Food and Drug Research Labs. (1973) evaluated propylene glycol for
teratogenlcHy In mice, rats, hamsters and rabbits. No adverse maternal or
fetal effects were attributed to propylene glycol administration In any
species. Male and female white rats exposed continuously to a super-
saturated atmosphere of propylene glycol for <18 months bred as regularly
0073d -35- 11/17/87
-------
and produced Utters as large as did the control animals (Robertson et al.,
1947). No differences 1n appearance or weight gain between the offspring of
treated and control groups were reported.
0073d -36- 11/17/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Propylene glycol is a substance with GRAS status (Food Drug Cosmetic Law
Reports, 1980) for which permissible levels in food have been established.
Maximum levels permitted are 5% for alcoholic beverages, 24% for confections
and frostings, 2.5/4 for frozen dairy products, 97% for seasonings and
flavorings, 5% for nuts and nut products, and 2.0% for all other food
categories.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of propylene glycol could not be located in the available
literature as dted 1n Appendix A.
0073d -37- 11/17/87
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenicHy of
Inhaled propylene glycol could not be located In the available literature as
cited 1n Appendix A.
8.1.2. Oral. As reported 1n Section 6.2.2., Gaunt et al. (1972) studied
the potential carclnogenicHy of propylene glycol In 30 male and 30 female
Charles River CD rats fed 0, 6250, 12,500, 25,000 or 50,000 ppm of the com-
pound In the diet for 2 years. The mean dally Intakes of propylene glycol
were reported to be 0', 0.2, 0.4, 0.9 and 1.7 g/kg/day In male rats and 0,
0.3, 0.5, 1.0 and 2.1 g/kg/day In female rats. Among both treated and
control rats, there was a high Incidence of mammary fIbroadenomas, pituitary
adenomas and subcutaneous fIbrosarcomas. According to the authors, mammary
flbroadenomas have been shown to occur spontaneously 1n a high proportion of
2-year-old rats of Charles River CD strain. In this study, no carcinogenic
effects could be attributed to propylene glycol when administered 1n the
diet of rats at doses <50,000 ppm for 2 years.
8.1.3. Other Routes. No Increase in tumor Incidence was observed In
carclnogenicHy studies when propylene glycol was administered to rats and
mice as a vehicle control (MUler, 1979). In these reports, the compound
was Injected subcutaneously or applied topically to the oral mucosa
repeatedly for >8 months. When twice weekly applications of 0.02 mi of
10, 50 and 100% propylene gltcol was applied to the shaved skin of groups of
50 female Swiss mice for the llfespan of the animals, no statistically
significant differences In Incidence of skin or other tumors were reported
(Stenbach and Shublck, 1974). Farsund (1978, 1981) observed changes In the
0073d -38- 11/17/87
-------
bladder mucosa cells, which were due to propylene glycol treatment, that
were qualitatively similar to but less severe than those observed after
administration of the bladder carcinogen, d1butyln1trosam1ne, and the
alkylatlng agent, cyclophosphamlde.
8.1.4. Weight of Evidence. No evidence of carclnogenlclty was found with
exposures of propylene glycol at levels of 50,000 ppm In the diet of rats
for a period of 2 years (Gaunt et al., 1972). This study used several doses
of the compound by a relevant route of exposure over the lifetime of the
animal; 1n addition, a comprehensive set of tissues was examined hlstopatho-
loglcally. No other human or animal data are available concerning the
cardnogenldty of the compound. According to the Guidelines for Carcinogen
Risk Assessment (U.S. EPA, 1986b), the an1ma-l and human data regarding car-
clnogenlcHy are Inadequate; therefore, propylene glycol would be classified
as an EPA Group D chemical, not classifiable as to human cardnogenldty.
8.1.5. Quantitative Risk Estimates. Insufficient data are available for
quantitative assessment of the cardnogenldty of propylene glycol by either
the oral or Inhalation exposure routes.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- One study
(Robertson et al., 1947) was available for consideration for the subchronlc
Inhalation RfD. In this study, 29 rhesus monkeys were exposed continuously
to an atmosphere of 100-220 or 230-350 mg/m3 propylene glycol vapors for
13 months. No compound-related pathological or hematologlcal effects were
reported; however, most of the control and treated animals were suffering
from Infections, and mortality In treated and control monkeys was high.
0073d -39- 11/17/87
-------
This study Is Inadequate for derivation of an RfD for subchronic Inhalation
exposure to propylene glycol. Therefore, the chronic inhalation RfD
(Section 8.2.1.2.) of 2 mg/kg/day or 116 mg/day for a 70 kg human 1s adopted
as the subchronic Inhalation RfO for propylene glycol. Discussion,
derivation and confidence In the RfD are presented in the following section.
