PB87-235578
\
Health Advisories for 25 Organics
(U.S.) Environmental Protection Agency
Washington, DC
U.S. DEPARTMENT OF COMMERCE
National Technical Information Service
NTIS
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TECHNICAL REPORT DATA
{Hear md Imtruciiori on the rt*tnt it fort evmp
E>Bd7-235o76 L
1 REPORT NO.
a
Health Advisories for 25 Organics
l REPORT Do It
March, 1987
• . PERFORMING ORGANIZATION CODE
?. AUTHOR(S)
U.S. Environmental Protection Agency
Office of Drinking Water
1. PERFORMING ORGANIZATION REPORT NO
PERFORMING ORGANIZATION NAME AND ADDRESS
U.S. Environmental Protection Agency
Office of Drinking Water (WH-550D)
401 M St., S.W.
Washington, D.C. 20460
10. PROGRAM ELEMENT NO.
ii. COnTAaCT/AAant NO
12. SPONSORING AGENCY NAME AND ADDRESS
Same as box 9-
13. TYPE OF REPORT AND PERIOD COVEREO
14 SPONSORING AGENCY CODE
0
jp'1
tin
15. supplementary notes
16. ABSTRACT
These documents summarize the health effects of 25 organics including: acrvlamide,
benzene, carbon tetrachloride, chlorobenzene, dichlorobenzene(s), 1,2-dichloroethane,
1,1-dichloroethylene, cis-1,2-dichloroethylene, trans-1,2-dichloroethylene,
dichloromethane, p-dioxane, dioxin, epichlorohydrin, ethylbenzene, ethylene glycol,
hexachlorobenzene, hexane, methyl ethyl ketone, styrene, tetrachloroethylene,
toluene, 1,1,1-trichloroethane, trichloroethylene, vinyl chloride, xylenes. Topics
discussed include: General Information and Properties, Pharmacokinetics, Health
Effects in Humans and Animals, Quantification of Toxicological Effects^__Qih.ej
Criteria Guidance and Standards, Analytical Methods and Treatment Technologi"!^.
REPRODUCED BY
U.S. DEPARTMENT OF COMMERCE
NATIONAL TECHNICAL
INFORMATION SERVICE
SPRINGFIELD, VA. 22161
17.
KEY WORDS AND DOCUMENT ANALYSIS
I ^5^
1 DESCRIPTORS
b.lDENTiFIERS/OPEN ENOED TERMS
c.
C> SATi Kid Group
Organics
Drinking Water
Health Advisory
Toxicity
18. DISTRIBUTION STATEMENT
Open Distribution
19. SECURITY CLASS ITHu Report/
non-sensitive
21
NO OP PAGES
30 SECURITY CLASS (Thu peget
non-sensitive
22
PRICE ' 1
EPA T~m 3220-1 (*•». 4.77)
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Marcn ji, is;
acrylamide
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
"\ The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
jrisk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess of
the stated values. Excess cancer risk estimates may also be calculated using
the One-hit, Weibull, Logit or Probit models. There is no current understands;
of the biological mechanisms involved in cancer to suggest that any one of
these models is able to predict risk more accurately than another. Because
each model is based on differing assumptions, the estimates that are derived
can differ by several orders of magnitude.
01
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Acrylamiae
March 31, 195 7
-2-
This HA is based on information presented in the Office of Drinking
Water's draft Health Effects Criteria Document (CD) for Acrylamide (U.S. EPA,
1985a). The HA and CD formats are similar for easy reference. Individuals
desiring further information on the toxicological data base or rationale for
risk characterization should consult the CD. The CD is available for review
at each EPA Regional Office of Drinking Hater counterpart (e.g., Water Supply
Branch or Drinking Water Branch), or for a fee from the National Technical
Information Service, U.S. Department of Commerce, 5285 Port Royal Rd.,
Springfield, VA 22161, PB # 86-117744/AS. The toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 79-06-1
Chemical Structure
Synonyms;
c 2-Propenamide, acrylic amide, acrylic acid amide, akrylamid, ethylene
carboxamide and propinoic acid amide.
Uses:
0 As the monomer, in:
Grouts
Soil stabilizers
° As the polyacrylamide, in:
Flocculant production - drinking water and wastewater treatment plant;
Additive for enhanced oil recovery
Fog dissipator
Soil stabilizer
Paper and paperboard strengthener
Adhesive/binder component
Metal coating
Food packaging
Photography applications
Chromatography gel
Electrophoresis gel
Dye applications
Properties (Windholz, 1976; Verschueren, 1983)
Chemical Ferujl-i
Molecuia.: Wevgnr.
Physical State (room temp.)
Boiling Point (at 25 mmHg)
Melting Point
Vapor Pressure (25°C)
H H 0
I l|| yU
H-C-C-C-N
XH
C3H5NO
71 .08
white crystals
125 °C
84.5 #C
0.007 mmHg
02
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Acrylamide March 31, 1987
-3-
Specific Gravity (30°C)
Water Solubility (30°C)
Chloroform Solubility (30°C)
Benzene Solubility (30°C)
Octanol/Water Partition Coefficient
Taste Ihreshold (water)
Odor Threshold (water)
Odor Threshold (air)
Conversion Factor
Conversion Factor
Occurrence
° The production of acrylamide in 1982 was estimated to be 86 million
pounds (U.S. ITC, 1984). Acrylamide is used primarily in the produc-
tion of polyacrylamide polymers and co-polymers. It is also used as
a grouting agent, and approximately 1 million pounds is used for this
purpose (U.S. EPA, 1984).
4 Acrylamide monomer occurs as a contaminant in polyacrylamide. The
monomer may be released to the environment during its production, its
use in manufacturing polymers and during the use of polyacrylamides.
However, the major source of release occurs as a result of its use as
a grout. No information on production and manufacture releases is
available. Due to the low vapor pressure of acrylamide, no releases
to air are expected (U.S. EPA, 1984).
0 Acrylamide has been shown to biodegrade in surface waters within a
few days (Brown and Rhead, 1979). Waters which routinely receive
acrylamide releases will degrade it even more readily. Hydrolysis of
acrylamide to acrylic acid has been reported to occur, but is likely
to be a relatively slow reaction (Brown and Rhead 1979; Brown et al.
1930s).
0 Acrylamide has not been surveyed for in U.S. food and drinking water.
Based upon standards recommended by EPA for polymers used in drinking
water, the levels of acrylamide monomer in drinking- water have been
reported to occur up to 0.5 ug/L (U.S. EPA, 1980). One study in
England has reported tap water levels of acrylamide in the low ug/L
range (Brown and Rhead, 1979). No information has been identified
on the occurrence of acrylamide in food. Low levels of acrylamide
also may occur in some foods from the use of polyacrylamides in the
manufacture of those foods (U.S. EPA, 1984).
1.122 g/mL
2155 g/L
26.6 g/L
3.46 g/L
1 mg/m3 ¦ 0.34 ppm
1 ppm ¦ 2.95 mg/m3
III. PHARMACOKINETICS
Absorption
0 When acrylamide (10 mg/kg) was administered to rats per os, it was
absorbed rapidly and completely from the gastrointestinal tract
(Miller et al., 1982).
03
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Acryiamide
March 31, 12
-4-
0 By comparing the' blood levels of acryiamide after iv or dermal
administration, it was calculated that approximately 25% of either
applied dose (2 or 50 mg/kg) was absorbed through the skin (Ramsey et
al., 1984).
° Recently, it was reported that 26% of a 0.5% solution of acryiamide
was absorbed through the skin of rats in 24 hours. An additional 35%
was present in the skin and, potentially, available for absorption.
Using excised skin preparations, they found that 67% (54% absorbed
and 13% present in skin after washing) of the acryiamide was either
absorbed or available for absorption (Frantz et al., 1985).
Distribution
° After acryiamide was administered to rats by gavage, the highest
concentrations were found in red blood cells, with lower amounts
found in all otner tissues examined (Ramsey et al., 1984).
0 Results reported by Hashimoto and Aldridge (1970) indicate that acryl
mide is bound covalently to proteins or other cellular macromolecules
° Acryiamide freely crosses the placenta in pregnant female rats,
rabbits, dogs and pigs (Edwards, 1976; Ikeda et al., 1983) and is
uniformly distributed throughout dog and pig fetal tissue (Ikeda
et al., 1983).
0 Autoradiographic studies revealed that, after oral administration of
120 mg/kg, acryiamide was widely distributed in male and female mice.
The fetuses of pregnant mice were uniformly labeled, except that ther
was a concentration of acryiamide in fetal skin (Marlowe et al., 1986
MetabolisT
0 In rats, acryiamide is metabolized primarily by conjugation with
cellular glutathione (Miller et al., 1982).
° The majcr metabolite (greater than 50%) of acryiamide is the mercaptu
acid, N-acetyl-S-(3-amino-3-oxypropyl) cysteine (detected in the urin
of rats given acryiamide orally or intravenously (Miller et al., 1982
Ramaey et al., 1984).
0 Another metabolite resembling cysteine-5-propionamide has been
tentatively identified (Dixit et al., 1982).
Excretion
° In rats, excretion of acryiamide and its metabolic products occurs
primarily via the urine (Miller et al., 1982; Ramsey et al., 1984).
° Over 6C° cf a dose of acryiamide, administered either orally or iv,
appeared in the urine of rats within 24 to 72 hours (Miller et al.,
1982; Ramsey et al., 1984).
04
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Aerylamide
March 31, 19S7
-5-
0 Minor routes (less than 6%) of aerylamide elimination in rats include
fecal excretion (Miller et al., 1982) and release of the amide carbon
as COj following oxidation (Hashimoto and Aldridge, 1970; Ramsey
et al., 1984).
IV. HEALTH EFFECTS
Humans
0 Aerylamide intoxication has been reported in five individuals (three
adults and two children) exposed via ingestion of drinking water
contaminated with 400 ppm aerylamide (Igisu et al., 1975). All three
adults exhibited symptoms of widespread central and peripheral nervous
system dysfunction. The children apparently consumed less water than
the adults and were less severely affected.
0 Additional reports on human exposure to aerylamide deal primarily
with dermal or inhalation exposure of workers, ftie predominant
effects included dysfunction of the central and/or peripheral nervous
systems. Quantitative data on dose and duration of exposure generally
were not available in these reports (Auld and Bedwell, 1967> Garland
and Patterson, 1967; Fullerton, 1969; Davenport et al., 1976; Kesson
et al., 1977).
Animals
0 Evaluation of the toxicological data base for aerylamide indicates
that this chemical is a cumulative poison. It has been shown that
when the total dose of aerylamide administered over either short or
longer periods of time reaches 100 to 150 mg/ltg, signs of neuropatholog
begin to appear in many species tested (U.S. EPA, 1985a).
Short-term Exposure
0 Reported acute oral LDjg values for rats, guinea pigs and rabbits
range from 150 to 180 mgAg (McCollister et al., 1964). Acute oral
LD50 values for mice have been reported to range from 107 to 170 mg/kg
(NIOSH, 1976; Hashimoto et al., 1981).
0 An acute oral LD50 for aerylamide in male F-344 rats was reported to
be 202.5 (range of 188.9 to 217.3) mg/kg (Pryor et al., 1983).
8 Single doses of aerylamide, administered at levels as low as 25 mgA3»
have been shown to significantly increase binding of the neurotrans-
mitter 3n-spiroperidol in rat brains (Agrawal et al., 1981).
0 Single doses of aerylamide (1 to 100 mg/kg), administered via ip
injection, were shown to cause significant inhibition of retrogade
axonal transport in rats at doses of 25 mgAg or greater. Doses of
1, 5, or 15 mgAg caused no inhibition of transport (Miller et al.,
1983).
05
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Acrylair.ide
March 31, 191"
-6-
® Cats given acrylaraide in the diet at levels of 20 mgAg/day for 2 or
3 weeks developed hind limb weakness and general unsteadiness of the
posterior half of the body which usually progressed to hind limb
paralysis (Leswing and Ribelin, 1969). Microscopically, the affected
nerves exhibited degeneration of myelin and axons.
0 Dogs that were given acrylamide orally at levels of 5 mgAg/day
developed ataxia and muscular weakness by day 21 of treatment}
de-myelination of nerves was evident after 60 days (Thomann et al.,
1974).
0 Rats administered acrylamide in their drinking water displayed hind
limb splaying afcer 14 days of treatment at a dose of 30 mg/kg/day.
Microscopic changes in peripheral nerves were observed in animals
dosed at 10 and 30 mgAg/day. A NOAEL of 3 mgAg/day was identified
(Gorzinski et al., 1979).
0 Monkeys treated with an average dose of 7.1 mgAg/day (administered
orally in fruit juice) developed signs of visual impairment after 28
days; ataxia and motor impairment occurred after 46 to 65 days of
exposure (Merigan et al., 1982).
Lon
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Acryiair.iae
March 31, 19S7
-7-
Developmental Effects
0 Acrylamide, administered by gavage at 20 mg/kg/day to pregnant rats on
days 7 through 16 of gestation, significantly reduced 3H-spiroperidol
binding in the striatal tissue of 2-week-old pups (Agrawal and Squibb,
1981).
Mutagenicity
• Acrylamide did not elicit mutagenic activity in the Salmonella Ames
test in strains TA 98, TA 100, TA 1535 and TA 1537 with or without
microsomal activation (Bull et al., 1984a).
e In the hepatocyte primary culture DNA repair test, acrylamide did not
exert mutagenic effects (Miller and McQueen, 1986).
0 Acrylamide induced chromosome breaks and aberrations in spermatogonia
of mice exposed to 75 mgAg/day in the diet for two or three weeks
(Sniraishi, 1978).
0 In a dominant lethal study, male rats received acrylamide at 0, 15,
30 or 60 mg/L for 80 days in their drinking water (0, 1.5, 2.8 or 5.8
mg/kg/day; Smith et al., 1986). The males were mated to untreated
females which were killed on day 14 of gestation. A significant
increase in preimplantation loss was noted in females mated to males
treated at 60 mg/L. Significant post-implantation loss was observed
in females mated to the mid- and high-dose males (30 and 60 mg/L).
The authors concluded that acrylamide produces dominant lethality in
the male rat. This effect was noted at dose levels at which no
hindlimb splaying was evident or significant histopathological lesions
of the sciatic nerve occurred as determined by light microscopy.
Carcinogenicity
1 Groups of male and female Fischer 344 rats received drinking water
containing acrylamide monomer at 0, 0.01, 0.1, 0.5 or 2.0 mg/kg/day
for 2 years (Johnson et al., 1986). After a year, significant
depression of body weight was observed in the highest dose males.
Distal neuropathy was observed in the peripheral nerves of animals in
this group. Tumor incidence was not increased significantly in the
groups receiving 0.01 or 0.1 mg/kg/day. Male rats receiving 0.5
mg/kg/day had significantly increased incidences of scrotal mesothe-
lioma. Statistically significant increased incidences of tumors in
the following tissues were determined in rata treated at 2^.0 mgAg =
Females — mammary gland (benign and malignant), central nervous
system (malignant), thyroid gland follicular epithelium (benign and
malignant), mouth (benign), uterus (malignant) and clitoral gland
(benign); male? — scrotal mesothelioma (malignant) and thyroid gland
follicular epithelium (benign).
0 Female Swiss-ICR mice, administered acrylamide orally at doses of
5.4, 10.7 or 21.4 mg/kg/day for 2 weeks had a dose-dependent increase
of tumors induced by the phorbal ester TPA (2.5 ug/mouse, 3 times per
week for 20 weeks; Bull et al., 1984b).
07
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Acryla-ide
March 31, 19c 7
-8-
° Male and female mice that received acrylamide orally or intraperitoneall
at average daily doses of 2.7, 5.4 or 10.7 mg/kg/for eight weeks
showed statistically significant increases in the incidence of lung
adenomas (Bull et al., 1984a). Acrylamide was more potent by gavage
than by systemic routes.
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA - (NOAEL or LOAEL) x (BW) „ /L (
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day » assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
No adequate dose-response data representing the oral route of exposure
are available from which to develop short term risk assessments. However, in
view of substantial chemical disposition evidence showing that acrylamide is
absorbed rapidly and completely by virtually any route of exposure, it is
considered acceptable to use data generated following exposure via other
routes.
One-day Health Advisory
The results of Miller et al. (1983) are considered appropriate for use
in calculating the One-day HA. In this study, male Sprague-Dawley rats (five
animals per dose) were injected intraperitoneally with a single dose of
acrylamide (1 to 100 mg/kg) and the rate of retrograde axonal transport of
iodinated nerve growth factor was measured. The authors determined that
significant inhibition of transport occurred at or above doses of 25 mgA<3»
while no significant changes were seen at or below 15 mgAg. A NOAEL of
15 mgAg was identified.
The One-day KA for the 10 kg child is calculated as follows:
One-day HA = H5 mg/kg/day)(10 kg) „ 1,5 mg/L (1500 ug/L)
(100) (1 L/day)
08
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Aerylamide
March 31 , IS"
-9-
where:
15 mg/kg/day = NOAEL, based on absence of neurotransport inhibition
in rats.
10 kg » assumed body weight of a child
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day a assumed daily water consumption of a child
Ten-day Health Advisory
The results of Gorzinski et al. (1979) are considered appropriate for
use in calculating the Ten-day HA. In this study, acrylamide was administered
at levels of 0, 1, 3, 10 or 30 mg/kg/day in drinking water to male and female
CDF Fischer 344 rats for 21 consecutive days. Based upon histological exam-
ination of peripheral nerves using both light and electron microscopy, it
was determined that axon degeneration and demylenization occurred at the 10
and 30 mg/kg/day dose levels while no significant changes were apparent at
the 0, 1 or 3 mg/kg/day dose levels. A NOAEL of 3 mg/kg/day was identified.
The Ten-day HA for the 10 kg child is calculated as follows:
3 mg/kg/day = NOAEL, based on absence of neuropathy in rats.
10 k: = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
— guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
The results of Burek et al. (1980) are considered appropriate for use in
deriving the Longer-term HA. In this study, acrylamide was administered in
drinking water for 90 days to male and female CDF rats at dose levels of
0, 0.05, 0.2, 1, 5 or 20 mg/kg/day. Electron microscopy revealed that animals
dosed at 1 mc/kg/day exhibited axolemmal invaginations of peripheral nerves.
No significant alterations were observed at the 0, 0.05 and 0.2 jng/kg/day
dose levels. Thus, based on the most sensitive measure of toxicity employed
in these studies (ultrastructural examination of peripheral motor nerves), it
was concluded that 0.2 mg/kg was the NOAEL.
The Longer-term HA for the 10 kg child is calculated as follows:
Ten-day HA
= <3 mg/kg/day)(10 kg) = 0,3 mg/L (300 ug/L)
(100)(1 L/day)
where:
09
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Aerylamice
March 31. 1967
-10-
Lonoer-term HA = (0'2 mg/kg/day) (10 kg) a 0>02 mg/L (20 ug/L)
(100) (1 L/day)
where:
0.2 mg/kg/day = NOAEL, based on absence of neuropathy in rats.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for the 70 kg adult is calculated as follows:
Longer-term HA = (0«2 mg/kg/day) (70 kg) D q.07 mg/L (70 ug/L)
(100) (2 L/day)
where:
0.2 mg/kg/day = NOAEL, based on absence of neuropathy in rats.
70 kg ¦ assumed body weight of an adult.
100 = uncertainty factor, chosen.in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived fron
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is ba^ed on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
10
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Acrylamide
March 31, 1987
-11-
The study by Burek et al. (1980) is the most appropriate from which to
derive the DWEL. The experimental details are described in the Longer-term
Health Advisory section. An additional uncertainty factor of 10 is included
in order to accommodate for use of a less-than-lifetime study. From the
results of the study, a-NOAEL of 0.2 mgAg was identified.
The RfD and DWEL are calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (0.2 mgAg/day) , 0.0002 mgAg/day
(1,000)
where:
0.2 mgAg/day = NOAEL.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.002 mgAg/day)(70 kg) , 0.007 ng/L (7 Ug/L)
(2 L/day)
where:
70 kg = assumed body weight of an adult.
2 L/day = assumed daily consumption of water of an adult.
Step 3: Determination of the Lifetime Health Advisory
Acrylamide may be classified in group B2: Probable Human Carcinogen.
Therefore, a Lifetime HA is not recommended for acrylamide.
The estimated excess cancer risk associated with lifetime exposure to
drinking water containing acrylamide at 7 ug/L is approximately 7 x 10-4.
This estimate represents the upper 95% confidence limit from extrapolations
prepared by EPA's Carcinogen Assessment Group using the linearized, multistage
model. The actual risk is unlikely to exceed this value, but there is consid-
erable uncertainty as to the accuracy of risks calculated by this methodology.
Evaluation of Carcinogenic Potential
0 The data from the Bull et al. (1984a,b) and the Johnson et al. (1986)
studies in mice and rats show that acrylamide has significant carcino-
genic potential.
0 On the basis of the results observed in the rat drinking water study
(Johnson et al., 1986), EPA's Carcinogen Assessment Group (CAG) has
prepared a draft quantitative risk assessment of acrylamide exposure
(U.S. EPA, 1985c). In this draft assessment, CAG derived several
11
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Acrylamide
March 31, 19S7
12
carcinogenic potency factors from different sets of dose-response
data. CAG recommended, however, that the human potency factor (qi*)
of 3.7 (mg/kg/day)~1 derived from the combination of tumor incidence
data on mammary gland,, thyroid and uterus in the females be used for
estimating the increased lifetime risk of human exposure to acrylamide.
(Assuming that a 70 kg adult ingests 2 L of water per day over a 70-year
lifetime, the estimated excess cancer risk at 10~4, 10~5 and 10~6 would
se 1 ug/L, 0.1 ug/L and-0.01 ug/L, respectively. (These estimates
were made by the Office of Drinking Water}. While recognized as
statistically alternative approaches, the range of risks described by
ising any of these modelling approaches has little biological signifi-
:ance unless data can be used to support the selection of one model
aver another. In the interest of consistency of approach and in
providing an upper bound on the potential cancer risk, the Agency has
recommended use of the linearized multistage approach.
Vpplying the criteria described in EPA's guidelines for assessment
3f carcinogenic risk (U.S. EPA, 1986), acrylamide is classified in
>roup B2: Probable human carcinogen. Group B2 contains substances
with sufficient evidence of carcinogencity in animals and inadequate
evidence from human studies.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
° Polyacrylamide products used as coagulant aids in the treatment
of drinking water should not have a residual monomer content
greater than 0.5 ug/L (U.S. EPA, 1980).
VII. ANALYTICAL METHODS
° There is no standardized method for the determination of acrylamide
in drinking water. An analytical procedure for the determination of
acrylamide has been reported in the literature (Brown and Rhead, 1979),
This procedure consists of bromination, extraction of the brominated
product from water with ethyl acetate and quantification using high
performance liquid chromatography (HPLC) with an ultraviolet detector.
The concentration of the ethyl acetate to dryness and dissolution in
a small volume of distilled water prior to HPLC analysis allows the
detection of acrylamide at concentrations of 0.2 ug/L.
VIII. TREATMENT
0 Croll et al. (1974) conducted laboratory experiments to determine the
effectiveness of conventional treatments such as coagulation and rapid
gravity sand filtration for removal of acrylamide. Several 400 ml sample
of Thames River water (pH 7.5) containing 25 mg/L kaolin were coagulated
by adding 32 n.g/L alum and 2 mg/L of an acrylamide-based polymer with a
residual acylamide monomer content of 0.19%. Only about 5% of the
residual monomer was removed by this method, suggesting that full-scale
water plants using conventional treatment techniques would not be
successful in removing acrylamide from drinking water.
12
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Acrylamide
March 31, 198 7
-1 3-
0 The removal of acrylamide from water by adsorption was studied by
Brown et al. (1980a) using various adsorbants including granular
activated carbon (GAC) and synthetic resins. The data indicated
that GAC may be an effective treatment process. GAC removed 94 to
96% of the acrylamide from a sample containing 0.5 mg/L and 68 to
70% from a sample containing 10 mg/L. The adsorption of acrylamide
was not affected significantly by changes.in pH. No significant
adsorption was achieved by any of the resins tested, including the
XAD-2 resin.
# In a laboratory experiment conducted by Croll et al. (1974),
water containing 6 ug/L acrylamide (at pH 5.0) was dosed with
8 mg/L powdered activated carbon (PAC) and mixed for 30 minutes.
Only 13% of the acrylamide was removed. These data indicate that PAC
may not be effective for acrylamide removal from drinking water
under conditions used generally in water treatment plants.
* No data were found on the removal of acrylamide by aeration. Since
its Henry's Law Constant is 4.38 x 10~3 atm (at 20°C), aeration
probably would not be very effective.
0 Croll et al. (1974) evaluated the effects of some chemical oxidative
treatments on removal of acrylamide. Potassium permanganate and ozone
were found to be highly effective in removing the substance. Additional
data to optimize these processes are needed. Oxidative degradation
products also should be identified and evaluated for toxicity and
reactivi ty.
0 Selection of individual or combinations of technologies to achieve
acrylamide reduction must be based on a case-by-case technical
evaluation and an assessment of the economics involved.
13
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Aerylamias
March 31, ISC,
-14-
IX. REFERENCES
Agrawal, A.K., p.k. Seth, R.E. Squibb, H.A. Tilson, L.L. Uphouse and S.C. Boncy.
1981. Neurotransmitter receptors in brain regions of acrylamide-treated
rats. I: Effects of a single exposure to acrylamide. Pharmacol.
Biochem. Behav. 14:527-531.
Agrawal, A.K., and R.E. Squibb. 1981. Effects of acrylamide given during
gestation on dopamine receptor binding in rat pups. Toxicol. Lett.
7:233-238.
Auld, R.B., and S.P. Bedwe'1. 1967. Peripheral neuropathy with sympathetic
overactivity from industrial contact with acrylamide. Can. Med. Assoc. J.
96:652-654.
Brown, L., and M. Rhead. 1979. Liquid chromatographic determination of
acrylamide monomer in natural and polluted aqueous environment. Analyst.
104:391-399.
Brown, L., K.C.C. Brancroft and M.M. Rhead. 1980a. Laboratory studies on
the adsorption of acrylamide monomer by sludge, sediments, clays, peat,
and synthetic resins. Hater Res. 14:779-781.
Brown, L., M.M. Rhead,- K.C.C. Bancroft and N. Allen. 1980b. Model studies
of the degradation of acrylamide monomer. Water Res. 14:775-779.
Bull, R.J., M. Robinson, R.D. Laurie, G.D. Stoner, E. Greisiger, J.R. Meier
and J. Stober. 1984a. Carcinogenic effects of acrylamide in SENCAR and
A/J mice. Cancer Res. 44:107-111.
Bull, R.J., M. Robinson and J.A. Stober. 1984b. Carcinogenic activity of
acrylamide in the skin and lung of Swiss-ICR mice. Cane. Lett. 24:209-212.
Burek, J.D., R.R. AlDee, J.E. Beyer, T.J. Bell, R.M. Carreon, D.C. Morden,
C.E. Wade, E.A. Hermann and S.J. Gorzinski. 1980. Subchronic toxicity
of acrylamide administered to rats in the drinking water followed by up
to 144 days of recovery. J. Environ. Pathol. Toxicol. 4:157-182.
Croll, B.T., G.M. Arkell and R.P.J. Hodge. 1974. Residues of acrylamide
in water. Water Res. 8:989-993.
Davenport, J.G., D.F. Farrell and S.M. Sumi. 1976. Giant axonal neuropathy
caused by industrial chemicals. Neurology. 26:919-923.
Dixit, R., P.K. Seth and H. Mukhtar. 1982. Metabolism of acrylamide into
urinary mercapturic acid and cysteine conjugates in rats. Drug Metab.
Disp. 10:196-197.
Edwards, P.M. IJ^-j. rhe insensitivity of the developing rat foetus to the
toxic effects of acrylamide. Chem.-Biol. Interact. 12:13-18.
14
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Aery lair.ide
-15-
March 31, 198"
Frantz, S.W., M.D. Dryzga, N.L. Freshoar and P.G. Watanabe. 1985. In vivo/
in vitro determination of cutaneous penetration of residual monomer from
polyacrylamides. Toxicologist. 5:39. (Abst.)
Fullerton, P.M. 1969. Electrophysiological and histological observations on
peripheral nerves in acrylamide poisoning in man. J. Neurol. Neurosurg.
Psychiat. 32:186-192.
Garland, T.O., and M.W.H. Patterson. 1967. Six cases of acrylamide poisoning.
Brit. Med. J. 4:134-138.
Gorzinski, S.J., D. C. Mord»n, R.R. Albee, C.E. Wade, R.M. Carreon, E.A.
Hermann, J.E. Beyer and J.D. Burek. 1979. Results of palatability
(12-day) and tolerance (21-day) studies on acrylamide monomer administerec
in the drinking water to rats.
Hashimoto, K., and W.N. Aldridge. 1970. Biochemical studies on acrylamide, a
neurotoxic agent. Biochem. Pharmacol. 19:2591-2064.
Hashimoto, K., J. Sakamoto and H. Tanii. 1981. Neurotoxicity of acrylamide
and related compounds and their effects on male gonads in mice. Arch.
Toxicol. 47:179-189.
Igisu, H., I. Goto, Y. Kawamura, M. Kato, K. Izumi and Y. Kuroiwa. 1975.
Acrylamide encephaloneyropathy due to well water pollution. J. Neurol.
Neurosurg. Psychiat. 38:581-584.
Ikeda, G.J., E» Miller, P.P. Sapienza, T.C. Michel, M.T. King, V.A. Turner,
H. Blumenthal, W.E. Jackson, III and S. Levin. 1983. Distribution of
14C-labeled acrylamide and betaine in foetuses of rats, rabbits, beagle
dogs and miniature pigs. Food Chem. Toxicol. 21:49-58.
Johnson, K.A., S.J. Gorzinski, K.M. Brodner, R.A. Campbell, C.H. Wolf, M.A.
Friedman and R.w. Mast. 1986. Chronic toxicity and oncogenicity study
on acrylamide incorporated in the drinking water of Fischer 344 rats.
Toxicol. Appl. Pharmacol. 85:154-168.
Kesson, C.M., A.w. Baird and D.H. Lawson. 1977. Acrylamide poisoning.
Postgrad. Med. J. 53:16-17.
Kuperman, A.S. 1958. Effects of acrylamide on the central nervous system of
the cat. J. Pharmacol. Exp. Ther. 123:180-192.
Leswing, R.J., and W.E. Ribelin. 1969. Physiologic - and pathologic changes
in acrylamide neuropathy. Arch. Environ. Hlth. 18:22-29.
Marlowe, C., M.J. Clark, R.W. Mast, M.A. Friedman and W.J. WaddeJ.1. 1986.
The distribution of [1 4C]acrylamide in male and female Swiss-Webster
mice studied by whole body autoradiography. Toxicol. Appl. Pharmacol.
86:457-465.
Mc^ollister, D.D., F. Oyen, and V.K. Rowe. 1964. Toxicology of acrylamide.
Toxicol. Appl. Pharmacol. 6:172-181.
15
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Acrylamide
March 31, 198"
-16-
Merigan, W.H., E. Barkdoll and J.P.J. Maurissen. 1982. Acrylamide-induced
visual impairment in primates. Toxicol. Appl. Pharmacol. 62:342-345.
Miller, M.J., D.E. Carter and I.G. Sipes. 1982. Pharmacokinetics of
acrylamide in Fischer-344 rats. Toxicol. Appl. Pharmacol. 63:36-44.
Miller, M.J., and C.A. McQueen. 1986. The effect of acrylamide on hepato-
cellular DMA repair. Environ. Mutagen. 8:99-108.
Miller, M.S., M.J. Miller, T.F. Burks and I.G. Sipes. 1983. Altered retrograde
axonal transport of nerve growth factor after single and repeated doses
of acrylamide in the rat. Toxicol. Appl. Pharmacol. 69:96-101.
Miller, M.S., and P.S. Spencer. 1984. Single doses of acrylamide reduce
retrograde transport velocity. J. Neurochem. 43:1401-1408.
NIOSH. 1976. National Institute for Occupational Safety and Health. Criteria
for a recommended standard...occupational exposure to acrylamide. U.S. Dept.
of Health, Education and Welfare, Public Health, Center for Disease Control.
Pryor, G.T., E.T. Uyeno, H.A. Tilson and C.L. Mitchell. 1983. Assessment
of chemicals using a battery of neurobehavioral tests: A comparative
study. Neurobehaviortl. Toxicol. Teratol. 5:91-117.
Ramsey, J.C., J.D. Young and S.J. Gorzinski. 1984. Acrylamide: Toxicodynamics
in rats. Unpublished report. Dow Chemical Co., Midland, MI.
Shiraishi, V. 1978. Chromosome aberrations induced by monomeric acrylamide
in bone marrow and germ cells of mice. Mutation. Res. 57:313-324.
Smith, M.K., H. Zenick, R. Preston, E.L. George and R.E. Long. >986. Dominant,
lethal effects of subchronic acrylamide administration in the male
Long-Evans rat. Mutat. Res. 173:273-278.
Thomann, P., W.P. Koella, G. Krinke, H. Petermann, F. Zak and R. Hess. 1974.
The assessment of peripheral neurotoxicity in dogs: Comparative studies
with acrylamide and clioquinol. Agts. Act. 4:47-53.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Coagulant aids in
the treatment of drinking water. Office of Drinking Water.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Miscellaneous
synthetic organic chemicals. Occurrence in drinking water, food, and
air. Office of Drinking Water.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Draft health effects
criteria document for acrylamide. Criteria and Standards Division.
Office of Drinking Water.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Draft technologies
and costs for the removal of synthetic organic chemicals from potable
water supplies. Science and Technology Branch. Criteria and Standards
Division. Office of Drinking Water.
16
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Acrylar.ice
March 31, 198"
-1 7-
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Assessment of
carcinogenic risk of exposure to acrylamide. (Draft). A staff
paper prepared by W.C. Pepelko and J. Cagliano for the Office of
Health and Environmental Assessment, Office of Research and Development.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185):33992-34003.
September 24.
U.S. ITc. 1984. United States International Trade Commission. Synthetic
organic chemicals. U.S. production and sales - 1983. U.S. ITC Publi-
cation No. 1588, Washington, D.C., pp. 255 and 268.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals.
2nd Edition. Van Nostrand Reinhold Co., Nev York.
Hindholz, M., ed. 1976. The Merck Index. 10th Edition. Merck and Co., Inc.
Rahway, NJ.
17
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BENZENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
INTRODUCTION
The Health Advisory (HA) Program, sponsored fcy the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate aiy potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or £ carcinogens are correlated with carcinogenic risk estimates b/
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ fcy several orders of magnitude.
18
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Ben: ene
March 31, 15="
-2-
This Health Advisory is based on information presented in the Office of
Drinking Water's Draft Health Effects Criteria Documents (CD) for Benzene
(U.S. EPA, 1983b, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CDs. The CDs are
available for review at each EPA Regional Office of Drinking Water counterpart
(e.g., Water Supply Branch or Drinking Water Branch), or for a fee from the
National Technical Information Service, U.S. Department of Commerce, S285
Port Royal Rd., Springfield, VA 22161, PB * 86-118122/AS. The toll-free
number is (800) 336*4700; in the Washington, D.C. areat (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 71-43-2
Structural Formula
• Additive to gasoline to increase the octane.
0 Chemical intermediate in the synthesis of compounds such as:
styrer.e, synthetic rubber, phenol, alkylarnesulfonate detergent,
nitrobenzene (aniline), and cyclohexane.
Properties (Von Gemert and Nettenbreijer, 1977; Windholz, 1983)
M
Synonyms
H
# None
Uses
Chemical Formula
Physical State
Boiling Point
Freezing Point
Density at 25°C
Vapor Pressure at 26°C
Water Solubility at 25°C
Odor Threshold, in air
Odor Threshold, in water
aromatic hydrocarbon
80.100°C
5.53#C
0.8765 g/mL
100 sunHg
m (characteristic odor)
2.0 ng/L
Occurrence
c Benzene is produced at low levels in a number of biological processes
and is a component of petroleum (U.S. EPA, 1983a).
19
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Benzene
-3-
March 31, 19E
' Benzene is produced in large amounts, e.g., 9 billion lbs in 1981
(U.S. ITC, 1984), and is used largely as a feedstock on the production
of other chemicals. Small amounts of benzene have been used as a
solvent; however, this use has been discontinued. Benzene also is
produced indirectly in large volumes, such aS during gasoline refining
and other operations. The average benzene content of gasoline is
less than 1% (Runion, 1975).
c Releases of benzene to the environment are largely to air due to its
volatile nature, with smaller amounts to water and soil. Releases
of benzene to water are mainly due to' spills of gasoline and other
petroleum products and from benzene's previous use as a solvent.
Because cf the widespread use of petroleum products, releases of
benzene occur nationwide (Mara and Lee, 1978; OSHA, 1978).
° Benzene released to surface water rapidly volatilizes to the air.
° Benzene degrades rapidly in air with a half life of less than one day.
0 Benzene released to the ground binds somewhat to soil and slowly
migrates with ground water. Benzene is biodegraded poorly and is
expected to be stable in ground water (Mara and Lee, 1978).
0 Benzene occurs in drinking water, food, and air (U.S. EPA, 1983b),
0 Benzene occurs ir. both ground water and surface public water supplies,
with highsr levels occurring in ground water supplies. Based upon
Federal drinking water surveys, approximately 1.3% of all ground
water syster.s are estimated to contain benzene at levels greater than
0.5 ug/L. The highest level reported in the surveys for ground water
was SO ug/L. Approximately 3% of all surface water system are esti-
mates to b€ contaminated at levels higher than 0.5 ug/L. None of the
systems are expected to contain levels higher than 5 ug/L.
0 Benzene is found at ppb levels in a large number of foods as a naturally
occurring compound (U.S. EPA, 1983b).
0 Benzene is found in air in urban and suburban areas, generally at
average levels of less than 10 ppb (U.S. EPA, 1963b), but at higher
levels it) certain metropolitan areas such as Los Angeles where Lonnpna-,
e >. al. (1968) measured an average benzene concentration of 15 ppb wit
a maximum of 57 ppb. Benzene has been reported to occur in indoor
air at levels higher than those found outdoors. Based upon the
available evidence, the major source of benzene exposure is believed
to be from air.
III. PHARMACOKINETICS
Absorption
° As a neutral, low molecular weight, lipid soluble material, benzene
is readily absorbed via inhalation and ingestion. It is poorly absorbed
through the intact skin (NIOSH, 1974).
20
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Benzene
narc/i 31, 1 987
-4-
0 Administration of benzene to rats via inhalation or ingestion results
in its rapid uptake and excretion, mainly via exhalation of unchanged
benzene (Rikert et al., 1979; Parke and Williams, 1953). The exhalation
of unchanged benzene has also been reported in dogs (Schrenk et al.,
1941), rabbits (Parke and Williams, 1953) and mice (Andrews et al.,
1977a).
0 When humans are exposed to benzene in air, absorption via inhalation
is approximately 50* (Nomiyaoa and Nomiyama, 1974 a,b)»
Distribution
a Benzene is highly lipid soluble which accounts for its tendency to
accumulate in fatty tissue (U.S. EPA, 1983b).
0 In mice, benzene is stored in the bone marrow, liver and body fat
(Snyder et al., 1978).
Metabolism
0 The metabolic pathway for benzene has been thoroughly delineated
in benzene background documents including U.S. EPA (1983b, 1985a).
In humans, phenol sulfate is the major metabolite of benzene until
400 mg/L levels are reached in the urine. Beyond that level, glucu-
ronide conjugates are also present in the urine (Sherwood, 1972).
Excretion
e The rate of elimination of benzene in humans is biphasic with initially
about 16.2% eliminated unchanged via exhalation in 5 hours (Nomiyama
and Nomiyama, 1974a,b). The remainder of the benzene is stored in
the fatty tissues and is excreted much more slowly. Benzene has a
half-life of 0.7 hours in rats (Rickert et al., 1979).
IV. HEALTH EFFECTS
Humans
0 Acute exposure to high levels of benzene produces primarily central
nervous system effects such as dizziness, giddiness, exhilaration,
nausea, vomiting, headache, drowsiness, staggering, loss of balance,
narcosis, coma and death. Exposure to 25,000 ppm in air is rapidly
fatal (NAS, 1976). At nonlethal levels, mild central nervous system
effects appear to be concentration-dependent and are rapidly reversible.
Lower levels of benzene do not seem to elicit these effects no matter
how long the exposure (U.S. EPA, 1983b).
° Benzene has been a known hematological poison since the 19th century
when cases of aplastic anemia in workers fabricating bicycle tires
were described fcy Santesson (1897).
21
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Benzene
-5-
March 31, 19£7
0 Benzene causes bone marrow toxicity resulting in a continuum of
changes in the circulating formed blood elements ranging from a mild
decrease in platelets to aplastic anemia, a rapidly fatal disease.
The lowest level that produced changes in platelet counts in workers
appears to be 10 ppm (Doskin 1971; Chang, 1972).
0 Benzene causes acute myeloblastic leukemia, acute myelomonocytic
leukemia and erythroleukemia (Rinsky et al., 1981). The exposure
levels resulting in leukemia have not been determined.
® Epidemiologic stulies show that exposure to benzene via inhalation
at levels of 10 ppm or lower for approximately-one year increases
the risk of cancer by 560 fold and exposure for five or more years
increases the risk by 2,100 fold (Rinsky et al., 1981).