8.2.1.2. CHRONIC EXPOSURES — In an Inhalation study reported by
Robertson et al. (1947), groups of 20 male and female white rats were
exposed continuously to an atmosphere of 170-350 mg/m3 propylene glycol
vapor for 18 months. Weight gain was higher 1n treated males than In
controls, but female weight data were not plotted because of the variation
resulting from giving birth to young. An average weight of 0.35 kg for
exposed male rats was estimated from graphic data provided by the Investi-
gators. No differences were noted 1n the general condition between treated
and control rats, and the treated rats bred as regularly and produced
Utters as large as did the controls. No pathological effects related to
exposure were observed In any of the tissues examined. No other parameters
of exposure were measured. A chronic NOEL of 260 mg/m3, the mean of 170
and 350 mg/m3, Is Identified from the rat data reported by Robertson et
al. (1947). An equivalent dosage of 166 mg/kg/day Is estimated by multiply-
ing the exposure concentration of 260 mg/m3 by 0.223 mVday, the refer-
ence Inhalation rate for rats, and dividing by 0.35 kg, the estimated body
weight of the exposed rats In this study. Applying an uncertainty factor of
100 to the rat NOEL of 116 mg/kg/day results 1n a chronic Inhalation RfD of
2 mg/kg/day or 116 mg/day for a 70 kg human. The uncertainty factor of 100
was selected based on a factor of 10 to account for Interspedes extrapola-
tion and another factor of 10 to protect the sensitive Individuals of the
population. The confidence in the RfD could be considered medium. Although
the sample size was small, several endpolnts of toxlcity were evaluated.
0073d -40- 11/17/87
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Data from the monkey study, although Inadequate for use In risk assessment,
do provide support for the RfO from the rat data, since a NOEL of 350
mg/m3 could also be Identified from the monkey data. In addition, data
from the literature Indicate no evidence of cardnogenldty, developmental
or reproductive toxldty resulting from the administration of propylene
glycol.
3.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Data regarding
the subchronlc oral toxldty of propylene glycol, although limited, suggest
that levels of 1-10% 1n the drinking water of rats are not associated with
adverse effects (Kesten et a!., 1939; Seldenfeld and Hanzllk, 1932;
Weatherby and Haag, 1938). The most comprehensive dietary study was that by
Guerrant et al. (1947) 1n which groups of five male and five female young
growing rats were fed diets containing 0, 1, 3, 6, 10, 15, 20, 30, 40, 50 or
60% propylene glycol for 20 weeks. At >40X of the diet, mortality occurred
within a few days. Growth rate was depressed at >30% and the Incidence and
severity of hlstopathologlcal lesions, particularly of the kidney, were
Increased at >10%. No effects were reported at 6% (60,000 ppm), which may
be considered a NOEL In this study. Assuming a food factor for rats of
0.05, a transformed dosage of 3 g/kg/day can be estimated. Applying an
uncertainty factor of 100, 10 for spedes-to-specles extrapolation and 10 to
protect sensitive Individuals, results 1n an RfD for subchronlc oral
exposure to propylene glycol of 0.03 g/kg/day or 2 g/day for a 70 kg human.
Confidence 1n this RfO 1s considered medium because the other limited
subchronlc oral data support the NOEL In rats. The cardnogenldty of
propylene glycol, however, has been adequately tested In only one species
and the developmental toxldty, although tested 1n four species, has not
been tested at levels as high as the subchronlc toxldty NOEL In rats.
0073d -41- 11/17/87
-------
8.2.2.2. CHRONIC EXPOSURES — Several chronic oral exposure studies
(see Section 6.1.2.1.) are-available for consideration for derivation of the
RfO. Gaunt et al. (1972) reported no statistically significant differences
in a dietary study between control Charles River CD rats and high-dose male
rats receiving dosages- of propylene glycol of <1.7 gAg/day or female rats
receiving dosages of <2.1 g/kg/day 1n cumulative death rate, body weight
gain, food consumption, hematology, urinary cell excretion or renal concen-
tration. A comprehensive histopathologlcal examination was conducted. The
Incidence of tumors was similar 1n both test and control animals, and the
changes observed were consistent with those expected In aging rats. There-
fore, a NOEL of 2.1 g/kg/day can be Identified from the female rat data 1n
this study.
Morris et al. (1942) reported no renal pathology 1n albino rats fed
propylene glycol at 2.45 or 4.9% of the diet for 2 years. Slight hepatic
damage was reported, but It was not clear at which dosage level this was
found, how many animals were Involved and what the nature of the damage was.