0 Immune system depression resulting from benzene exposure is a well
known toxicological phenomenon. Susceptibility to tuberculosis
(White and Gammor., 1914) and pneumonia (Winternitz and Hirschfelder,
1913) have been demonstrated to be increased in benzene-treated
rabbits.
° Serum levels of IcG and IgA (immunoglobulins) were shown to be decreased
in benzene workers (Lange et al.,- 1973; Smolick et al., 1973).
• These observations in conjunction with the well known ability of benzene
to depress leukocytes which play a significant role in protection
against infectious agents, may explain why individuals regularly
exposed to benzene readily succumb to infection and the terminal
event in severe benzene toxicity is often acute overwhelming infection.
° Benzene has caused chromosomal aberrations in exposed workers (Kisslir.r
and Spec-:, 1969; Tough et al., 1970; Forni et al., 1971).
Animals
Short-term Exposure
° Dogs exposed to benzene by inhalation at 600 to 1,000 ppn for 12 tc
15 days developed leukopenia (reduction in the number of circulating
leukocytes) (Hough and Freeman, 1944).
0 Mice exposed to benzene by inhalation at 600 to 1,000 ppm developed
fatal anemia within 12 to 15 days (Petrini, 1941).
0 When exposed to benzene by inhalation at 80 to 85 ppm, rats (136
dosesl, guinea pigs (193 doses), rabbits (187 doses) and monkeys
(187 acses) developed leukopenia (Wolf et al., 1956).
0 Deichrr.ann et al. (1963) conducted a series of experiments in which
Sprague-Dawley rats (40/group) were exposed to benzene vapor for 5
hours per day, 4 days per week for 6 to 31 weeks. Average exposure
concentrations ranged from 15 to 831 ppm. Rats exposed to benzene
vapor at 61, 65 or 831 ppm developed severe leukopenia within 2 to 4
22
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Benzene
-6-
March 31, 151¦
weeks. At 44 and 47 ppm, moderate leukopenia was observed, especially
in females, in 5 to 8 weeks, and no leukopenia was observed when
animals were exposed to 29 or 31 ppm for 4 months. Therefore, 31 pp-.
(96 mg/m3) is identified as the NOAEL for this study.
Long-tern Exposure
° Sprague-Dawley rats and both AKR/J and C57BL/6J mice were exposed to
benzene by inhalation at concentrations of either 100 ppm or 300 ppm
6 hours per day, 5 days per week for life by Snyder et al. (1980).
Both rats and mice exhibited lymphocytopenia, anemia and decreased
survival time. Tn mice these effects were accompanied by granulocytosis
and reticulocytosis. A later evaluation of the same study showed
preliminary evidence of carcinogenicity, bone marrow hypoplasia,
anemia and lymphocytopenia (Snyder et al., 1980).
Reproductive Effects
0 There is no strong evidence that benzene produces teratogenic effects.
It is a potent inhibitor of growth in utero (U.S. EPA, 1983b).
Mutagenicity
° Benzene was found not to be mutagenic in Drosophila melanogaster by
Nylander et al. (1978). In this study, newly hatched larvae were
exposed to media containing benzene at a concentration of 1% or 2%.
Mutation, as measured by a shift in eye pigmentation, was not noted
at either concentration.
° Benzene at 20 or 600 ug/plate was shown not to be mutagenic in Salmonella
typhimurium when tested with or without metabolic activation in
strains TA100, TA98, TA1535, TA1537 and TA1538. Levels up to 880
ug/plate with activation were not mutagenic in strains TA98 and TAi0?r
(Dean, 197B).
° Benzene oxide , the presumed initial metabolite of benzene, was
mutagenic without activation in an Ames test using S^. typhimuriun
(Pulkrabek et al., 1980).
° A marked increase in sister chromatid exchanges (SCE) was reported in
DBA/2 mice exposed to benzene at 3100 ppm by inhalation for 4 hours
(Tice et al., 1980).
Carci noaeni ci ty
° Benzene has produced both solid tumors and leukemias in Sprague-Dawley"
rats (Maltoni and Scartano, 1979). Benzene dissolved in olive oil
was administered by gavage to 13 week old Sprague-Dawley rats at
doses of 50 or 250 mg/kg/day 4 to 5 days a week for 52 weeks. The
animals were then allowed to live until spontaneous death. The high
dose group consisted of 35 rats of each sex; the low dose and vehicle
control goups consisted of 30 rats of each sex. After 20 weeks of
exposure, the denominators were corrected (numbers of animals
23
-------
Benzene
-7-
surviving) to reflect compound-related deaths. The 250 mgAg group
then consisted of 33, males and 32 female rats; the 50 mgAg and
control groups consisted of 28 male and 30 female rats each. At the
end of 144 weeks, 25% of the females had Zymbal gland tumors, 6.2%
had skin carcinomas and and 12.1% had leukemias.
V. QUANTIFICATION OF TOXICOLOCICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA b (NOAEL or LOAEL) x (BW) B ng/L ( Ug/L)
(UF) x ( L/day )
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effeet-Level
i n mgAg bw/day .
BW = assumed bocfr weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
Insufficient data are available to calculate a One-day HA for benzene.
Similarly, the National Acadeny of Sciences (1982) has stated that there are
insufficient data to determine a one-day SNARL. The Ten-day HA (0.235 mg/L
or 235 ug/L) is considered to be adequately protective for a one-day exposure
as well.
Ten-day Health Advisory
The calculation of the Ten-day HA is based on the study of Deichman,
et al. (1963) who exposed Sprague-Dawley rats to benzene by inhalation
6 hours per day, 4 days per week, at a broad range of concentrations and
monitored their hematology weekly. By the second week of treatment, there
was definite hematological impairment, including severe leukopenia, at the
61, 65 and 831 ppra exposure concentration and moderate leukopenia, especially
in females, at the 44 end 47 ppm exposure concentrations. Leukopenia was not
observed, however, at 29 or 31 ppm.
Using the NOAEL of 31 ppm (96 mg/m^), the Ten-day HA is calculated as
follows:
24
-------
Benzer.c
March 31, 196"
-8-
Step 1: Determination of the Total Absorbed Dose (TAD)
TAD = (96 B,V/m3)(7Q6k**) <0'5> {*} "2.35 mg/kg/day
where:
96 mg/m3 ¦ 31 ppm exposure; NOAEL for leukopenia in rats.
6 k3 « volume of air inhaled during 6 hours of exposure; based
upon equivalent lung to whole body ratios for adult humans
and rats (Olson and Gehring, 1976).
0.5 » pulmonary absorption factor for benzene (Nomiyama and
Nomiyama, 1974a,b).
4/7 = conversion of total weekly dose to equivalent daily dose.
Step 2: Determination of the Ten-*3ay Health Advisory
Ten-day HA » (2.35 mg/kg/day)(10 kg) „ 0.235 mg/L (235 ug/L)
(100) (1 L/day)
where:
2.35 mg/kg/day * TAD.
10 kg « assumed boty weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day « assumed daily water consumption of a child.
Longer-terr Health Advisories
Longer-term Health Advisories have not been calculated because of the
carcinogenic potency of benzene.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risr. of deleterious effects over a lifetime, and is derived frorc
the NOAEL (or LGAEL), identified from a chronic (or subchronic) study, divided
ty an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinkinc
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
25
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Benzene
March 31, 19c?
-9-
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20* is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. Zf the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
A Lifetime Health Advisory has not been calculated because of the
carcinogenic potency of benzene.
Evaluation of Carcinogenic Potential
0 Benzene is a known human carcinogen.
° U.S. EPA (1985a) has estimated that excess upper-bound lifetime cancer
risks of 10-4, io-5 and 10~6 correspond to benzene in drinking water
at concentrations of 70, 7 and 0.7 ug/L, respectively.
° IARC (1982) has classified benzene as a Group 1: Human carcinogen.
® Applying the criteria.in the EPA guidelines for assessment of carcino-
genic risk (U.S. EPA, 1986), benzene may be classified as a Group A:
human carcinogen. This category is for substances for which there is
sufficient evidence from epidemiologic studies to support the causal
association between exposure to the agents and cancer.
VI. OTHER CRITERIA, STANDARDS AND GUIDANCE
6 The National Academy of Sciences has not calculated SNARLS or ADIs for
benzene (NAS, 1982).
0 Tne current OSHA recommendation for a 10-hour time-weighted average
(TWA) exposure to benzene in air is 3.2 ug/L (1 ppm) and is a lowest
feasible level in the work place. This level would allow a daily
dose of 16 mg.
VII. ANALYTICAL METHODS
0 Analysis of benzene is by a purge-and-trap gas chromatographic proce-
dure used for the determination of volatile aromatic and unsaturated
organic compounds in water (U.S. EPA, 1965b). This method includes
the bubeling of an inert gas through the sample and trapping benzene
on an adscrber.t material which is then heated to drive off benzene onto
a gas chromatographic column. Tfce gas chromatograph is temperature-
programmed to separate the resulting analytes which are then detected
by the photoionization detector. This method is applicable to the
measurement of benzene over a concentration range of 0.02 to 1500 ug/L.
Confirmatory analysis is by mass spectrometry (U.S. EPA, 1985c), which
has a detection limit of 0.2 ug/L for benzene.
26
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Benz ene
March 31, 1
-10-
VIII. TREATMENT TECHNOLOGIES
0 Treatment technologies which will remove benzene from water include
granular activated carbon (GAC) adsorption, air stripping and boiling.
0 Dobbs and Cohen (1980) developed adsorption isotherms for several
organic chemicals including benzene. It was reported that Filtrasorb®
300 carbon columns exhibited adsorptive capacities of 0.007 mg, 0.03 mg,
1 mg and 40 mg benzene/g carbon (Beaudet et al., undated, Bilello and
Beaudet, 1981).
• Air stripping is an effective, simple and relatively inexpensive
process for removing benzene and other organics from water. Benzene
is amenable to air stripping on the basis of its Henry 's Law Constant
of 240 atm at 20°C (Kavanaugh and Trussel, 1980). Cummins (1985)
reported that benzene could be removed from water contaminated by a
gasoline spill ty packed column air stripping. In this field study,
24' x 2' columns packed with plastic saddles were used to treat water
containing 190 ug/L benzene and other contaminants. Removal effi-
ciencies of 70 to 100% were obtained using air-to~water ratios of
8.1:1 to 87:1. At air-to-water ratios of 17:1 or greater, efficiencies
were 97% or better. Use of this process, however, transfers the
contaminant directly to the air stream. When considering the use of
air stripping as a treatment process, it is suggested that careful
consideration be given to the overall environmental consequences and
various hazards associated with release of this chemical into the
air.
° Boiling also is effective in eliminating benzene from water. Studies
have shown that 10 minutes of vigorous boiling will remove 99% of
the benzene (Love et al., 1983).
27
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Benz ene
March 31, 195-7
-11-
REFERENCES
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Effects of toluene on the metabolism, disposition and hemopoietic toxicity
of 3H-benzene. Biochem. Pharmacol. 26:293-300.
Beaudet, B.A., E.M. Keller, L.J. Bilello and R.J. Turner. Undated. Removal
of specific organic contaminants from industrial wastewaters by granular
activated carbon adsorption. Incomplete citation.
Bilello, L.J., and B.A. Beaudet. 1981. Evaluation of activated carbon by
the dynamic mini-column adsorption technique. Incomplete citation.
Chang, I.w. 1972. Study on the threshold limit value of benzene and early
diagnosis of benzene poisoning. J. Cath. Med. Coll. 23:429.
Cummins, M.D. 1985. Field evaluation of packed column air stripping.
U.S. EPA.
Dean. B.J. 1978. Genetic toxicolo®' of benzene, toluene, xylenes and phenols.
Mut. Res. 47:75.
Deichmann, W.B-, W.E. Mac2onald and E. Bernal. 1963. The hemopoietic tissue
toxicity of benzene vapors. Toxicol. Appl. Pharmacol. 5:201-224.
Dobbs, R.J., and J.M. Cohen. 1980. Carbon isotherms for toxic organics.
U.S. EPA.
Doskin, T.A. 1971. Effect of age-on the reaction to a combination of hydro-
carbons. H/giene and Sanitation. 36:379.
Forni, A., E. Pacifico and A. Limonta. 1971. Chromosome studies in workers
exposed to benzene or toluene or both. Arch. Environ. Health. 22:373-354.
Gemert Von, L.J., and A.H. Nettenbreijer. 1977. Compilation of odor threshold
values in air and water. National Institute for Mater Supply, Voorburg,
Netherlands.
Gerarde, H.W. 1960. Toxicolocy and biochemistry of aromatic hydrocarbons.
Elsevier Publishing Company., N.Y.
Hough, H., and S. Freeman. 1944. Relative toxicity of commercial benzene
and a mixture of benzene, toluene and xylene. Fed. Proc. 3:20.
IARC. 1982. International Agency for Research on Cancer. IARC monographs,
some industrial chemicals and dyestuffs. 29, 63.
Kavanaugh, M.C., and R.P.. Trussel. 1980. Design of aeration towers to strip
volatile contariunants from drinking water. JAWWA. Dec.
Kissling, M., and B. Speck. 1969. Chromosome aberrations in experimental
benzene intoxication. Helv. Med. Acta 36:59.
28
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Benzene
March 31, 19£?
-12-
Lange, A.R., Smolick, W. Zatonski and J. Syzmanska. 1973. Serum immunoglobulin
levels in workers exposed to benzene, toluene and xylene. Int. Arch.
Arbeitsmed. 31:248.
Lonneman, W.A., T.A. Bellar and A.P. Altshuller. 1968. Aromatic hydrocarbons
in the atmosphere of the Los Angeles basin. Environ. Sci. Technol.
2( 11): 1017.
Love, O.T., R.J. Miltnen, R.G. Eilers and Fronk-Leist. 1983. Treatment of
volatile organic compounds in drinking water. U.S. EPA, MERL,
Cincinnati, OH 45268. EPA-600/8-83-019.
Maltoni, C., and C. Scartano. 1979. First experimental demonstration of the
carcinogenic effects of benzene: Long term bioassays on Sprague-Dawley
rats by oral administration. Med. Lav. 70:352-357.
Mara, S.J., and S.S. Lee. 1978. Assessment of human exposures to atmospheric
benzene. U.S. Environmental Protection Agency, Research Triangle Park,
NC. EPA-450/3-78-031.
NAS. 1976. National Acadeny of Sciences. Health effects of benzene: A
review. Committee on Toxicology, Assembly of Life Sciences, National
Research Council. Wash. O.C.
NAS. 1982. National Acadeny of Sciences. Drinking Hater and Health.
Voluir? 4. National Academy Press, Washington, O.C..
NIOSH. 1974. National Institute of Occupational Safety and Health. Criteria
for a recommended standard . . . occupational exposure to benzene. U.S.
DHEK, Washington, DC. PB246 700.
Nomiyama, K., and H. Nomiyama. 1974a. Respiratory retention uptake and
excretion of organic solvents in man. Benzene, toluene, n-hexane,
trichloroethylene, acetone, ethyl acetate, and ethyl alcohol.
Int. Arch. Arbeitsmed. 32:75-83.
Nomiyama, K., and H. Nomiyama. 1974b. Respiratory elimination of organic
solvents in man. Benzene, toluene, n-hexane, trichloroethylene, acetone,
ethyl acetate, and ethyl alcohol. Int. Arch. Arbeitsmed. 32:85-91.
Nylander, P., H. Olaffsson, B. Rasmuson and H. Svahlin. 1378. Mutagenic
effects of petrol in Drosphila melanogaster. I. Effects of benzene and
1,2-dicloroethane. Mut. Res. 57:163.
OSHA. 1978. Occupational Safety and Health Administration. Final environ-
mental impact statement. Benzene. U.S. Dept. of Labor, Washington, DC.
Parke, D.V., and R.T. Williams. 1953. Studies in detoxication. The metabo-
lism of benzene containing 14C benzene. Biochem. J. 54:231-238.
Petrini, M. 1941. Investigations on acute and subacute poisoning by benzene.
Rass. Med. Ind. 12^435-476. (In Italian)
29
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Benzene
March 31, 19 5"
-13-
Pulkrabek, P., T. Kinoshita and A.M. Jeffery. 1980. Benzene oxide: In Vitro
mutagenic and toxic effects. Proc. 16th Ann. Meeting Amer. Soc. Clin.
Oncol. 21:107.
Rinsky, R.A., R.J. Young, A and B. Smith. 1981. Leukemia in benzene workers.
Amer. J. Ind. Med. 2:217-245.
Rickert, D.E., T.S. Baker, J.S. Bus, C.S. Barrow and R.D. Irons. 1979.
Benzene disposition in the rat after exposure ty inhalation. Toxicol.
Appl. Pharmacol. 49:417-423.
Runion, H.E. 197S. Benzene in gasoline. An. Xndust. fyg. Assn. J.
36:338-350.
Santesson, C.G. 1897. uber chronische vergiftung mit steinkohlentheerbenzin;
vir todesfalle. Arch. Hyg. Berl. 31:336.
Schrenk, H.H., W.P. Yant, S.J. Pearce, F.A. Patty and R.R. Sayers. 1941.
Absorption, distribution and elimination of benzene by body tissues and
fluids of dogs exposed to benzene vapor. J. Ind. tyg. Toxicol. 23:20-34.
Sherwood, R.J. 1972. Benzene: The interpretation of monitoring results.
Ann. Occup. B/g. 15:409-421.
Smolick, R., K.Grzybek-Hryncewica, A. Lange and W. Zatonski. 1973. Seruni
complement level in workers exposed to benzene, toluene and xylene.
Int. Arch. Arbeitmed. 31:243.
Snyder, R., E.w. Lee and J.J. Kocsis. 1978. Binding of labeled benzene
metabolites to mouse liver and bone marrow. Res. Commun. Chem. Pathol.
Pharmacol. 20:191-194.
Snyder, C.A., B.D. Goldstein and A.R. Sellakumar. 1980. Hematotoxicity of
inhaled benzene, to Sprague-Dawley rats and AKR mice at 300 ppir..
J. Toxicol. Environ. Health. 4:605-618.
Tice, R.R., D.L. Costa and R.T. Drew. 1980. Cytogenetic effects of inhaled
benzene in murine bone marrow; Induction of sister chromatid exchanges,
chromosomal aberrations, and cellular proliferation inhibition in DBA/2
mice. Proc. Natl. Acad. Sci. USA 77:214831S2B.
Tough, I.M., P.G. Smith, W.M. Court Brown and D.G. Harnden. 1970. Chromosome
studies on workers exposed to atmospheric benzene: The possible influence
of age. Europ. J. Cancer 6:49-55.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water related environ-
mental fdte of 129 priority pollutants. Office of Water Planning and
Standards, EPA-440/4-79-029, December 1979.
U.S. EPA. 1S82a. U.S. Environmental Protection Agency. Benzene occurrence in
drinking water, food, and air. Office of Drinking Water. Washington, DC.
30
-------
Benzene
Ma r ch 31, 1S c7
-1 4-
U.S. EPA. 1983b. U.S Environmental Protection Agency. Benzene draft criteria
document. Office of Drinking Water. Washington, DC.
U.S. EPA. 1984a. U.S. Environmental Protection Agency. Intermedia priority
pollutants guidance documents. Office of Toxic Substances. Washington, DC.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. National primary
drinking water regulations; Volatile synthetic organic chemicals; Proposed
rulemaking. Fed. Reg. 49(114}<24330-24355. June 12.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Proposed RMCL background
document for Benzene for the Office of Drinking Water, Criteria and
Standards Division. Washington, DC.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Method 503.1.
Volatile aromatic and unsaturated organic compounds in water by purge
and trap gas chromatography. Environmental Monitoring and Support
Laboratory, Cincinnati, Ohio. June 1985.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio. June 1985.
J.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for car-
cinogenic risk assessment. Fed. Reg. 51(185):33992-34003. September 24.
J.S. ITC. 198'1. U.S. International Trade Commission. Synthetic organic
chemicals. United States production, 1983. U.S. ITC Publication 1422.
Washington, D.C.
hite, w.Cm, and A.M. Gammon. 1914. The influence of benzol inhalation on
experimental pulmonary tuberculosis in rabbits. Trans. Assoc. Amer. Phys.
29:332-337.
indnolz, M. 1983. The Merck Index. 10th Edition. Merck and Co., Inc.
Rahway, NJ.
internitz, M.C., and A.D. Hirschfelder. 1913. Studies on experimental
pneumonia in rabbits: Parts I-III. J. Exptl. Med. 17s664.
olf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and F. Cyen.
1956. Toxicological studies of certain alkylated benzenes and benzene.
Arch. Ind. Health. 14:387-389.
31
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March 31, 19S~
CARBON TETRACHLORIDE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten^Jay, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk fro-Ti such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A o:
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit,
risk is usually derived from the linear multistage model with 95% upper
confidence limits. Tnis provides a low-dose estimate of cancer risk tc
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
32
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Carbon Tetrachloride
March 31, 19S~
-2-
This Health Advisory (HA) is based on information presented in the
Office of Drinking Water's Health Effects Criteria Document (CD) for carbon
tetrachloride (U.S. EPA, 1985a). The HA arid CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Water
counterpart (e.g., Water Supply Branch or Drinking Water Branch), or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB #85-118155/AS.
The toll-free number is (800) 336-4700; in the Washington, D.C. area:
(703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 56-23-5
Structural Formula
CI
I
Cl-C-Cl
I
CI
Synonyms
8 Methane tetrachloride, tetrachloromethane, CCI4, perchloroethane.
Us es
0 The major use of CCI4 is in the production of chlorofluorocarbons,
which are used as refrigerants, foam-blowing agents and solvents.
Carbon tetrachloride also is used in fumigants, as a solvent in
metal cleaning and in manufacture of paints and plastics (Rams,
et al., 1979). It is being replaced in grain fumigation by other
registered pesticides (U.S. EPA, 1980a).
Properties (U.S. EPA, 1985a)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Water-Solubility
Taste Threshold
Odor Tnreshold
Conversion Factor
CCI4
153.8
Colorless liquid
76.5#C
-23°C
&l° 1 .594 -•
115.2 mm Hg at 25°C
800 mg/L
not available
0.52 mg/L (Amoore and Hautala, 1983)
6.4 mg/m3 a 1 ppm
33
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Carooa Tetrachloride
March 31, 19
-3-
Occurrence
0 Carbon tetrachloride (CCI4) a synthetic chemical with no natural
sources (U.S. EPA, 1983).
0 Production of CCI4 was approximately 600 million lbs in 1983 (U.S.ITC,
1983). Carbon tetrachloride also is produced as a by-product of the
manufacture of a number of other chlorinated materials.
8 Current major sources of CCI4 released to the environment are from
accidental releases from production and uses. Previously, large
amounts of CCI4 were released from its use as a solvent. Most of the
releases of CC14 occur to the atmosphere by evaporation because of
its high volatility. Some CCI4 may be released to the environment
during the disposal of wastes in landfills or surface waters. The
majority of releases will occur in the areas near its production ana
use (U.S. EPA, 1983).
0 Carbon tetrachloride released to: (1) the environment is fairly stable;
(2) the air, degrades slowly; (3) surface waters, migrates to the
atmosphere in a few days or weeks; and (4) the land, does not sorb
onto soil and migrates readily to ground water. Carbon tetrachloride
is expected to remain in ground water for months to years. Unlike
more highly chlorinated compounds, CCI4 does not bioaccumulate in
individual animals or food chains (U.S. EPA, 1979).
0 Carbon tetrachloride occurs ubiquitously in the air but at concen-
trations of iess than 10 ppt. Carbon tetrachloride is a fairly rare
contaminant in ground and surface waters, with higher levels found in
ground water. The Agency estimates that less than 1% of all ground
waters derived drinking water systems have levels of CCI4 greater
than 0.5 ug/L and less than 0.2 % greater than 5 mg/L (U.S. EPA, 19S3,.
0 Very limited information is available on the occurrence of carbon
tetrachloride in food. In the past, CCI4 has been used as a gram
fumigant and low levels have been reported to occur in some foods fror
this use (U.S. EPA, 1983).
0 The major source of exposure to CCI4 is from contaminated air. Water
and food are only a minor sources.
III. PHARMACOKINETICS
Absorption
0 Carbon tetrachloride is absorbed readily from the gastrointestinal
tract, the respiratory tract and the skin. About 60% of an oral dose
(1600 mg/kg) was absorbed by rats within six hours (Reddrop et al.,
1981), and 65 to 86% of oral doses of 2,000-4,000 mg/kg were absorbed
by rats within 24 hours (fi-1 and Rubinstein, 1963; Seawright and
McLean, 1967; Marchand et al., 1970).
34
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Carbon Tetrachloride
Mc.rcn 31, 1 9i ~
-4-
Absorption from the lung has been reported as about 30% in monkeys
exposed to 290 mg CCl4/ra3 for 139, 344 or 300 minutes (McCollister
et al., 1952).
Bruckner et al. (1986a) assessed potential effects of different vehicles
on the pharmacokinetics of CCI4. Fasted 200 g male Sprague-Dawley
rats with indwelling arterial cannulas received 25 mg/kg CCI4 by
gavage: in corn oil; as an aqueous emulsion; in water; and as pure
undiluted chemical. A 25 mg/kg dose was given intravenously for
calculation of bioavailability. Serial blood samples were taken and
analyzed for CCI4. Peak concentrations of CCI4 in the blood were
reached within 8 minutes after dosing in the emulsion and saturated
water groups. These peak levels were slightly higher than in the
pure CCI4 group and substantially higher than in the corn oil group.
There was evidence of later secondary peaks of lesser magnitude in
the corn oil group. The absolute bioavailability for the emulsion
and saturated water groups was higher than for the corn oil and pure
chemical groups, and comparable to the intravenous group.
Distribution
0 Carbon tetrachloride appears to be distributed to all major organs
following absorption (U.S. EPA, 1985a). Carbon tetrachloride has been
found in fat, liver, blood, brain, kidney and muscle, with particularly
high concentrations in fat. Carbon tetrachloride reaches maximal
concentrations in most tissues at approximately two to four hours
following intragastric administration (Marchand et al., 1970).
Metabolism
0 Carbon tetrachloride metabolism occurs primarily in the liver. The
first step is thought to be formation of a trichloromethyl radical ir.
the cytochrome heme moiety. This trichloromethyl radical undergoes a
variety of reactions, including hydrogen abstraction to form chloro-
form, dimerization to form hexachloroethane and addition to cellular
molecules. Further metabolism of the heme-bound trichloromethyl
radical is postulated to result in the eventual formation of carbonyl
chloride (phosgene) (Shah et al., 1979 with an in vitro study witn
rat liver).
0 After a single oral dose of CCI4 in Wistar rats, Bini et al. (1975)
proposed that the trichloromethyl free radical was the main metabolite
of CCI4 after they found chloroform and hexachloroethane as metabolites
in the rats. Fowler (1969) found these metabolites in rabbits given
CCI4 orally. McCollister et al. (1951) detected labeled carbon
dioxide exhaled by monkeys exposed to 14C-CC14 by inhalation.
Excretion
0 Carbon tetrachloride and its volatile metabolites are excreted pri-
marily in exhaled air and also in the urine and feces (U.S. EPA,
1985a). Elimination of orally ingested CCI4 occurs with an estimated
half-time of four to six hours, and most of an oral dose is excreted
35
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Caroo.n Tetrachloride
March 1?-:
-5-
within one to two days. No reports were located regarding the tissue
accumulation and retention of CCI4 during chronic exposure.
HEALTH EFFECTS
Humans
° The effects of CCI4 exposure in humans are similar to effects seen
in animals, with the liver, kidney and lungs being mo3t sensitive.
8 Single oral doses of 2.5 to 15 mL (57 to 343 mg/kg) are usually
without effect, although changes may occur in liver and kidney
(U.S. EPA, 1985a). Some individual adults suffer adverse effects
(including death) from ingestion of as little as 1.5 mL (34 mg/kg),
and 0.18 to 0.92 mL may be fatal in children (29 to 150 mg/kg)
(U.S. EPA, 1985a).
0 Inhalation exposure also results in central nervous system depression
and renal and hepatic damage (U.S. EPA, 1985a). No ill effects
result from three hours of exposure to 63 mg/m3, but 70 minutes of
exposure to 2,309 mg/m3 may produce liver effects. High levels
(1,500 mg/m3) may produce severe poisoning and death.
Animals
Short-terrr. Exposure
0 Carbon tetrachloride is toxic to animals, with oral LD50 values ranging
froir 1 ,000 to 12,800 mg/kg (U.S. EPA, 1985a).
c The tissue most affected by CCI4 is the liver. Using release of
liver enzymes into serum and histological examination as end-points,
single oral doses (in corn oil) of 40 mg CCI4A9 did not produce
adverse effects, while doses of 80 mg/kg or higher did in male Sprague-
-Dawley rats (Bruckner et al., 1986b). Numerous studies have founc
that oral doses ranging from about 100 to 4,000 mgAg produce fatty
infiltration, loss of cytochrome P-450 and other enzymes, inhibition
of protein synthesis and histological alterations in the liver. When
damage is severe, hepatocellular necrosis may result, but the effects
observed following lower doses are largely reversible (U.S. EPA, 1985a).
® Kidney and lung also are affected following oral exposure to CC14
(U.S. EPA, 1985a). Single doses of about 4,000 mg/kg result in lesions
of the renal proximal tubule in rats and pulmonary Clara cells and
endothelial cells in rats and/or mice. These changes also appear to
be reversible when damage is not too severe.
0 Bruckner et al. (1986b) found hepatotoxic effects (increased serum
enzymes, pathology) in rats given CCI4 in corn oil at daily doses of
20 mgAg and higher by gav=ge for 9 days in an 11-day study.
36
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Carbon Tetrachloride
March 31, ISi
-6-
0 Hayes et al. (1986) observed hepatotoxicity (increased serum enzymes,
increased organ weight) in male and female CD-1 mice given CC14 in
corn oil by gavage at doses of 625, 1,250 or 2,500 mgAg for 14
consecutive days.
8 The objective of a study by Kim et al. (1986) was to assess the
influence of dosing vehicles on the acute hepatotoxicity of CCI4.
Fasted 200 g male Sprague-Dawley rats were given 0, 10, 25, 50,
100, 250, 500, 1,000 or 2,000 ag CCl^/kg by gavage in: corn oil;
as an aqueous emulsion; as the undiluted chemical; and in the 10 and
25 mgAg doses only in water. Blood and liver samples were taken
24 hrs after dosirg for measurement of serum and microsomal enzymes.
Pathological exa-r.ination of liver samples was also conducted. Dose-
dependent increases in serum enzyme levels and pathological changes,
and dose-dependent decreases in microsomal P-450 and glucose-6-
phosphatase activity were observed in each vehicle group. CCI4 was
less hepacotoxic at each dosage level when given in corn oil than
when given as an emulsion or as the pure chemical. CCI4 in corn oil
was also less toxic than CCI4 water at the 10 and 25 mgAg doses.
Long-term Exposure
0 The effects of longer-term exposure to CCI4 are similar to the effects
of short-tern exposure: the liver is the most sensitive tissue,
showing fatty infiltration,. release of liver enzymes, inhibition of
cellular enzyme activities, inflammation and, ultimately, cellular
necrosis (L'.S. EPA, 1985a).
0 Rats exposed by gavage to CCI4 in corn oil at doses of 1 mgAg
5 days/week for 12 weeks did not show measurable adverse effects,
while doses of 10 or 33 mgAg resulted in enzyme release, centri-
lobular vacuolization and necrosis in liver (Bruckner et al., 19S6c).
0 Condie et al. (1985) investigated the' effects of a corn oil vehicle
as well as Tween-60 on the subchronic hepatotoxicity of carbon
tetrachloride (CC14). Male and female CD-1 mice were given 0, 1.2,
12 and 120 mgAg CCI4 by gavage in either corn oil as a solution or
1% Tweeri-60 as a suspension once daily for five consecutive days per
week for 90 days. Hepatotoxicity was greater in the corn oil vehicle
groups of mice than in the Tween-60 groups. Significant increases in
serum enzyme activities were detected in the 12 mgAg CCI4 corn oil
male and female groups but not in the corresponding Tween-60 groups.
When comparing the serum enzyme activities in the high dose groups,
there were dramatic increases in both the male and female corn oil
groups as compared to the corresponding Tween-60 groups. Liver and
liver/body weights were significantly greater in each high dose
group. Histopathological findings indicated that hepatocellular
changes occurrinq during the administration of CCI4 at the 12 mgAg
(hepatocellular cytomegaly, fat and necrosis) and 120 mgAg (necrosis
and fat) dose levels were more frequently observed when CC14 was
given in corn oil than wher. it was administered in Tween-60. The
experimental findings indicate that the corn oil vehicle lowered the
no-observed-adverse-effect level (NOAEL) from CCI4 exposure by an
37
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Carooa Tetrachloride
March 31, lSc~
-7-
order of magnitude (from 12 mg/kg to 1.2 mg/kg) compared to tne
Tween-60 vehicle and also enhanced the hepatotoxicity of CCI4 in the
high dose treatment groups.
0 Hayes et al. (1986) reported hepatotoxic effects (increased serum
enzymes, increased organ weight, pathological lesions) in male and
female CD-1 mice given CCI4 in corn oil by gavage at doses of 12,
120, 540 or 1,200 mg/kg for 90 consecutive days.
0 Alumot et al. (1976) fed 18 male and 18 female rats (strain not
given) 0, 80 or 200 ppm CCI4 in the diet until final sacrifice at two
years. The authors equated 200 ppm to 10-18 mgA? body weight/day.
No adverse effects from exposure to CCI4 were observed. However,
tissues were not examined microscopically, liver weights were not
taken, and survival was below 50% at 21 months. In an earlier 6-week
study, Alumot et al. (1976) found no effect with 22 mgAg and
increased lipid and triglyceride in liver with 40 and 76 mg/kg. Only
body weight was additionally measured.
0 Prendergast et al. (1967) found hepatotoxicity in guinea pigs, rats,
monkeys, rabbits and dogs exposed to 515 mg CCl4/m3 air eight hours/day,
five days/week for six weeks. Liver effects were also found in these
species after continuous exposure to 61 mg/m3 for 90 days but not to
6.1 mg/m3. After inhalation exposure of Wistar rats to CC14 eight
hours/day, five days/week for ten months, Smyth et al. (1936) found
liver toxicity with levels above 315 mg/m3 and kidney changes with at
least 315 mg/ir.3 (lowest level tested). Adams et al. (1952) noted
liver damage in Wistar rats, guinea pigs, and rabbits at some inhalation
exposures ranging from 32.5 to 2,600 mg/m3, seven hours/day, five
days/week for 258 days and no observable effect in a Rhesus monkey
similarly exposed to 25 mg/m3 for 212 days, but the study cannot be
adequately assessed from the limited details reported.
Reproductive Effects
0 No reproductive ewects were noted in rats fed diets containing CCI4
at 80 and 200 ppm for up to two years (Alumot et al., 1976)
Developmental Effects
0 No evidence was located to demonstrate that CCI4 is teratogenic (U.S.
EPA, 1985a). Newborn rats appear to be less sensitive to liver damage
by CCI4 than 7-day-old rats (Dawkins, 1963), An intraperitoneal dose
of 2,400 mgA9 has resulted in adverse effects on testicular function
in rats (Chatterjee, 1966).
Mutagenicity
0 No evidence of mutagenic activity for CCI4 has been found in bacterial
test systems or in cultured liver cells (U.S. EPA, 1985a), except that
Sina et al. (1983) found CCI4 weakly positive at cytotoxic levels in
an alkaline elution/rat hepatocyte assay to measure DNA single-strand
breaks. Increased gene crossover and mitotic recombination were
38
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Carbon Tetrachloride
March 31, 15="
-8-
obserVed in yeast cells exposed to CCI4 at 3,300 to 5,400 mg/L buffer
(Callen et al., 1980). Amacher and Zelljadt (1983) concluded CC14 as
positive for cell transformation in Syrian hamster embryo cells.
0 In an in vivo-in vitro hepatocyte DNA repair assay by Mirsalis,
et al. (1985), CCI4 failed to induce unscheduled DNA synthesis in
male and female BgCjFi mice but did significantly elevate hepatic
cell proliferation. The latter effect was also induced by CCI4 in
male Fischer 344 rats but at higher doses.
Carcinogenici ty
0 Carbon tetrachloride is carcinogenic in animals, producing mainly
hepatic neoplasms. Doses of about 30 mgAg/day or higher for six
months or longer have been found to produce an increased frequency of
hepatocellular tumors in mice, rats and hamsters (U.S. EPA, 1985a).
0 In an exploratory study of a large number of solvents and cancers in
rubber industry workers, Wilcosky et al. (1984) associated exposure
to carbon tetrachloride with lymphosarcoma and lymphatic leukemia,
but they stressed cautious interpretation because of the modest number
of cases and biases.
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive aoncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) = mg/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
.BH ° assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day <» assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The acute animal study by BrucKner et al. (1986b) has been selected to
serve as the basis for the One-day Health Advisory in the 10-kg child because
this study clearly defined a one-day NOAEL (40 mg/kg) and LOAEL (80 mg/kg)
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Carbon Tetrachloride
March 31, 19£~
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for CCI4. based on changes in BUN, GPT, SDH and OCT and histopathological
changes in the liver and kidneys of rats sacrificed 24 hours after dosing.
The abstract report of the study by Kim et al. (1986) does not provide
sufficient details for assessment as a basis for the One-day HA.
The One-day HA for a 10-kg child is calculated as follows:
One-day HA = (40 mg/kg/day) (10 kg) a 4,3 mg/L (4,000 ug/L)
(100) (1 L/day)
where:
40 mg/kg day = NGAEL based on absence of liver toxicity following
one-day exposure in rats.
10 kg • assumed body weight of a child.
100 " uncertainty factor, chosen in accordance with ODW/NAS
guidelines for use with a NOAEL from an animal study•
1 L/day = assumed water consumption of a child.
Ten-day Health Advisory
The short-term study by Bruckner et al. (1986b) has been selected to
serve as the basis for the Ten-day HA for the 10-kg child. This study identi-
fied a LOAEL of 20 mg/kg/day in rats given 9 doses over 11 days, based on
significant increases in serum enzyme levels and hepatic midzonal vacuolization
by 11 days. Higher doses of CCI4 caused even more extensive liver damage.
The 14-day study by Hayes et al. (1986) is not selected because all doses
used were effect levels above those in the Bruckner et al. (1986b) study.
The Ten-day ha for a 10-kg child is calculated as follows:
Ten-aay HA = (20 mg/kg/day) (10 kg) (9) M 0.16 mg/L (160 ug/L)
(1,000) (1 L/day) (11)
where:
20 mg/kg/day = LOAEL based on liver toxicity in rats.
9/11 = factor accounting for 9 doses given over 11 days.
1 0 kg = assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with NAS/ODa
guidelines for use with a LOAEL from an animal study.
1 L/day = assumed water consumption of a child.
40
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Carbon Tetrachloride
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-1 0-
Longer-term Health Advisory
The 12-week study by Bruckner et al. (1986b) has been selected to serve
as the basis for calculation of the Longer-term HA. Bruckner and co-workers
dosed rats with CCI4 in corn oil by gavage five times weekly for 12 weeks
with doses of 1, 10 or 33 mgAg« ®is study identified a NOAEL of 1 mgAg/day
and a LOAEL of 10 mg/kg day for hepatotoxicity. Condie et al. (1985) obtained
similar results with a NOAEL of 1.2 mg/kg/day and a LOAEL of 12 mgAg/day in
CO-mice given CCI4 in corn oil by gavage five times weekly for 90 days. In
the same study/ Condie et al. (1985) found.a NOAEL of 12 mg/kg/day with CCI4
suspended in Tween-60, but these data are not selected for the Longer-Term HA
calculation because of use of a rather insoluble form of CCI4 (suspension) as
the method of dosing. Tne 90-day study by Hayes et al. (1986) is not selected
because a NOAEL was not found, although the LOAEL of 12 mgAg/day approximates
the 10 mgAg/day LOAEL in the Bruckner et al. (1985) study.
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA = (1 mg/kg/day) (10 kg) (5) B 0.071 mg/L (71 -ug/L)
(100) (1 L/day) (7)
where:
1 mgAg/day = NOAEL based on absence of liver toxicity in rats.
10 kg ¦ assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODw
guidelines for use with a NOAEL from an animal study.
5/7 = factor to account for dosing five days per week.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (1 mg/kg/day) (70 kg) (5) s q.25 mg/L (250 ug/L)
(100) (2 L/day) (7)
where:
1 mgAg/day = NOAEL based on absence of liver toxicity in rats.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
5/7 = factor to account for dosing five days per week.
2 L/day = assumed dail;- water consumption of an adult.
41
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Carbon Tetrachloride
March 31, 196"
¦11
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process* Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The R£D is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). Bie RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The 12-week study by Bruckner et al. (1986b) described under Longer-term
Health Advisory is the most appropriate from which to derive the DWEL in that
the available animal toxicity studies with chronic exposure to CCI4 are
concluded to be insufficient for use in the DWEL calculation. Prom these
results, a NOAEL of 1 mg/kg was identified.
The two-year study in rats by Alumot et al. (1976) was not chosen
because the assessment of CCI4 toxicity was deficient with respect to tissue
examination. Tne inhalation studies by Prendergast et al. (1967), Smyth
et al. (1936), and Adams et al. (1952) were not used since inhalation data
are less desirable for HA development.
Using the NOAEL of 1 mg/kg, the DWEL is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = H mg/kg/day) (5) = 0.0007 mg/kg/day
(1,000) (7) y/
./here:
1 mgAg/day
1 . 000
5/7
42
= NOAEL based on absence of liver toxicity in rats orally
given CCI4 for 90 days.