Therefore, since other well-documented studies are available, the study
reported by Morris et al. (1942) will not be used for derivation of the RfD.
Well et al. (1971) fed groups of beagle dogs diets that provided dosages
of 2.0 and 5.0 g/kg bw/day propylene glycol for 2 years. In addition to a
comprehensive hlstopathologlcal evaluation, the dogs were evaluated for
mortality, organ and body weights, hematology, blood chemistry and urlnaly-
s1s. No effects were observed 1n any of the parameters evaluated In dogs
receiving 2 g/kg/day. High-dose dogs had lower erythrocyte counts, hemo-
globin and hematocrlt values, and an Increase In total blUrubln. These
changes were considered Indicative of some erythrocyte destruction with
replacement from the bone marrow, although there was no evidence of damage
to the bone marrow or spleen and the changes appeared to be reversible.
0073d -42- 11/17/87
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Therefore, a NOEL of 2 g/kg/day can be Identified from the dog data reported
by Well et al. (1971).
Okumura et al. (1986) reported elevation 1n erythrocyte and leukocyte
counts 1n male F-344 rats and mean corpuscular volume In female rats fed
propylene glycol In the diet at 2.5 and 5% for 2 years. Some serum bio-
chemical data 1n the males differed from controls, but may not have differed
from the normal state. The presence of an Infection In the colony was not
disregarded. Because no hematologlcal effects were observed 1n two other
well-conducted chronic oral exposure studies where comparable doses were
administered to rats (Gaunt et al., 1972) or dogs (Well et al., 1971) for 2
years, the Interpretation of data from this study Is unclear. Hlstopatho-
loglcal examination was apparently not performed.
The most adequate study for derivation of an RfO for chronic oral
exposure 1s the 2-year rat study by Gaunt et al. (1972). The highest NOEL
of 2.1 g/kg/day comes from the female rat data reported by Gaunt et al.
(1972). Applying an uncertainty factor of 100 to the rat NOEL of 2.1
g/kg/day results 1n a chronic oral RfD of 0.02 g/kg/day or 1 g/day for a 70
kg man. An uncertainty factor of 100 was selected, based on a factor of 10
to account for Interspedes extrapolation and another factor of 10 to
protect the most sensitive Individuals of the population. The confidence 1n
the RfD 1s medium since the study provided adequate toxldty endpolnts 1n a
well-designed oral study. The available data from the literature do not
Indicate evidence of cardnogenlclty or developmental or reproductive
toxldty of propylene glycol, but the carclnogenlcHy has not been tested 1n
more than one species and the developmental toxldty has not been tested at
doses equivalent to the NOEL In rats. A NOEL of 2 g/kg/day from the 2-year
dog study reported by Well et al. (1971) also supports the RfO.
0073d ' -43- 11/17/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxic effects of subchronlc and chronic Inhalation and oral exposure
to propylene glycol were discussed 1n Chapter 6. The dose-response data
from these studies considered suitable for the derivation of the RQ are
summarized 1n Table 9-1.
The only effects associated with exposure to propylene glycol were
reduced body weight gain and kidney lesions 1n rats (Guerrant et a!., 1947),
and changes Indicative of some erythrocyte destruction with replacement from
the bone marrow reported In dogs by Well et al. (1971). The effects 1n dogs
occurred at a dose of 5 g/kg/day 1n dogs fed the compound for 2 years. The
changes did not appear to be Irreversible and there was no evidence of
damage to the bone marrow or spleen. CSs are calculated and presented In
Table 9-2. A CS Is not calculated for reduced body weight gain 1n rats
because a more severe effect, h1stopatholog1c lesions In the kidney,
occurred at a lower survival dosage. A CS of 6 associated with kidney
lesions 1n rats In a subchronlc study corresponds to an RQ of 1000 and Is
chosen to represent the chronic toxldty of propylene glycol (Tables 9-2
and 9-3).
9.2. BASED ON CARCINOGENICITY
No evidence of cardnogenldty of propylene glycol was found In rats
receiving multiple doses of the compound In the diet for a period of 2 years
(Gaunt et al., 1972). Propylene glycol 1s assigned to EPA Group 0, not
classifiable as to carclnogenldty. Therefore, Insufficient data preclude
the derivation of carcinogenic potency factors and hazard ranking based on
carclnogenldty.
0073d -44- 11/17/87
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CJ
a.