= uncertainty factor, chosen in accordance with NAS/ODw
guidelines for use with a NOAEL from an animal study
of less-than-iifetime duration.
= factor to account for dosing 5 days per week.
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Carbon Tetrachloride
March 31, 19=~
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Step 2: Determination of the Drinking Vfeter Equivalent Level (DWEL)
DWEL = (0.0007 ug/kg/day) (70 kg) = 0.025 mg/L (25 ug/L)
(2 L/day)
where:
0.0007 ug/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water oonsunption of an adult.
Carbon tetrachloride nay be classified in Group B: Probable human
carcinogen. The estimated excess cancer risk associated with lifetime exposure
to drinking water containing carbon tetradiloride at 25 ug/L is approximately
8 x 10~5. This estimate represents the upper 95% confidence limit from extrap-
olations prepared fcy EPVs Carcinogen Assessment Group using the linearized,
multistage model. The actual risk is unlikely to exceed this value, but
there is considerable uncertainty as to the accuracy of risks calculated by
this methodology.
Evaluation of Carcinogenic Potential
0 The IARC (1979) classified carbon tetrachloride as a 2B carcinogen with
sufficient aninal evidence and inadequate human evidence.
# Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), carbon tetrachloride may be
classified in Group B2: Probable human carcinogen. This category is
for agents for which there is inadequate evidence from human studies
and sufficient evidence from animal studies.
0 U.S. EPA calculated a unit risk estimate (the 95% upper limit by the
linearized imiltistage model) of 0.37 x 10"^ for a human continuously
exposed to 1 ug CCI4 per liter of water (U.S. EPA, 1984). The
corresponding 10~6, 10~5 and 10-4 risks are associated with 0.3, 2.7
and 27 ug/L, respectively.
# It should be noted that this approach, which involved using the
geometric mean of risk estimates based on four studies, for calculating
unit risk estimates for CCI4 is from U.S. EPA (1984) which was reviewed
by the U.S. EPA's Science Advisory Board.
# There was an attenpt to conpare risk estimates derived with the
multistage model with other models in U.S. EPA, 1984. Of the studies
used (0=1la Porta efc al., 1961; Edwards et al., 1942? NCI rat and
mouse, 1976), rink estimates could not be calculated with the Weibull
and log probit models, and a time-to-tumor model was successful only
with the NCI (1976) data which gave 95% upper confidence limits similar
to those obtained with tht multistage model. Unit (ingestion of 1 ug
CCI4/L water/lifetime) risk estimates (95% upper confidence limits)
with individual studies and the nultistage model were 3.4 x 10-^
43
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Carbo-. Tetrachloride
March 31, 198'
-13
(Delia Porta et al., 1961), 9.4 x 1 0~® (Edwards et al., 1942),
1.8 x 10~6 (NCI mouse, 1976) and 3.1 x 10"7 (NCI rat, 1976). Unit
risk estimates (maximum likelihood estimates) with individual studies
and the multistage model were 2.1 x 10~5 (Delia Porta et al., 1961),
7.1 x 10~6 (Edwards et al.f 1942), 1.4 x 10~6 (NCI mouse, 1976) and
1.9 x 10~7 (NCI rat, 1976). While recognized as statistically
alternative approaches, the range of risks described by using any of
these modeling approaches has little biological significance unless
data can be used to support the selection of one model over another.
In the interest of consistency of approach and In providing an upper
bound on the potential cancer risk, the EPA has recommended use of
the linearized multistage approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 Data from the animal studies have been used by NAS (1977) and U.S. EPA
(1980b, 1984) to calculate the upper 95% bound on the number of
additional cancer cases that may occur when CC14 is consumed in
drinking water over a 70-year lifetime. By these methods, a 10-6
lifetime excess cancer risk was associated with CC14 in drinking
water at levels of 4.5 ug/L by the NAS (1977), 0.4 ug/L by the U.S.
EPA (l?&0a) and 0.3 ug/L by the U.S. EPA (1984).
0 The criteria for the U.S. EPA, OHEA and NAS risk calculations differ
in two respects: (1) NAS used the multistage model, while U.S. EPA
used an "improved" multistage model; and (2) NAS used the data set
from the National Cancer Institute (NCI) study in male rats while
U.S. EPA initially used the data set from the NCI study in male mice
(U.S. EPA, 1980b) and subsequently used a geometric mean of four
studies (NCI, 1976 - mice; NCI, 1976 - rats; Edwards et al., 1942 -
mice; and Delia Porta et al., 1961 - hamsters) (U.S. EPA, 1984J.
0 Ambient water quality criteria for CCI4 calculated by the EPA (U.S.
EPA 1980b) were based on increased lifetime cancer risk estimates cf
10~5 (4.0 ug/L), 10-6 (0.40 ug/L), and 10"7 (0.04 ug/L). It is note-
worthy that these estimates were derived by assuming a lifetime con-
sumption of both drinking water (2 L/day) and aquatic species (6.5 g
fish and shellfish/day) taken from waters containing the corresponding
CCI4 levels. Specifically, daily CCI4 exposure assumptions were as
follows: 94% from ingesting drinking water and 6% from consuming
seafood "fish factor." The corresponding "drinking water only"
concentrations were 4.41, 0.44, and 0.04 ug/L, respectively.
0 Using the carcinogenicity data set and a linear multistage model,
WHO (1984) derived a recommended tentative limit for CC14 of 3 ug/L
as a level which should result in less than one additional cancer
per "00,0CC population (10-5) for a lifetime of exposure assuming
daily consumption of two liters of drinking water.
0 The U.S. EPA (1981) and NAS (1980) previously calculated SNARLS
(Suggested No-Adverse-ResF'jnse Levels) for CCI4 in drinking water.
These guidelines are summarized in Table 1.
44
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Carbon Tetrachloride
March 31, 198"
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TABLE 1
Summary of Existing Guidelines for CCI4
USEPA*
NASb
One-day
0.2 mg/L
14 mg/L
Seven-dayc
-
2 mg/L
Ten-dayc
0.02 mg/L
-
Long-term
None^
Nonee
aU.S. EPA (1981) used a LOAEL of 20 mg/kg (Korsrud et al., 1972) as the
basis for their calculations.
bNAS (1980) used a LOAEL of 400 mg/kg (Murphy and Malley, 1969) as the
basis for their calculations.
cIn the absence of subacute oral data, the NAS (1980) and U.S. EPA (1981)
calculated 7- and 10-*3ay SNARLS by dividing their one-day values by
7 and 10, respectively.
<^The U.S. EPA (1981) did not calculate a long-term SNARL due to a lack
of acceptable chronic oral exposure data at that time.
e,Rie NAS (1980) did not determine a long-term SNARL because of NAS policy
at that time not to calculate such values for animal carcinogens.
0 The final RMCL by the U.S. EPA Office of Drinking Water is 0, the
proposed MCL. is 5 ug/L, and the practical quantitation level is 5 ug/L
(U.S. EPA, 1985e).
0 The U.S. EPA Office of Pesticide Programs has published a notice of
intent to cancel registrations of grain fumigation products contain^::
CCI4 (U.S. EPA, 1986b).
The OSHA standard in 10 ppm (TWA), and the ACGIH (1983) has recommended
a TLV of 5 ppm and an STEL of 20 ppm.
0 The U.S. EPA (1985d) has published a notice of intent to list CCI4
under Section 112 of the Clean Air Act.
VII. ANALYTICAL METHODS
0 Analysis of CCI4 is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile organohalides in drinking water
(U.S. EPA, 1985b). This method calls for the bubbling of an inert
gas through the sample and trapping CCI4 on an adsorbent material.
?he adsorbent material is heated to drive off the CCI4 onto a gas
chromatographic column, TTv-s method is applicable to the measurement
of CCI4 over a concentration range of 0.03 to 1500 ug/L. Confirmatory
analysis for carbon tetrachloride is by mass spectrometry (U.S. EPA,
45
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Carzor. Tetrachloride
March 31, 19E
-15
1985c). The detection limit for confirmation by mass spectrometry is
0."3 ug/L.
VIII. TREATMENT TECHNOLOGIES
# Treatment techniques which will remove carbon tetrachloride from
drinking water include granular activated' carbon adsorption, boiling,
and aeration (Combs, 1980).
° Pilot plant studies by EPA's Drinking Hater Research Division have
shown consistently that conventional treatment processes (coagulation,
sedimentation, filtration), even when augmented by the addition of pow-
dered activated carbon, provide little removal of carbon tetrachloride.
0 The use of powdered activated carbon was only partially effective at
doses as high as 30 ug/L (Love et al., 1983; Symons et al., 1979;
Lykins et al., 1980).
0 Carbon tetrachloride at a raw water concentration of 12 ug/L treated
using Filtrasorb® 400 granular activated carbon exhibited breakthrough
after three weeks. The empty bed contact time reported was 5 minutes.
When the empty bed contact time was increased to 10 minutes, break-
through occurred at 14 to 16 weeks (Symons, 1978).
0 A full-scale installation investigation conducted by Calgon using twin
granular activated carbon beds in series (EBCT of 130 minutes) reported
that, along with other chemicals, carbon tetrachloride was removed to
below detection from an influent concentration of 73 ug/L (O'Brien
et al., 1981).
0 A study demonstrated that the synthetic resin (Ambersorb XE-340)
removed carbon tetrachloride from treated drinking water with an
effectiveness similar to Filtrasorb® 400 (Symons et al., 1979). It
should be noted that these resins are not commercially available.
0 Boiling also is effective in eliminating carbon tetrachloride fror, a
solution. Studies have shown that five minutes of vigorous boilin?
will remove upwards of 99% of the carbon tetrachloride originally
present (Combs, 1980; Love and Eilers, 1981).
0 Finally, aeration may be used to remove carbon tetrachloride from
water. Laboratory studies conducted by Love et al. (1983) showed
that a diffused air aerator could remove 91% of the carbon tetra-
chloride in the water using a 4:1 air to water ratio.
0 Air stripping is an effective, simple, and relatively inexpensive
process for removing carbon tetrachloride and volatile organics from
water. However, use of this process then transfers the contaminant
directly to the air stream. When considering use of air stripping as
a treatment process, it is suggested that careful consideration be
given to the overall environmental occurrence, fate, route of exposure
and various hazards associated with the chemical.
46
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IX. REFERENCES
ACGIH. 1983. American Conference of Governmental Industrial Hygienists,
Inc. Documentation of the threshold limit values. 4th ed. Cincinnati.
Adams, E.M., H.C. Spencer, V.K. Rowe, D.D. McCollister and 0.0. Irish. 1952.
Vapor toxicity of carbon tetrachloride determined by experiments on
laboratory animals. Arch. Indust; Hyg. Occup. Med. 6«50-66.
Alumot E., E. Nachtomi, E. Mandel and P. Holstein. 1976. Tolerance and
acceptable daily intake of chlorinated fumigants in the rat diet.
Food Cosmet. Toxicol. 14:105-110.
Amacher, O.E., and I. Zelljadt. 1983. Bie morphological transformation of
Syrian hamster embryo cells by chemicals reportedly nonmutagenic to
Salmonella typhimurium. Carcinogenesis. 4(3):291-296.
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety:
Odor thresholds compared with threshold limit values and volatilities
for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol.
3:272-290.
Bini, A., G. Veccni, G. Vivioli, V. Vannini and C. Cessi. 1975. Detection
of early metabolites in rat liver after administration of CCI4 and CBrClj.
Pharmacol. Res. Comrnun. 7:143-149.
Bruckner, J.v., H.J. Kim, C.E. Dallas, R. Ramanathan, S. Muralidhara and J.x.
Gallc. 1986a. Effect of dosing vehicles on the pharmacokinetics of
orally administered carbon tetrachloride (CCI4). Society of Toxicology
1987 Annual Meeting. (In press) (Abstract)
Bruckner, J.V., W.F. MacKenzie, S. Muralidhara, R. Luthra, G.M. Kyle and
D. Acosta. 1986b. Oral toxicity of carbon tetrachloride: acute, sub-
acute and subchronic studies in rats. Fund. Appl. Toxicol. 6:16-34.
Callen, D.F., £.R. Wolfe and R.M. Philpot. 1980. Cytochrome P-450 mediate-:
genetic activity and cytotoxicity of seven halogenated aliphatic hydro-
carbons in Saccharomyces cerevisiae. Mutation Res. 77:55-63.
Chatterjee, A. 1966. Testicular degeneration in rats by carbon tetrachloride
intoxication. Experientia. 22:394-396.
Combs, w.s. 1980. Removal of chlorinated solvents from water by boiling.
State of Rhode Island and Providence Plantations Dept. of Health, Provi-
dence, RI. (MIMEO)
Condie, L.W., R,D. Laurie, M. Robinson and J.F. Bercy. 1985. Effect of corn
"oil cavage on hepatotoxicit; of carbon tetrachloride in CD-1 mice.
Fund. Appl. Toxicol. In press.
Dawkins, M.J.R. 1963. Carbon tetrachloride poisoning in the liver of the
newborn rat. J. Pathol. Bacteriol. 85:189-196.
47
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Della Porta, G., B. Terraci.nl, and P. Shubik. 1961. Induction with carbon
tetrachloride of liver cell carcinomas in hamsters. J. Natl. Cancer
Inst. 26:855-863.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/880-023, Office of Research and Development, Cincinnati,
OH.
Edwards, J.E., H.E. Heston and A.J. Dalton. 1942. Induction of the carbon
tetrachloride hepatoma in strain L. mice. J. Natl. Cancer Inst.
3:297-301.
Fowler, J.s.L. 1969. Carbon tetrachloride metabolism in the rabbit. Brit.
J. Pharmacol. 37:733-737.
Hayes, J.R., L.w. Condie, Jr., and J.F. Borzelleca. 1986. Acute, 14-day
repeated dosing, and 90-day subchronic toxicity studies of carbon tetra-
chloride in CD-I mice. Fund. Appl. Toxicol. 7:454-463.
IARC. 1979. International Agency for Research on Cancer. IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Man. 20:371-399.
Kix, H.J., S. Qdend'hal, R. Ramanathan, C.E. Dallas, S. Muralidhara and J.v.
Bruckner. 1986. Effect of oral dosing vehicles on acute hepatotoxicity
of carbon tetrachloride (CCI4) in rats. Society of Toxicology 1987
Annual Meeting. (In press) (Abstract)
Korsrud, G.O., H.C. Grice and J.M. McLaughlan. 1972. Sensitivity of several
serum enzymes in detecting carbon tetrachloride-induced liver damage in
rats. Toxicol. Appl. Pharmacol. 22:474-483.
Love, O.T., Jr., and R.G. Eilers. 1981. Treatment for the control of tri-
chloroethylene and related industrial solvents in drinking water. U.S.
EPA, Office of Research and Development, Cincinnati, OH.
Love, O.T., Jr., R.J. Miltner, R.G. Eilers and C.D. Fronk-Leist. 1983.
Treatment of volatile organic compounds in drinking water. U.S. EPA,
Municipal Environmental Research Laboratory. EPA-600/8-83-019.
Lykins, B.W., and J. DeMarco. 1980. An overview of the use of powdered
activated carbon for removal of trace organics in drinking water.
U.S. EPA, Office of Research and Development, Cincinnati, OH. (Draft)
Marchand, C., S. McLean and G.L. Plaa. 1970. The effect of SKF 525A on the
distribution of carbon tetrachloride in rats. J. Pharmacol. Exp. Ther.
174:232-238.
McCollister, D.D., W.H. Beamer, G.J. Atchison and H.C. Spencer.. 1951.
The absorption, distribution and Tlimination of radioactive carbon
tetrachlori.de by monkeys upon exposure to low vapor concentrations.
J. Pharmacol. Exp. Ther. 102:112-124.
48
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Carbon Tetrachloride
March 31, 19C ~
-18-
Mirsalis, J.C., C.K. Tysn, E.N. Loh, O.K. Spek and J.W. Spalding. 1985.
Induction of hepatic cell proliferation and unscheduled DNA synthesis
in mouse hepatocytes following In vivo treatment. Carcinogenesis.
6:1521-1524.
Murphy, S.D., and S. Mailey. 1969. Effect of carbon tetrachloride on induc-
tion of liver enzymes by acute stress or corticosterone. Toxicol.
Appl. Pharmacol. 15:117-130.
NAS. 1977. National Academy of Sciences. Drinking Water and Health.
Volume 1. Safe Drinking Water Committee. National Research Council.
National Academy Press. Washington, D.C. pp. 703-707.
NAS. 1980. National Academy of Sciences. Drinking water and health. Vol. 3.
Safe Drinking Water Committee. Board on Toxicology and Environmental
Health Hazards, Assembly of Life Sciences, National Research Council.
Washington, DC: National Academy of Sciences, pp. 96-98.
NCI. 1976. National Cancer Institute. Report on carcinogenesis bioassay of
chloroform. Bethesda, Maryland: Carcinogenesis Program, Division of
Cancer Cause and Prevention.
O'Brien, R.P., D.M. Jordan and W.R. Musser. 1981. Trace organic removal
from contaminated groundwaters with granular activated carbon. Presented
to: American Chemical Society, Atlanta, GA. March, 1981.
Paul, B.P., and D. Rubinstein. 1963. Metabolism of carbon tetrachloride and
chloroform by the rat.. J. Pharmacol. Exptl. Therap. 141:141-148.
Prendergast, J.A., R.A. Jones, L.J. Jenkins and J. Seigel. 1967. Effects on
experimental animals of long-term inhalation of trichloroethylene, carbon
tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and
1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270-289.
Rams, J.M., M. Pilgrim, S. Rauth, G. Hunt, T. Shannon and K. Slimak. 1 979.
Draft report, Level I materials balance: carbon tetrachloride. Prepared
by JRB Associates for Office of Pesticides and Toxic Substances, U.S.
Environmental Protection Agency, Washington, D.C.: U.S. Environmental
Protection Agency. Contract No. 68:01-5793.
Reddrop, C.J., W.Riess and T.F. Slater. 1981. Interactions of carbon tetra-
chloride and promethazine in the rat. II. Elimination of carbon tetra-
chloride and chloroform in expired air as indications of their metabolis-
in the intact animal. Biochem. Pharmacol. 30:1449-1455.
Seawright, A.A., and A.E.M. McLean. 1967. The effect of diet on carbon
tetrachloride metabolism. Biochem. J. 105:1055-1060.
Shah, H., S. Hartman ?.nd S. Weinhouse. 1979. Formation of carbonyl chloride
in carbon tetrachloride metabolism by rat liver in vitro. Cancer Res.
39:3942-3947.
49
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Carbon Tetrachloride
March 31, 196 7
-19-
Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 19S3.
Evaluation of the.alkaline elution/rat hepatocyte assay as a predictor
of carcinogenic/mutagenic potential. Mutat. Res. 113:357-391.
Smyth, H.F., H.F. Smyth, Jr. and C.P. Carpenter. 1936. The chronic toxicity
of carbon tetrachloride: Animal exposure and field studies. J. Indust.
Hyg. Toxicol. 18:277-298.
Symons, J.M. 1978. Interim treatment guide for controlling organic contami-
nants in drinking water using granular activated carbon* U.S. EPA,
Office of Research and Development, Cincinnati, OH.
Symons, J.M., J.K. Carswelj., J. DeMarco and O.T. Love, Jr. 1979. Removal of
organic contaminants from drinking water using techniques other than
granulated activated carbon alone - a progress report. In: Proceedings,
Practical Applications of Adsorption Techniques in Drinking Water, EPA/
NATO, Challenges of Modern Society, Reston, VA. (In press)
U.S. EPA. 1979. Water related environmental fate of 129 priority pollutants.
Office of Water Planning and Standards. EPA-440/4-79-029.
U.S. EPA. 1980a. U. S. Environmental Protection Agency. Carbon tetrachloride;
Pesticide Programs; rebuttable presumption against registration and
continued registration of certain pesticide products. Federal Register
45(201). Part IV:68534-68584. (Oct. 15).
U.S. EPA. 1980b. u. S. Environmental Protection Agency. Ambient water
quality criteria for carbon tetrachloride. Environmental Protection
Agency. Office of Water Regulations and Standards, Criteria and Standards
Division. Washington, D.C.
U.S. EPA. 1981. U.S. -Environmental Protection Agency. Advisory opinion for
carbon tetrachloride. Office of Drinking Water, Washington, D.C.
U.S. EPA. 1S83. U.S. Environmental Protection Agency. Carbon tetrachloride
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Health assessment
document for carbon tetrachloride. Cincinnati, OH: EPA Publ. No.
600/8-82-001F, Environmental Criteria and Assessment Office.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Final draft criteria
document for'carbon tetrachloride. TR-540-131A. Office of Drinking Water.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory, Cincinnati,
Ohio 45266.- June 1985.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June 1985.
50
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Carbon Tetrachloride
March 31, 19S7
-20-
U.S. EPA. 1985d. U.S. Environmental Protection Agency. Assessment of carbon
tetrachloride as a potentially toxic air pollutant. Federal Register.
50(156):32621-32627.
U.S. EPA. 1985e. U.S. Environmental Protection Agency. National primary
drinking water regulations; Volatile synthetic organic chemicals; Final
rule and proposed rule. Federal Register 50(219)s46880-46933. November 13.
U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register 51(185):33992-34003.
September 24.
U.S. EPA. 1986b. U.S. Environmental Protection Agency. Pesticide products
containing carbon tetrachloride; Notice of intent to cancel registrations
and notice of transmittal and availability of draft notice to cancel.
Federal Register. 51(78)t15372—15373. April 23.
U.S. ITC. 1983. U.S. International Trade Commission. Synthetic organic
chemicals, United States production. USITC Publication 1422. Washington,
D.C.
Wilkosky, C., H. Checkoway, E.G. Marchall and H.A. Tyroler. 1984. Cancer
mortality and solvent exposures in the rubber industry. Am. Indust.
Hyg. J. 45:809-811.
WHO. 1984. World Health Organization. Guidelines for drinking water quality.
Volume I, Recommendations. EPP/82.39.
51
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March 31, is
CHL0R0BEN2ENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. Cfoe HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures basec on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group n or
B), Lifetime Hns are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates oy
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no .current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
52
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Chlorobenzene
March 31, 1987
-2-
This Health Advisory (HA) is based on information presented in the Office
of Drinking Water's draft Health Effects Criteria Document (CD) for Chloroben-
zene (U.S. EPA, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for review at each EPA Regional Office of Drinking Hater counterpart (e.g.,
Water Supply Branch or Drinking Hater Branch), or/for a fee from the National
Technical Information Service, U.S. Department of Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB #86-117769/AS. Hie toll-free number is (800)
336-4700» in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPOERTIES
CAS No. 108-90-7
Structural Formula
CI
Synonyms
° Monochlorobenzene, benzene chloride, chlorobenzol, phenyl chloride.
Uses
° Production of chloronitrobenzene and diphenyl ether; rubber inter-
mediates; solvent in adhesives, paints, waxes, polishes; and iner-
solvent.
Properties: (Irish, 1963)
Chemical Formula
Molecular Weight
Pnysical State (room temp.)
Boiling Point
Melting Point
Density
Vapor Pressure
Specific Gravity
Water Solubility
Oil/water Coefficient
Log Octanol/Water Partition
Coefficient
Odor/Taste Threshold (water)
Odor Tnreshold (water)
Odor Threshold (medium unknown)
Conversion Factor (air)
C6H5C1
112.6
Colorless, neutral liquid
1 32°C
-45°C
11.8 mm Hg (at 25°C)
1 .106 (at 25°C)
500 mg/L (at 20°C)
918 (Sato and Nakajima, 1979)
2.84 (Leo et al., 1971 )
0.41-1.5 ug/L (Tarkhova, 1965)
10-20 ug/L (Varshavskaya, 1968)
50 ug/L (Amoore and Hautala, 1983)
0.21 mg/L (A.D. Little, 1963)
1 ppm ¦ 4.7 mg/m3
53
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Cnlorobenzene
March 31, 19""
-3-
Occurrence
0 There are no natural sources of chlorobenzene.
0 Chlorobenzene production in 1984 was 256 million lbs (USITC, 1985).
The majority of releases result from chlorobenzene's use as a solvent.
Due to chlorobenzene's volatility, most of its environmental releases
occur to air. Chlorobenzene is released to water and the ground
during the disposal of waste solvent. Because chlorobenzene is used
in metal cleaning operations, releases occur in industrial areas
nationwide (U.S. EPA, 1987).
0 Chlorobenzene released to the atmosphere is expected to degrade slowly
by free radical oxidation. Chlorobenzene released to surface water
is expected to partition rapidly to air where it also is expected to
degrade. Chlorobenzene has been shown to be relatively resistant to
biodegraaation. Based on limited studies, EPA estimates the half-life
of chlorobenzene in soil to be several months. When released to the
ground, chlorobenzene is expected to bind to soil and to migrate slowly
to ground water. Chlorobenzene has been reported to bioaccumulate in
fish, aquatic invertebrates and algae. In higher organisms, chloro-
benzene has been shown to be metabolized to other compounds (U.S. EPA,
1979).
° Chlorobenzene rarely occurs as an environmental contaminant. Federal,
surveys of drinking waters derived from surface water have not reported
the presence of chlorobenzene. A few groundwater systems have been
found with chlorobenzene levels in the low ppb range. No information
of the occurrence of chlorobenzene in food has been identified.
Chlorobenzene has been identified as a contaminant of air at very low
levels (less than 1 ppb) in urban and suburban areas. Even with tne
low levels of chlorobenzene in air, inhalation is probably the r.s;or
route of environmental exposure (U.S. EPA, 1983).
III. PHARMACOKINETICS
Absorption
0 No data are available which demonstrate the percentage of the dose
absorbed following oral exposure. Based upon what is known about the
high lipid solubility of chlorobenzene along with absorption charac-
teristics of benzene and the smaller chlorinated ethanes and ethylenes
which are also highly lipid soluble, it will be assumed, for the
purpose of the development of Health Advisories, that 100% of any
orally administered dose is absorbed, while 60% of a dose inhaled
over a period of one to several hours is absorbed and retained
(Astrand, 1975; Dallas et al., 1983).
Distribution
0 Sullivan et al. (1^83) studied the distribution of 14C-chlorobenzene
in male Spra^ue-Dawley rats following single or multiple 8-hour
inhalation exposures at 100, 400 or 700 ppm (460, 1,880 or 3,290
54
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Chlorobenzene
March 31, Mz 7
-4-
mg/m3). The highest concentrations were found in the fat (epididymal
and perirenal). The kidneys and liver also showed significant amounts.
The amounts found in these tissues were proportional to dose except
for adipose tissue which showed greatly exaggerated accumulation with
dose when compared to the other tissues. The 14C burden of adipose
tissue increased with increasing exposure concentrations. In addition,
there also was a tendency for multiply-exposed rats to exhibit higher
tissue burdens than rats exposed only once.
Metabolism
0 The metabolic transformation of chlorobenzene has been studied in
several mammalian species, including the human (Williams et al.,
1975). While absolute quantities and ratios differ between species,
the principal metabolites for each species are p-chlorophenol,
p-chlorocatechol and p-chlorophenyl-mercapturic acid.
0 Because of its lipophilicity (log P »2.96), chlorobenzene tends to
bioaccumulate in adipose tissue as exposure continues (Sullivan,
et al., 1983). Upon termination of exposure, the chemical would
be expected to be released from the fat stores and become available
for metabolic activation and potential continuation of induction
of toxicity.
Excretion
° Tne chlorophenoi metabolite is excreted as the ethereal sulfate or
the glucuronide (Spencer and Williams, 1950; Azouz, et al, 1953).
Other excretion products include the chlorophenyl mercapturic acid,
4-chlorocatechol, and to a lesser degree in some species, phenol and
hydroquinone (Williams et al., 1975; Sullivan et al., 1983).
0 When the metabolic pathways for chlorobenzene biotransformation
become saturated, increasing amounts of the chemical are exhaled
unchanged (Sullivan et al., 1983). In rats exposed to 100 ppr.
(470 mg/m3) (a dose which did not saturate metabolic pathways) in air
for 8 hours, 5% was excreted via inhalation and 95% in the urine.
Repeated dosing (8 hr/day for 4 or 5 days) at 700 ppm (a dose that
does saturate metabolic pathways) results in 32% being exhaled and
68% excreted in the urine.
IV. HEALTH EFFECTS
Humans
0 The only information available on the effects of chlorobenzene in the
human comes from case reports of poisonings or occupational exposures
No data on actual exposure concentrations are presented in any of
these reports.
° Inhalation exposure to chlorobenzene has been observed to result ir.
signs of central nervous depression (sedation and narcosis) as well
55
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Chlorobenzene
March 3", 19S"
-5-
as irritation of the eye and respiratory tract (Rozenbaum et al.,
1947; Girard et al., 1969; Smirnova and Granik, 1970).
0 Rozenbaum et al. (1947) also noted thrombocytopenia and leukopenia
in some of the workers described in their study. The question arises
as to whether this effect was induced by the chlorobenzene or some
contaminant.
0 Cardiac effects such as chest pain, bradycardia and ECG irregularities
and toxemia of pregnancy have been noted in individuals exposed to
chemicals used in the production of chlorobenzene (Dunaeveskii, 1972;
Petrova and Vishne^skii, 1972). Chlorobenzene^cannot be identified
as the causative agent since these workers were exposed to mixtures
of substances over varying periods of time.
Animals
Short-term Exposure
° Reported oral LDsq's in adult animals range from 2.8 to 3.4 g/kg
(Irish, 19G3; Vecerek et al., 1976). Reported inhalation LCso's
range from 0.05 (guinea pig) to 20 mg/1 (mouse-2 hour exposure)
(Rozenbaum et al., 1947; Lecca-Radu, 1959).
° In rats, single subcutaneous doses greater than 5 gAg produced hyper-
excitability and muscle spasms, followed by CNS depression and death
(Rozenbaum, et al, 1947; von Oettingen, 1955).
0 Chlorobenzene causes necrosis of the li^ver and interferes with
porphyrin metabolism (Rimington and Ziegler, 1963; Khanin, 1969;
Knapp et al., 1971). Oral doses of 1140 mgAg/day administered to
rats for 5 days resulted in increases in urinary excretion of coprc-
porphyrin III, uroporphyrin and porphobilinogen (Rimington and Ziegler,
1963)._ Delta-aminolevulinic acid levels also were increased as were
liver protoporphyrin and uroporphyrin.
0 Kidneys of rabbits receiving 2 to 20 doses of chlorobenzene at 0.9 mg'kc
by injection over a two-week period showed swelling of the tubular ani
glomerular epithelia (Rozenbaum et al., 1947).
0 Chlorobenzene has been shown to produce alterations in bile duct-
pancreatic flow (a phenomenon of unexplained significance)(Yang et al.,
1979), and blood dyscrasias such as leukopenia and lymphocytosis
(Cameron et al. 1937; Rozenbaum et al., 1947> Zub, 1979). As noted
for the human, there is a question as to whether these hematopoietic
effects resulted from chlorobenzene or a contaminant.
0 Administration of chlorobenzene in corn oil by gavage for 14 consecutive
days to male ana female F344/N rats and B6C3F1 mice was ineffective
in rats and mice at doses of 500 mg/kg/day. Rats were also given
1,000 and 2,000 mg/kg/day doses, which were fatal. Survival, bod/
weights and necropsies data were obtained. Histopathology was not
performed.
56
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Chlorobenzene
March 31, 19.'"
-6-
Long-term Exposure
0 Adolescent dogs (6/sex/group) were exposed to chlorobenzene vapors
at target levels of 0, 0.78, 1.57 or 2.08 mg/1 air for 6 hr/day, 5
days/week for 6 months (Monsanto, 1980). Significant changes included
a decrease in absolute adrenal weights in males at the mid- and high-
dose levels, an increase in liver:body weight ratio in females at the
mid- and high-doses, a sex-independent, dose-related increased inci-
dence in emesis and an increase in the frequency of abnormal stools
in treated females. TOie NOAEL is 0.78 mg/L.
° Oral administration of chlorobenzene by capsule at doses of 0, 27.25,
54.5 or 272.5 mg/kg/day to male and female beagle dogs daily, 5 days/
week, until sacrifice at 93 days resulted in observable effects
(mortality, lesions, various toxic effects) only at the high dose
(Knapp et al., 1971; Hazelton, 1967a). 13ie NOAEL is 54.5 mgAg/day.
0 Oral dosing of rats at levels of 14.4, 144 or 288 mg/kg/day, 5 days/
week for 6 months yielded significant increases in liver and kidney
weights and histopathological changes in the livers of mid- and
high-dose animals (Irish, 1963). Mo changes were observed at the
low dose. The NOAEL is 14.4 mg/kg/day.
0 Male and female rats were fed chlorobenzene in their diets at levels
equal to 12.5, 50, 100 or 150 mg/kg/day for 90 to 99 days (Knapp, et
al., 1971; Hazelton, 1967b). Males showed retarded growth at the
highest dose. At the mid- and high dose levels, significant increases
in liver and kidney weights were noted. The two lowest dose produced
nc adverse effects. The NOAEL is 50 mg/kg/day.
0 In sufcchronic (90 or 91 day) studies in which both sexes of rats and
mice received chlorobenzene in corn oil by gavage five times weekly
with 0, 60, 125, 250, 500 or 750 mg/kg/day (NTP, 1985; Battelle,
1978a,b). Rats and mice showed depressed body weight gain at the
highest three doses. In rats, polyuria and porphyria were noted at
the two highest doses. Histopathology was noted in the liver, kidney
and lymphoid tissue in both species at the three highest doses.
Liver and liver/body weights were increased in male mice and ferr.aie
rats at doses above 60 mgAg» The NOAEL is 60 mg/kg/day.
0 She only chronic exposure study available on chlorobenzene is the NTP
gavage bioassay in rats and mice (NTP, 1985). On five days/week, both
sexes of rats and female mice received 60 or 120 mg chlorobenzene/kg
day in corn oil; male mice received 30 or 60 mgAg/day. Significant
changes included equivocal mild to minimal liver necrosis in the rati
and a decrease in the survival rate for low dose male mice, but not
high dose male mice. The NOAEL is 60 mgAg/day.
Reproductive £ftects
0 There are no available data on reproductive effects of chlorobenzene.
57
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Chlorobenzene
-7-
Developmental Effects
° John et al. (1984) and Hayes et al. (1982) have reported the results
of a two-phase teratology study in which pregnant rats and rabbits
were exposed via inhalation to 0, 75, 210 or 590 ppm chlorobenzene,
6 hr/day, during the period of major organogenesis (days 6 through
15 for ratsjdays 6 through 18 for rabbits). In the rats, maternal
toxicity (decreased body weight gain) was observed at the highest
dose. No teratological changes were observed in fetuses from rats
exposed at any dose. Rabbits showed maternal toxicity (statistically
significant increase in relative and absolute liver weights) at the
mid and high dose*. Again, no structural malformations were noted
in the fetuses. However, since the control group exhibited malforma-
tions at levels higher than historically noted, the rabbit study was
repeated, using doses of 0, 10, 30, 75 or 590 ppm. In this study, no
significant changes in rates and types of malformations were observed.
Mutagenicity
0 Chlorobenzene has been shown to cause mitotic disturbances in Allium
cepa (Ostergen and Levan, 1943) and reverse mutations in Streptococcus
antibioticus (Koshkinova, 1968) and Aspergillus nidulans (Prasad and
Pramer, 1968;Prasad, 1970).
0 Chlorobenzene was not mutagenic in the Ames Salmonella assay or in
E. coli, either with or without metabolic activation (Monsanto, 1976a;
Dupon^, 1S77;."erck, 1978; Simmon et al., 1979).
0 Chlorobenzene did not induce specific locus forward mutations in mouse
lymphona L5178Y cells, either with or without activation (Monsanto,
1976b).
° Chlorobenzene did induce reciprocal recombination in the yeast
Saccharomvces cerevisiae strain D3 in the presence of the metabolic
activation system (Simmon et al. 1979).
Carcinooenici ty
0 Chlorober.zene has been tested for carcinogenic potential in rats and
mice in the NTP Bioassay Program (NTP, 1985). Ihe report of these
studies states that the chemical produced a statistically significant
increase in the incidence of neoplastic nodules of the liver in high
dose (120 mgAg/day) male rats. Incidences of neoplastic nodules in
male rats were 2/50 in untreated controls, 2/50 in vehicle controls,
4/49 in low dose and 8/49 in high dose. However, there were also
hepatocellular carcinomas in two vehicle control male rats, and
combining these with the neoplastic nodule data results in an increase
in hi^h dose males of borderline significance (P = 0.048) by one
statistical test (life table) of the three used (also incidental tumor
test and Fischer's exact test) by the NTP, No increased incidence
was observed in numbers of hepatocellular carcinomas in male rats or
of neoplastic nodules or hepatocellular carcinomas in female rats or
mice of either sex.
58
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Chlorobenzene March 31, 19;7
-8-
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) 0 ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL ° No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW a assumed body weight of a child (10 kg) or
an adult (70 kg)•
UF ¦ uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
___ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day and Ten-day Health Advisories
No satisfactory data are available from which to calculate One-day and
Ten-day HAs for the 10 kg child. The 14-day studies in rats and mice by the
NTP (1985) are not selected because of inadequate assessment of toxicity ir.
these studies. It is recommended that, for this duration of exposure, the
Longer-term HA for a 10-kg child be applied. Therefore, the One-day and
Ten-day Health Advisories are 4.3 mg/L (4,300 ug/L).
Longer-term Health Advisory
Subchronic studies were conducted in which both rats and mice were dosed
by gavage five times weekly with chlorobenzene at 0, 60, 125, 250, 500 or 750
mgAg in corn oil (10 animals/species/sex/dose level) (NTP, 1985; Battelle,
1978a,b). Deaths were found with the three highest doses in mice and the two
highest doses in rats. Food consumption did not vary among the groups in
mice, but it was lower in the two highest dose rat groups. Body weight gain
was affected in both species, with significant changes observed in mice and
rats at the three highest doses. No clinically significant chlorobenzene-
related changes were observed in any of the hematological parameters measured
in either species. None of the clinical chemistry parameters measured in mice
were changed. However, in the rats, alkaline phosphatase and GGPT levels
were slightly elevated at 500 and 750 mgAg* Urinalyses of the.controls and
two highest dose groups revealed a dose-dependent polyuria with concomitant
decreases in specific gravity and creatinine concentration. At the two highest
doses, urinary coproporphyrin excretion was increased in rats. In mice, this
increase was observed only in females at 250 and 500 mgAg. Liver and body
weight ratios were increased significantly in female mice at 250 and 500 mg/kc
and in male mice at 125 and 250 mgAg. Both male and female rats at 250 and
59
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Chrorobensene
March 31, 19'
-9-
500 mg/kg and females at 125 mg/kg showed these increases. Absolute and
organ/body weights for spleen were decreased in all treated groups of male
rats but with no clear dose response. Mice and rats at the three highest
doses (250, 500 and 750 mg/kg) all exhibited significant histopathological
changes including hepatic necrosis, nephrosis, myeloid depletion, lymphoid
depletion and lympnoid necrosis. The 60 mgAg/day NOAEL with 5 days/week
treatment of rats and mice in the NTP (1985) study is equivalent to the 54.5
mg/kg/day, 5 days/week NOAEL in dogs and the 50 mgAg/day, 7 days/week NOAEL
in the Hazelton (1967a,b) studies.
From the NTP (1985) data, a NOAEL of 60 mgAg/day was identified.
A Longer-term Health Advisory is calculated as follows:
For the 10—Jig child:
Longer-term HA = I60 "ig/kg/day) (10 kg) (5) . 4<3 /L (4 300 /L)
(100) (1 L/day) (7)
where:
60 mgAg/day * HCAIL, based upon absence of various effects at
higher doses in rats and mice.
10 kg = assumed body weight of a child.
5/7 = conversion of 5 day/week exposure to 7 day/week
exposure.
100 = uncertainty factor, chosen in accordance with NAS/ODv;
guidelines for use with a NOAEL from an animal study.
1 l/cay = assumed daily water consumption of a child.
For the 70-kq adult:
Longer-term HA = (6° m9/.k9/day > (.70 k9] (5) = 15.0 mg/L (1 5,000 ug/L)
(100) (2 L/day) (7)
where:
60 mgAg/day = NOAEL, based upon absence of various effects at
higher doses in rats and mice.
70 kg = assumed body weight of an adult.
5/7 =• conversion of 5 day/week exposure to 7 day/week
exposure.
100 = uncertainty factor, chosen in accordance with NAS/ODv
guidelines for use with a NOAEL from an animal study
2 L/day = assumed daily water consumption of an adult.
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Chlorobenzene
March 3i, 1 j:;
-10-
Lifetime" Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. Hie Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The data base used for the derivation of the Longer-term Health Advisories
also is selected for deriving the Lifetime Health Advisory in that more toxico-
logic endpoints and species were assessed in the subchronic studies compared
to the NTP (1985) carcinogenicity bioassay.
The Lifetime Health Advisory is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (60 mg/kg/day) (5 ) = 0#043 mgAg/day
1,000) (7)
where:
60 mg/kg/day = NOAEL based upon absence of various effects at higher
doses.
5/7 = conversion of 5 day/week exposure to 7 day/week exposure.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = t0-043 nq/Kg/day) (70 kg) = 1#51 mg/L (1f510 /L)
(2 L/day)
61
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Chlorobenzene
March 3",
-11-
where:
0.043 mg/kg/day » RfD.
70 kg = assumed body weight of an adult.