TABLE 9-1
Oral Toxlclty Sunnary for Propylene Glycol
en
i
Species/
Strain Sex
Dog/beagle H.f
Rat/NR H.f
Rat/NR H.F
No. at Average Vehicle/
Start Weight Physical Purity Exposure
(kg) State
5/sex 14b diet USP 5 g/kg/day
for 2 years
5/sex 0.35b diet NR >30X of diet
T30.000 ppm)
for 20 weeks
5/sex 0.35b diet NR >10X of diet
(10.000 ppm)
for 20 weeks
Transformed Transformed
Animal Dose Human Dose3 Response
(g/kg/day) (g/kg/day)
5 2.9 lower hemoglobin
and hematocrlt •
values, lower
total erylhrocyte
counts. Increase
In total blllrubln
( Increase In
anlsocylosls.
polkllocytes and
retlculocytes)
15C . 0.26d Reduced growth
rate
5C 0.09d Hlstopathologlc
lesions of kidney
Reference
Well et al..
1971
Guerrant
et al.. 1947
Guerrant
et al.. 1947
'Calculated by multiplying the transformed animal dose by the cube root of the ratio of the average animal body weight to the human body
weight (14 kg/70 kgp^.
Reference body weight (U.S. EPA. 1985)
(Calculated by using a reference food factor for rats of 0.05 (U.S. EPA. 1985).
dA factor of 10 was applied to expand from subchronlc to chronic exposure, although data from the chronic dietary study (Gaunt et al.. 197?)
suggest this manipulation may be unnecessarily conservative, since kidney lesions were not observed In the chronic study at 1.7 or 2.1
g/kg/day.
NR - Not reported
CO
-------
o
o
CJ
CL
Dog
Rat
TABLE 9-2
Oral Composite Scores for Propylene Glycol
Species
Animal Dosea
(g/kg/day)
Chronic
Human HEDb RVd Effect
(g/day)
RVe CSC RQ Reference
203
6.3
1.0 Lower hemoglobin
and hematocrlt
values, lower
total erythrocyte
counts. Increase
In total btllrubln
1.0 Htstopathologlc
lesions of kidney
5000
5000
Well et al..
1971
Guerrant
et al., 1947
Calculated by multiplying the transformed anlm 1 dose by the cube root of the ratio of the average
animal body weight to the human body weight.
^Calculated by multiplying the equivalent human dose expressed In g/kg/day (see Table 9-1) by 70 kg.
CCS -- HVdxRVe
CO
-------
TABLE 9-3
Propylene Glycol
Minimum .Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral/diet
Dose*: 6.3 g/day
Effect: degenerative and Inflammatory lesions and
calcification 1n the kidney
Reference: Guerrant et al., 1947
RVd: 1.0
RVe: 5
Composite Score: 5
RQ: 5000
*Equ1valent human dose
0073d -47- 11/17/87
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r-
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0073d -59- 11/17/87
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APPENDIX A
' LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986-1987. TlVs: Threshold Limit Values for Chemical Substances 1n
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill 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 Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0073d -60- 11/17/87
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Grayson, M. and 0. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WHey and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Habey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
P884-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n 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.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, 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.
0073d -61- 11/17/87
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In addition, approximately 30 compendia of aquatic toxlcity data were
reviewed, Including the fo>1ow1ng:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on 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.T. Flnley. 1980. Handbook of Acute ToxIcHy
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
ToxIcHy Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. 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. PubT. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0073d -62- 11/17/87
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CJ
a.
APPENDIX B
SiiMury Table for Propylene Glycol
CJ
i
Species
Inhalation Exposure
Subchrontc rat
Chronic rat
Carcinogenic tty NA
Oral Exposure
Subchronlc rat
Chronic rat
Carclnogenlclty NA
RE PORT ABLE QUANTITIES
Based on chronic toxtclty:
Based on carclnogenlclty:
Exposure
170-350 Mg/M»
(Mean: 260 Mg/M»)
continuously for
<18 Months
170-350 Mg/M»
(Mean: 260 Mg/M>)
continuously for
<18 Months
NA
6X of diet
(3 g/kg/day)
for 20 weeks
50.000 ppM In diet
(2.1 g/kg/day)
for 2 years
NA
5000
NA
Effect RfD or qj* Reference
NOEL 2 Mg/kg/day or Robertson et al..
116 Mg/day 1947
*
NOEL 2 Mg/kg/day or Robertson et al..
116 Mg/day 1947
NA NA NA
NOEL 0.03 g/kg/day or Guerrant et al.. 194;
2 g/day for a 70 kg Man
NOEL 0.02 g/kg/day or Gaunt et al.. 1972
1 g/day for a 70 kg Man
NA NA NA
Guerranl et al.. 1947
NA
NA = Not applicable
CO
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