2 L/day » assumed daily water consumption of an adult.
t
Step 3s Determination of the Lifetime Health Advisory
Lifetime HA » 1.5 mg/L x 20% <• 0.3 mg/L (300 ug/L)
It is important to note that the taste and odor threshold in water has
been identified at levels ranging from 0.41 to 1.5 ug/L (Tarkhova, 1965) to
10 to 20 ug/L (Varshavskaya, 1967). All of the Health Advisories derived in
this document have been developed on the basis of toxicity, not on the aesthetic
characteristics of the water quality. Any guidance developed on a site-specific
basis may, however, require one to consider the aesthetic, in addition to.the
toxic, consequences following exposure to chlorobenzene in the drinking water.
Evaluation of Carcinogenic Potential
0 Tne EPA Carcinogenic Assessment Group (CAG) did not derive a carcino-
genic potency factor or range of risk estimates for chlorobenzene
(U.S. EPA, 1985b).
° EPA has classified chlorobenzene as to its carcinogenic potential,
using the weight of evidence classification scheme in its risk assess-
ment guidelines for carcinogens (U.S. EPA, 1986). Bie Agency has
placed the chemical in Group D: Inadequate evidence. EPA's Carcinoge-
Assessment Group has not derived a carcinogenicity potency factor
(qi*) or a range of excess lifetime cancer risk estimates.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
° EPA (1980) proposed ambient water quality criteria for chlorobenzene,
one based upon available toxicity data (488 ug/L) and one based upor.
organoleptic effects (20 ug/L). These criteria were derived for the
70 kg adult, assumed to drink 2 liters of water per day and eat
6.5 g of contaminated fish and seafood per day. The toxicity-based
criteria were calculated using the 14.4 mg/kg/day NOAEL from the
study by Irish et al. (1963) and an uncertainty factor of 1,000.
0 ACGIh' (1982) has adopted a TLV of 75 ppm (350 mg/m^) for chloro-
benzene in the workplace.
0 On the basis of a 1983 draft of the NTP report (NTP, 1985), the
National Academy of Sciences performed a quantitative risk assessment
to estimate excess lifetime cancer risk (NAS, 1983). The upper 95%
confidence limit estimate of that risk was 2.13 x 10~7 per ug/L of
drinking water. This corresponds to a drinking water concentration
of 2.35 ug/L being equivalent to a 1 in a million excess risk.
62
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Chlorobenzene
March 31, 1?
-12-
Assumptions were defined for a 70-kg adult, drinking 2 liters of
water per day.
0 WHO (1984) recommended a guideline for chlorobenzene of 3 ug/L
based upon avoidance of taste and odor problems.
0 The U.S. EPA Office of Drinking Hater proposed an RMCL of 0.06 mg/L
(U.S. EPA, 1985c).
VII. ANALYTICAL METHODS
0 Analysis of chlorobenzene is by the purge-and-trap gas chromatographic
prpcedure used for the determination of volatile organohalides in
drinking water (U.S. EPA, 1984a). This method calls for the bubbling
of an inert gas through the sample and trapping chlorobenzene on an
adsorbant material. The adsorbant material is heated to drive off
the chlorobenzene onto a gas chromatographic column. This method is
applicable to the measurement of chlorobenzene over a concentration
range of 0.05 to 1500 ug/L. Confirmatory analysis for chlorobenzene
is by mass spectrometry (U.S. EPA, 1985d). Bie detection limit for
confirmation by mass spectometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
° Treatment techniques which are effective in removing chlorobenzene
from drinking water include adsorption on granular activated carbon
(GAC) or powdered activated carbon (PAC). Aeration, reverse osmosis
and boiling also are capable of removing chlorobenzene.
0 Dobbs and Cohen (1980) developed adsorption isotherms for a number
of organic chemicals, including chlorobenzene. Wiey found that
Filtrasorb ® 300 carbon had a capacity of 91 mg of chlorobenzene
per gram of carbon at an equilibrium concentration of 1.0 mg/L and
9.3 mg/g at a concentration of 100 ug/L.
0 PAC gave inconsistent removal rates when it was added to well water
containing several contaminants including chlorobenzene (U.S. EPA,
1985b).
0 Conventional coagulation filtration treatment does not appear to be
effective in chlorobenzene removal. Limited data collected at Water
Factory 21 indicated that there was an 18.2% removal of chlorobenzene
when only filtration was used (U.S. EPA, 1985b). Another study of
conventional treatment practices found them to be completely ineffective
in chlorobenzene removal (Love et al«, 1983).
0 The Henry's Law Constant for chlorobenzene is 145 atm at 20°C (U.S.
EPA, 1985b). This indicates that the chemical might be amenable to
removal by aeration. In a bench-scale study, a diffused air aerator
reduced the chlorobenzene in a 97 ug/L solution by 90% using a 15:1
air-to-water ratio (Love et al., 1983).
63
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Chlorobenzene
March 31, 19C7
-13
0 Air stripping is an effective, simple and relatively inexpensive
process for removing chlorobenzene and other volatile organics from
water. However, the use of this process then transfers the contaminant
directly into the air stream. When considering use of air stripping
as a treatment process, it is suggested that careful consideration be
given to the overall environmental occurrence, fate, route of exposure
and various hazards associated with the chemical.
° Degradation with ozone is ineffective as a method for removing
chlorobenzene (U.S. EPA, 1985d).
0 Reverse osmosis appears to have the potential for use in chlorobenzene
removal. A labor«cory study reviewed by EPA reported successful
decontamination with 97 to 100% of the chlorobenzene removed.
64
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Chlorobenzene
March 3i, l3;
1 4
IX. REFERENCES
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TLVs. Threshold limit values for chemical substances and physical
agents in the work environment with intended changes for 1982.
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Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety:
Odor threshold compounds with threshold unit values and volatilities for
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Astrand, I. 1975. Uptake of solvents in the blood and tissue of man.
Scand. J. Work Environ. Hlth. 1i199-218.
Azouz, W.M., D.V. Parke and R.T Williams. 1953. Studies in detoxication.
51: The determination of catechols in urine, and the formation of
catechols in rabbits receiving halogenobenzenes and other compounds,
dihydroxylation in vivo. Biochem. J. 55(1):146—151.
Battelle. 1978a. Battelle's Columbus Laboratories. Chlorobenzene.
Prechronic test phase review - mouse. Establishment of doses for sub-
chroni-. Unpublished report. NTP Subcontract No. 76-34-106002.
Battelle. 1S78b. Battelle's Columbus Laboratories. Chlorobenzene. Pre-
chronic test phase review - rat. Establishment of doses for subchronic.
Unpublished report. NTP Subcontract No.76-34-106002.
Cameron, G.R., J.C. Thomas, S.A. Ashmore, J.L. Buchan, E.H. Warren and A.w.
McKenny Hughes. 1937. The toxicity of certain chlorine derivatives of
benzene with special reference to o-dichlorobenzene. J. Path. Bact.
44:281-295.
Dallas, C.E., F.K. Weir, S. Feldman, L. Putcha and J.V. Bruckner. 19S3. Trie
uptake and disposition of 1,1-dichloroethylene in rats during inhalatio-
exposure. Toxicol. Appl. Pharmacol. 68:140-151.
Dobbs,. R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/8-80-023. MERL, Cincinnati, Ohio.
Dunaeveskii, G.A. 1972. Functional condition of circulatory organs in workers
employed in the production of organic compounds. Gig. Tr. Prof. Zabol.16:4S.
Dupont, 1977. Mutagenic activity of monochlorobenzene in the Salmonella-
microsome assay. Haskell Laboratory for Toxicology and Industrial
Medicine. Unpublished Report.
Girard, R., F. Toiot, P. Martin and J. Bourret. 1969. Serious blood disorders
and exposure to chlorine derivatives of benzene (A report of seven
cases). J. Med. Lyon 50(1164):771-773. (Fr.)
65
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Chlorobenzene
March 31, 196"
15-
Hayes, W.C, T.S. Gushaw, K.A. Johnson, T.R. Hanley, Jr., J.H. Ouellette and
J.A. John. 1982. Monochlorobenzene inhalation teratology study in rats
and rabbits. Unpublished Report. Toxicology Research Laboratory. Dow
Chemical Company. 115 pp.
Hazelton Laboratories. 1967a. 13-Week oral administration — dogs. Mono-
chlorobenzene. Final report. Submitted to Monsanto Company. Project
No. 241-105. February 24.
Hazelton Laboratories. 1967b. Three-month subacute oral study — rats.
Monochlorobenzene. Final report. Submitted to Monsanto Company.
Project No. 241-104. March 9.
Irish, D.D. 1963. Halogenated hydrocarbons. II. Cyclic In: Patty's Industrial
Hygiene and Toxicology. Volume II. D.W. Fassett and D.D. Irish, eds.
Interscience Publishers. New York, N.Y. pp. 1333-1362.
John, J.A., w.C. Hayes, T.R. Hanley, Jr., K.A. Johnson, T.S. Gushow and K.S.
Rao. 1984. Inhalation teratology study on monochlorobenzene in rats
and rabbits. Toxicol. Appl. Pharmacol. 76:365-373.
Khanin, A.G. 1969. Pathohistological changes in the central nervous system
and internal organs of experimental animals after chronic, 24-hour
inhalation of toxic substances. T. Tsent. Inst. Vsoversh, Vrachei.
135:97-106. (Russ.)
Knapp, w.K., w.M. Su;?ey and W. Kundzins. 1971. Subacute oral toxicity of
monochlorobenzene in dogs and rats. Toxicol. Appl. Pharmacol. 19:393
(Abstract).
Koshkinova, D.v. 1 968. The effect of dimethylcyclodiazomethane in chlorobenzer.
solution on mutagenesis in Actinomyces antibiotius 400. Genetika.
4(8):121-125. (Russ.)
Lecca-Radu. 1959. Modifications of blood carbonic anhydrase and leucocytic
indophenol oxidase in chronic benzene and monochlorobenzene intoxication.
Igiena 8:231-240.
Leo, A., C. Hansek and B. Elkins. 1971. Partition coefficients and their
uses. Chem. Rev. 71(6):525-616.
Little, A.D. 1968. Research of chemical odors: Part I. Odor thresholds
for 53 commercial chemicals. Manufacturing Chemists Association, Wash-
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Love, G.T., R.J. Miltner, R.G. Eilers and C.D. Pronk-Leist. 1983. Treatment
of volatile organic compounds in drinking water. U.S. EPA. MERL. EPA
600/8-83-019.
Merck. 1978. Monochlorobenzene: Bacterial mutagen test (Ames test), west
Point, Ph. Merck and Co., Inc. Unpublished.
-------
Chlorobenzene
March 31, 19;~
-16-
Monsanto Company. 1976a. Mutagenicity evaluation of B1 0-76-86^P-5535 (WGK).
Final report. LBI Project No. 2547. Kensington, MO. Litton Bionetics.
Unpublished.
Monsanto Company. 1976b. Mutagenicity evaluation of B10-76-86^P-5535 (LOX).
Final report. LBI Project No. 2547. Kensington, MD. Litton Bionetics.
Unpublished.
Monsanto Company. 1980. Subchronic inhalation toxicity study of monochloro-
benzene to male and female dogs. Environmental Health Laboratory Report.
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NAS. 1983. National Academy of Sciences. Drinking Water and Health.
Volume 5. National Academy Press, Washington, DC. pp. 28-33.
NTP. 1985. National Toxicology Program. Toxicology and carcinogenesis
studies of dichlorobenzene (CAS No. 108-90-7) in F344/N rats and B6C3Fi
mice (gavage studies). U.S. Department of Health and Human Services.
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Prasad, I. 1970. Mutagenic effects of the herbicide 3,4-dichloroproprion-
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Prasad, I., and D. Pramer. 1968. Mutagenic activity of some chloroanilines
and cnlorobenzenes. Genetics. 20:212-
Rimington, G.E., and G. Ziegler. 1963. Experimental porphyria in rats induce
by chlorinated benzenes. Biochem. Pharmacol. 12:1387-1397.
Rozenbaum, N.D., R.S. Block, S.N. Kremneva, S.L. Ginzburg and I.V. Pozhatiskii
1947. Use of chlorobenzene as a solvent from the standpoint of industna
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Simmon, V.F., E.C. Ricco and M.V. Pierce. 1979. In vitro microbiological
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-------
Chlorobenzene
March 31, 1987
-1 7-
Spencer, B., and R.T. Williams. 1950. Studies in detoxication. 33. The
metabolism of halogenobenzenes. A comparison of the glucuronic acic,
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47:279-284.
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environmental fate of 129 priority pollutants. Office of Water Planning
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Volatile organic compounds in water by purge and trap gas chromatography,-
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September 24.
68
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Chlorobenzene
March 31, 19£?
-18-
U.S. EPA. 1987. U.S. Environmental Protection Agency. Occurrence of
synthetic organic chemicals in drinking water, food, and air. Office of
Drinking Water.
USITC. 1985. U.S. International Trade Commission. Synthetic organic
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332-135), USITC Publication 1745. U.S. Government Printing Office.
Washington, D.C.
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benzene and dichlorobenzene (ortho- and para- isomers) in relation to
the sanitary protection of uater bodies. Gig. Sanit. 33(10):17-23.
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Xenobiological characteristics of chlorobenzene. Bratisl. lek. Listy.
65(1 ): 9-1 4.
von Oettingen, W.F. 1955. The halogenated aromatic hydrocarbons. In: The
halogenated aliphatic, olefinic, cyclic, aromatic and aliphatic aromatic
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and potential dangers. U.S. Dept. Health, Education and Welfare,
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5fang, K.H., R.E. Peterson and J.M. Fujimoto. 1979. Increased bile duct-
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Toxicol. Appl. Pharmacol. 47:505-514.
Sub, Y.. 1979. Reactivity of the white blood cell system to toxic action of
benzene and its derivatives. Acta Biol. Cracov Serv. Zool. 21(2):163-174.
69
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March 3", 19:
ORTHO-, META-, AND PARA-DICHLOROBENZENES
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatorv
concentrations of drinking water contaminants at which adverse health effect
would not be anticioated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federa
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for -One-day, Ten-day, Longer-tern
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based cn aa~a describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogen
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A c.r
B), Lifetime HAs are not recommended. The chemical concentration values fcr
Group A or E carcinogens are correlated with carcinogenic risk estimates bv
encloymg a car.c^r potency (unit risk) value together with assumptions for
lifetime exposure ann the consumption of drinking water. The cancer uni-
ris'< is usually derived fron the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest tha
any one of these models is able to predict risk more accurately than another
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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Ortho-, Meta-, and Para-Dichlorobenzenes
March 31, 1 9?"
-2-
This Health Advisory (HA) is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for ortho-, meta-,
and para-dichlorobenzenes (U.S. EPA, 1987). The HA and CD formats are
similar for easy reference. Individuals desiring further information on
the toxicological data base or rationale for risk characterization should
consult the CD. The CD is available for review at each EPA Regional Office
of Drinking Water counterpart (e.g., Water Supply branch or Drinking Water
Branch), or for a fee from the National Technical Information Service,
U.S. Department of Commerce, 5285 Port Royal Rd., Springfield, VA 22161,
PB #86-117918/AS. The toll-free number is (800) 336-4700; in the Washington,
D.C. area: (703) 487-4650.
GENERAL INFORMATION AND PROPERTIES
CAS No. o-DC3 m-DCB p-DCB
95-50-1 541-73-1 106-46-7
Structural Formula
CJ. CI CI
CI CI CI
Synonym
0 o-DCB, m-DCB, p-DCB; 1,2-dichlorobenzene, 1,3-dichlorobenzene,
1,4-dichlorobenzene.
Uses (U.S. EPA, 1927)
o-DCB
p-DCB
m-DCE
Solvent, chemical intermediate, deodorizer
Deodorizer, insecticide
None documented
Properties (U.S. EPA, 1987,- 1985a)
qtDCB
Molecular Formula CgH^C^
Molecular Weight 147.01
Physical State Colorless liquid
Boiling Point 179°C
Melting Point -17.6°C
Density 1.3 g/mL at 20°C
Vapor Pressure 1.56 mm Hg at 25°C
Water Solubilit'/ 145 mg/L
Log Olive Oil/Water Partition 3.65
Coeff ici ent
Odor Threshold (water) 0.01-0.03 mg/L
Taste Threshold
Conversion Factor (air) 1 ppm = 6.01 mg/L
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Ortho-, Meta-, and Para-Oichlorobenzenes
March 31, 19£7
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m-DCB
Molecular Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Loq Olive Oil/Water Partition
Coefficient
Odor Threshold (water)
Taste Threshold
Conversion Factor
C6H4C12
147.01
Colorless liquid
172°C
-24.2°C
1;2~9 g/mL at 20°C
5 nun Hg at 39 °C
1.23 mg/L
3.69
0.01-0.03 mg/L
p-DCE
Molecular Formula Cgi^Clj
Molecular Weight 147.01
Physical State Colorless crystals
Boiling Point 174°C
Melting Point 53°C
Density 1.46 g/mL at 20°C
Vapor Pressure 0.4 mm Hg at 25°C
Loq Olive Oil/Water Partition 3.65
Coefficient
Water Solubility 79 mg/L
Odor Tnreshold (water) 0.01-0.03 mg/L
Taste Threshold
Conversion Factor (air) 1 ppm = 6.01 mg/n3
Occurrence
0 Tnere are no nat-iral sources for the three isomers of dichlorobenzen?
(DCS).
° Production of the DCB isomers in 1981 was 11 million lbs for the
ortho isomer and 15 million for the para isomer". Production of the
meta isomer was not reported and is believed to be small.
° Releases of the ortho and meta isomers to the environment are believer
to be small. The majority of the para isomer produced is released to
the environment during its use as a deodorant and moth repellent.
Dichlorobenzenes, while they have a low vapor pressure, are released
to the environment largely by evaporation. Dichlorobenzenes in air
are expected to degrade within a few days or weeks. Dichlorobenzenes
released to surface waters weld tend to be removed either by vola-
tilization or adsorptior. or.tc soil and sediments. Dichlorobenzenes
are hiodegraded poorly in the environment. When released to the
ground the compounds are expected to bind to soil and only slowly
migrate to ground water. Dichlorobenzenes have been reported to
bioaccunulaf? in fish, aquatic invertebrates and algae.
72
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Ort/io-, Meta-, an3 Para-Dichlorobenzenes
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0 The DCBs rarely occur as environmental contaminants (U.S. EPA, 19S3).
Based upon Federal surveys of drinking water, it is estimated that
the ortho and para isomers occur at detectable levels in approximatelv
0.2 and 1.1 percent of all'ground water supplies and 0.3 and 0.1 of
all surface water supplies, respectively. No levels have been detected
greater than 5 ug/L. Federal surveys of drinking waters have not
reported finding the meta isomer. No information on the occurrence
of DCB in food has been identified. Dichlorobenzenes have been
identified as contaminants of air at very low levels (< 40 ppt) in
urban and suburban areas. There are insufficient data on the DCBs to
identify the major route of environmental exposure.
II. PHARMACOKINETICS
Absorption
° No studies have been reported which determine the percentage of a
dose of DCB absorbed following oral or inhalation exposure. However,
it will be assumed that 100% of an oral dose of any of the isomers of
DCB is absorbed and that 60% of an inhalation dose is absorbed when
exposure persists for longer than one to three hours (Astrand, 1975;
Dallas -it ai., 1983).
D istributior.
0 The ortho- and para- isomers are lipophilic and can be expected to
bioaccumulate to some extent, particularly in tissues with high fat
content, during prolonged, continuous exposures. Para-DCB has beer,
detected in human adipose tissue and all three isomers have been
detected in blood (Dowty et al., 1975; Morita et al., 1975; Morita
anc Ohi, 19751.
Hetabolisr.
c After oral administration to rabbits, the DCBs are oxidized princi-
pally to phenols. ¦ Ortho- and meta-DCB also form catechols (Azouc
et al., 1955; Williams, 1959). Although .small amounts of the metabo-
lites are excreted as free phenols or catechols, the overwhelming
percentage are eliminated as conjugates of glucuronic or sulfuric
acids. Ortho- and meta-DCB form mercapturic acids as well, but p-DCE
does not (Williams, 1959). The conjugated dichlorophenols appear to
be the principal metabolic products of the DCB isomers in humans
(Halloweil, 1959; Pagnatto and WaDcley, 1965).
Excretion
Hawkins et al. (1980) found \^iat, after exposure of female CFY rats
to 1^C p-DCE, more than 90% of the ^C was eliminated in urine within
five days post-treatment, with the remainder in feces and expired air.
During the first two days following treatment, 50 to 60% of the 14C was
excreted in bile, thus indicating reabsorption in the enterohepatic
circulation.
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IV. HEALTH EFFECTS
Humans
0 Cases have been reported in which individuals suffered moderate to
severe anemia following exposure to DCBs (c.oncentrations not estimated)
(U.S. EPA, 1987). Several instances of skin lesions (e.g., pigmen-
tation and allergic dermatitis) developing after contact also have
been reported. Exposure levels were not estimated in these reports.
0 In other reported cases, patients complained of vomiting, headaches,
irritation of the «yes and upper respiratory tract and profuse rhinitis
and periorbital swelling (U.S. EPA, 1987). Anorexia, nausea, vomiting,
weight loss, yellow atrophy of the liver and blood dyscrasias also
were reported for higher exposure concentrations. Liver damage was
sometimes accompanied by porphyria (Hallowell, 1959). Exposure levels
were not estimated in these reports.
0 Zapata-Gayon (1932) reported headache, dizziness, nausea, and
chromosomal breaks in blood samples from men and women exposed to o-
DC3 (exposures not given) 8 hours per day for 4 days with reduced
chromosomal breaks by 6 months after exposure.
Animals
Short-term Exposure
0 The DCBs produce sedation and anesthesia in animals after acute oral
or parenteral administration (U.S. EPA, 1987). Relatively high doses
are needsd to produce acute effects. Acute poisoning is characterize.:
by signs of disturbance of the central nervous system including
hyperexcitability, restlessness and muscl® spasms or tremors. The
most frequent cause of death is respiratory depression. Acutp an.'
subcnronic exposures also may result in kidney and/or liver damage.
Liver alterations may be manifested as necrosis/degeneration, pe r'nz
coincident with porphyria.
0 Fourteen-day repeated dose gavage studies in mice (30 to 4,000 mg/ka)
and rats (60 to 1,000 mg/kg) were conducted with both o- and p-DCB in
the prechronic testing phase of the National Toxicology Program (NTP)
bioassay on these two substances (Battelle-Columbus, 1978a,b,d,e,f,g,h) ,
In addition to early deaths and lack of body weight gain at the higher
doses, animals exhibited histopathological changes indicative of
hepatic centrolobular necrosis and degeneration, occasionally with
cyto- and karyomegaly, as well as lymphoid depletion of the spleen
and thymus. The N0AEL for o-DCB in mice cannot be determined sines
degeneration and necrosis in liver found at 250 and 500. mg/kg were
not as.sv.sed at lower doses. Tn rats given o-DCB, the NOAEL was
250 mg/kg with the LOAEL Dem~ 500 mg/kg for decreased body weight=
in males. For animals given p-DCB, the LOAEL in mice was 250 mg/kg
(lowest doss tested) for tissue lesions and in rats the NOAEL was
250 mg/kg and the LOAEL 500 mg/kg (lower body weight in males).
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Long-tertn Exposure
0 Gavage doses of o-DCB at 250 and 500 mg/kg given to rats and mice
over a thirteen-week schedule of five days/week resulted in hepatic
necrosis as well aB porphyria (Battelle-Columbus, 1978c,i). Serum GPT
levels were increased in mice exhibiting liver histopathology at the
highest dose level. Some mice also exhibited myocardial and skeletal
muscle mineralization and lymphoid depletion of the thymus and spleen
and necrosis of the spleen. Rats also showed pathological changes in
their kidneys, characterized by tubular degeneration. No treatment-
related effects were observed with doses of 30, 60 and 125 mg/kg.
0 Hollingsworth et al. (1958) gave rats a series of 138 doses of o-DC«
over a period of 192 days (18.8, 188 or 376 mg/kg/day, five days a
week) by gastric intubation. No adverse effects were noted at the
lowest dose. With the intermediate dose, slight increases in the
weights of th« liver and kidney were noted. At the highest dose,
there was a moderate increase in the weight of the spleen and
swelling and cloudy appearance of the liver.
0 Hollingsworth et al. (1958) also assessed the effects of multiple
inhalation exposures to o-DCB in rats, guinea pigs, mice, rabbits and
monkeys. The animals were exposed seven hours a day, five days a
week, for six to seven months. No adverse effects were observed in
rats, guinea pigs or mice exposed to 49 ppm (0.29 mg/L), or in rats,
guinea pigs, rabbits and monkeys exposed to 93 ppm (0.56 mg/L).
0 Twenty oral doses of 10, 100 or 500 mg/kg p-DCB given five days/week
to rats produced marked hepatic effects including cloudiness, swelling
and centrilobular necrosis at only the highest dose (Hollingsworth
et al., 195SK No adverse effects were observed at the other doses.
° Thirteen-week exposures to p-DCB by gavage resulted in histopathologic^!
alterations in the liver similar to those observed with o-DCB, but at
somewhat higher doses (675 and 800 mg/kg in the mouse, 300 and 600
mg/kq in th? rat) (Battelle-Columbus, 1978a,b, 1980a,b). Hepatic
necrosis, degeneration and porphyria were found in both species. The
spleen and thymus also exhibited histopathological changes similar to
those observed with o-DCB. In mice and rats, hematopoietic hypoplasia
of the bone marrow occurred in survivors at the highest dose (1,500
mg/kg/day). Rats at the two highest dose levels (1,000 and 1,500
mg/kg) also exhibited epithelial necrosis of the nasal turbinates and
small intestine as well as villar bridging of the mucosa of the latter
tissue. Again, the rats exhibited multifocal degeneration or necrosis
of the cortical tubular epithelium of the kidney. A NOAEL of 150
mg/kg/day for rats and 337.5 mg/kg for mice was identified.
0 Oral doses of 188 or 376 mg o-DCB/kg given five days a week, for 192
days (138 doses) to rats produced an increase in the weights of the
liver and Kidneys (Hollingsworth et al., 1956). At 376 mg/kg,
increased splenic weight and slight cirrhosis and focal necrosis of
the liver were observed. No adverse effects were seen with the 18.8
mg/kg dose.
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March 31, 19S7
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0 Inhalation studies also were carried out by Hollingsworth et al.
(1956) with p-DCB in rats, rabbits, mice and monkeys. The concentra-
tions used were 96, 158, 173, 314 and 798 ppm (0.58, 0.95, 1.04, 2.05
and 4.8 mg/L, respectively). Exposures were conducted seven hours/day,
five days/week for six to seven months. Adverse effects observed
included liver and kidney lesions with increased organ weights,
pulmonary edema and congestion, splenic weight changes and reversible,
non-specific eye changes. The NOAELs were 96 ppm in rats and 158 ppm
in the other species.
0 Because available studies with lifetime exposures were conducted to
assess carcinogenicity, they are discussed in the Carcinogenicity
section.
Reproductive Effects
0 Data on reproductive effects were not found in available literature.
Developmental Effect?
0 Several teratogenicity studies have been conducted on two of the
three isomers of DCB. Hayes et al. (1985) observed no
teratogenic or fetotoxic effects in rator rabbit fetuses whose dans
wsri exposed by inhalation to doses of o-DCB at levels up to 400 ppr..
Similarly, no fetotoxic or teratogenic effects were noted in rabbits
subjected to exposures of p-DCB at levels up to 500 ppm. In addition,
the results of a study by Hodge et al. (1977, summarized in Loeser
and Litchfield, 1993), support the conclusions of the Hayes et al.
(1985) stddy in showing that maternal exposure to atmospheric levels
of p-DC3 up to 500 ppm on days 6 through 15 of pregnancy in the rat •
does not result in any embryotoxic, fetotoxic or teratogenic effects
in the offspring.
Mutagenicity
0 Para-dichlorobenzene induces abnormal mitotic division in higher
plants. Observed effects include shortening and thickening of
chromosomes, precocious separation of chromatids, tetraploid cells,
binucleate cells and chromosome bridges (c-mitosis) (Sharma and
Battacharva, 1956; Sharma and Sarkar, 1957; Srivastava, 1966; Gupta,
1972). Ortho-DCB was shown to produce abnormal mitotic division in
the onion Allium cepa (Ostergren and Levan, 1943).
0 Ortho- and para-dichlorobenzene were not mutagenic when tested in a
culture of histidine-requiring mutants of Salmonella typhimurium or
in the E. coli WP2 system (Anderson et al., 1972; Anderson, 1976;
Simmon et al., 1979; Shimizu et al., 1983; NTP, 1985; NTP, 1986).
However, all three isomer; ircreased the frequency of back mutation
of the methionine-requiring locus in the fungus Aspergillus nidulans
(Prasad and Pramer, 1968; Prasad, 1970). In addition, the meta
isomer was shown to increase mitotic recombination in the Saccharomyces
cerevisiae C3 yeast system (Simmon et al., 1979). The results with
the para isomer were ambiguous. These investigators also showed that
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Ort.io-, Me La-, and Pa"?.-Dichlorobenzenes
March 31, 195"
-3-
both o- and m-DCB interacted with and damaged bacterial DNA in the
coli W3110 polA+/p3478 polA" differential toxicity assay system.
Treatment with p-DCB did not induce forward mutations in mouse lymph or.?,
cells (NTP, 1986), sister-chromatid exchange in Chinese hamster ovary
cells (NTP, 1986), and unscheduled DNA synthesis in human lymphocytes
(Perocco et al., 1983).
0 DCB has not been found to be mutagenic in animals. Guerin et al.
(1971) showed chat DCB (unspecified isomer) did not produce a sig-
nificantly different number of mitoses in rat lung cell cultures.
Cytogenetic studies with rat bone marrow cells and a dominant lethal
study in CD-1 mice following exposure to p-DCB were all negative
(Anderson and Hodge, 1976; Anderson and Richardson, 1976; NTP, 1986).
Carcinogenicity
0 Hollingsworth et a]. (1956, 1958) exposed several species of animals
to various oral and inhalation exposures of ortho- and para-dichloro-
benzene for six to seven months. No evidence of carcinogenicity was
observed; however, the exposure duration was too short to allow
conclusions on carcinogenicity to be drawn.
0 An assessment of the data from an NTP bioassay using o-DCB administered
by gavage indicates that, under the conditions of the study, this
substance is not carcinogenic in Fischer 344 rats or B6C3Fi mice
(NTP, 1985). The NTP Board of Scientific Counselors added that no
non-neoplastic. lesions were noted in either the mice or the rats,
suggesting that the maximum tolerated dose was not achieved. Both
rats and nice (50/sex/dose) were given o-DCB in corn oil by gavage
5 days/week for 103 weeks at doses of 0, 60 or 120 mg/kg. No effect
on survival, body weight, and pathology was noted except for lower
(p <0.001) survival in high-dose male rats and increased tubular
regeneration n kidney of high-dose male mice.
0 In an NT? (1936) bioassay on p-DCB in F344 rats and B6C3F"i 'mice,
treatment-related neoplastic effects include renal adenocarcinomas ir.
male rats (1/50, controls; 3/50, low dose, p >0.05; 7/50, high dose,
p <0.05) and carcinomas and adenomas in liver of high-dose male and
female mice (P <0.001). Rats and mice (50/sex/group) were given
p-DCB in corn oil by gavage 5 days/week for 103 weeks at 0, 150 or
300 mg/kg (male rats) and 0, 300 or 600 mg/kg (remaining groups).
Other treatment-related effects include kidney lesions in male and
female rats at both doses, kidney and liver lesions in male and
female mice at both doses, and reduced survival (p <0.05) in high-dose
male rats.
0 A long-tem (76 wseks exposure, 36 weeks further observation) inhalation
study re"ftslod «c increase In tumor incidence or type after exposure
to p-DCB in Alderley Park Wistar rats (Riley et al., 1980, summarized
in Loeser and Litchfield, 1983). At the high exposure level (500 pp^n),
observed effects included increases in liver, kidney, heart and lung
weights (both sexes) and an increase in urinary protein and copropor-
phyrin output (males). The low exposure level of 75 ppm was a NOAEL.
The 500 and 75 ppm levels equal 3,005 and 451 mg/m3, respectively.
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Ortho-, Meta-, and Para-Dichlorobenzenss March 31, 192"
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qua;:tificatio.v or toxicqlogical effects
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-ten (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity
The HAs for noncarcinogenic toxicants are derived using the following formula
HA = (NOAEL or LOAEL) x (BW) 3 mg/L (___ ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in nig/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UP = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
o-Dichlorobenzene (and/or m-Dichlorobenzene)
One-day and Ten-day Health Advisories
No satisfactory dose-response data are available from which to derive a
One-day HA or Ten-day HA for the 10-kg child. It is recommended, that for
tnis dura-ion of exposure, the Longer-term HA for the 10-kg child (8.93 mg/L)
be applie.i (see below).
Longer-term Health Advisory
Subchromc treatment studies with o-DCB in rats and mice were conducted
in which daily doses were administered in corn oil by gavage at dose levels
of 30, 60, 125, 250 and 500 mg/kg/day five days/week for 13 weeks (Battelle
Columbus, 1978c,l). The NOAEL in these studies was 125 mg/kg. Renal and
hepatic lesions, lower body weights and increased uro- and coproporphyrin
levels were found with higher doses.
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA = (125 mg/kg/day) (10 kg) (5) = 8-93 mg/L (8(93o ug/L)
(100) (1 L/day) (7)
where:
123 mg/kg/day = NOAEL based on absence of renal and hepatic effects
in rats and mice exposed to o-DCB for 13 weeks.
10 kg = assumed body weight of a child.
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Ortho-, Meta-, and Para-Dichlorobenzenes
March 31, 19®7
-10-
5/7 = conversion of 5 day/week dosing regimen to 7 day/wee-:
exposure pattern.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
For a 70-kg adult consuming 2 I. of water per day, the Longer-term HA is
calculated as follows:
Longer-term HA = (125 ir.g/kg/dav) (70 kg) (5) „ 3U25 mg/L (31f250 ug/L)
(100) (2 L/day) (7)
125 mg/kg/day = NOAEL based on absence of renal and hepatic effects
in rats and mice exposed to o-DCB for 13 weeks.
70 kg = assumed body weight of an adult.
5/7 = conversion of 5 day/week dosing regimen to 7 day/wee>
exposure pattern.
100 = uncertainty factor, chosen in accordance with NAS/0DW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfO), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of. a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divider,
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an-
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carciriogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
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Ort'no-, Meta-, ar.3 Para-Dicnlorobenzenes
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The fact that the HAs generated from the chronic studies in the NT?
bioassay with a NOAEL of 120 mg/kg/day would be larger than those derived
from the subchronic studies preceding then with a NOAEL of 125 mg/kg/day
would suggest that the extra 10-fold uncertainty factor used with the
subchronic data to estimate a Lifetime HA from subchronic data may not be
necessary for this compound. However, the chronic /studies offer a narrower
evaluation of toxicity in that urinalysis, clinical chemistry and .hematology
were not included in the chronic study protocols. In view of this considera-
tion, the extra 10-fold uncertainty factor may be appropriate.
The results of Hollingsworth et al. (1958) suggest a safe daily level
of 0.94 mg/day to be used in the calculation of a lifetime HA, while those of
the subchronic studies preceding the NTP bioassay suggest a level of 6.25
mg/day. Each of these levels was derived from a NOAEL (18.8 mg/kg and 125
mg/kg, respectively). Since the highest NOAEL should be used to derive a
Lifetime HA, it is more appropriate to use the NOAEL established in the NT?
subchronic studies than the NOAEL from the Hollingsworth study. Furthermore,
the minimal effect dose identified in the Hollingsworth study (18^jng/kg) is
somewhat higher than the NOAEL established in the NTP subchronic studies.
The Lifetime HA is, therefore, calculated as follows:
Step 1: Deterraination of the Reference Dose (RfD)
RfD = (125 mg/kg/day) (5) = 0.089 mg/kg/day (89 ug/kg/day)
(1,000) (7)
whsre:
125 mg/kg/day = NOAEL used for Longer-term HA.
1,000 = uncertainty factor, chosen in accordance with NAS/ODv:
guidelines for use with a NOAEL from an animal stud.-
of less-than-lifetime duration.
5/7 = conversion of 5 day/week dosing to 7 day/week.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.089 mg/kg/day) (70 kg) = 3>13 mg/L (3 125 u /L)
(2 L/day)
where:
0.089 mg/kg/day = RfD.
7C kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = 3.13 mg/L x 20% = 0.62 mg/L (620 ug/L)
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Ortho-, Met..-.-, sr.; Para-Oichlorobenzenes March 31, 198"
-12-
where
3.13 mg/L « DWEL.
20% = assumed relative source contribution from water.
m-Dichlorobenzene
There are no toxicity studies on m-DCB on which to base Health Advisories;
however, because certain properties of o-DCB and m-DCB are similar, the HAs
for o-DCB are recommended for m-DCB (U.S. EPA, 1987).
p-Dichlorobenzene
One-day and Ten-day Health Advisories
No satisfactorv dose-response data are available from which to derive
a One-day HA or a Ten-day HA for p-DCB for the 10-kg child. It is recommended
that for this duration of exposure, the Longer-term HA for the 10-kg child
(10.7 mg/L) be applied (see below).
Longer-term Health Advisory
The 90-day treatment study with p-DCB by Battelie-Columbus (1979a) is
selected for calculation of a Longer-term HA; results in rats were used since
they indicated a lower NOAEL compared to that in mice (Battelle-Columbus,
1979b). In addition, a 90-dav study is considered to provide a stronger
evaluation of toxicity than 14-day treatment studies which preceded the
90-day studies. The rats were given p-DCB in corn oil by gavage, 5 days/week,
for 13 weeks. The NOAEL was 150 mg/kg/day since renal lesions were observe;
in males at higher doses.
The Longer-term HA for the 10-kg child is calculated as follows:
Lonaer-terr, H.^ = (150 mg/kq/day) (10 kg) (5) = io.7 mg/L (10,700 ug/L}
(100) (1 L/day) (7)
where .-
150 mg/kg/day = NOAEL, based on absence of renal lesions.
1 0 kg = assumed body weight of a child.
5/7 = conversion of 5 day/week dosing regimen to 7 day/week
exposure pattern.
*.00 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 I./day - assumed daily water consumption of a child.
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For a 70-kg adult, the Longer-term HA is calculated as follows:
Lonaer-ter™ HA = (150 mg/kg/day) (70 kg) (5) =,37.5 mg/L (37,500 ua/I)
(100) (2 L/day) (7)
where:
150 mg/kg/day = NOAEL, based on absence of renal Tesions.
70 kg » assumed body weight of an adult.
5/7 = corversion of 5 day/week dosing regimen to 7 day/week
exposure pattern.
100 = uncertainty factor, chosen in accordance with nas/odw
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
p-Dichlorobenzene
The EPA has developed for comparison with cancer-based criteria, a
presumed safe daily intake level based on non-carcinogenic effects as indicat
in U.S. EPA (1997). For consistency, the rationale used by EPA for the
calculation of this value by U.S. EPA (1987) is used here for the DWZL
calculation. The rationale as presented in U.S. EPA (1987) is as follows:
The results of the Hollingsworth et al. (1956) study and the subchror.i-
studies preceding the NTP bioassay, as well as the acute toxicity studies
described earlier, indicate that the rat is somewhat more sensitive to p-DCB
toxicitv tha;-: i= t-':- mouse. Therefore, when estimating potential ris'-t to
hunan, the data from the experiments in the rat should be used in deriving s.
Lifetime HA.
The NOAEL derived from the Hollingsworth studv was 18.8 mg/kq; the
NOAEL from the NTP subchronic study in the rat was 150 mg/kg. Since the
highest NOAEL snould be used to calculate a daily level of intake, the NOAEL
established in the NTP subchronic study will be used. In addition, it should
be noted that the minimal effect level identified in the Hollingsworth study
(188 mg/kg) was somewhat higher than the NOAEL established in the NTP sub-
chronic study.
As with o-DCB (and m-DCB), any Lifetime Health Advisories derived fron
the NTP chronic studies might be higher than those derived from the subchroni
studies preceding them because the 10-fold uncertainty factor applied to
accommodate for the difference in duration of exposure may be unnecessarily
large. Howsvsr, as mentioned for o-OZ-, the lack of certain parameters in
the chronic study (urinalysis, clinical chemistry and hematology) may make
the use of a 10-fold uncertainty factor appropriate. Also, the finding
of renal lesions with 150 mg/kg/day in the NTP (1986) chronic study in rats
further supports use of an extra 10-fold uncertainty factor.
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Ortho-, Metd-, and Para-Dichlorobenzenes March 31, 19S"
-1 4-
The Lifetime HA is, therefore, calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (150 mg/kg/day) (5_) « o.l mg/kg/day (100 ug/kg/day)
(1,000) (7)
where:
150 mg/kg/day = NOAEL used for Longer-term HA.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
5/7 = conversion of 5 day/week dosing to 7 day/week.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
Dw~ = (0.1 mg/kg/day) (70 kg) „ 3<75 mg/L (3,750 Ug/L)
(2 L/day)
where:
0.1 mg/kg/day = RfD.
70 = assumed body weight of an adult.
2 L/oav = assumed daily water consumption of an adult.
Step 3: Deteminaticr. of the Lifetime Health Advisory
Lifetims = (s-75 niq/L) (20%) _ 0.075 mg/L (75 ug/L)
10
where:
3.75 mg/L = DWEL.
20% = assumed relative source contribution from water.
10 = additional uncertainty factor for Group C carcinogens per
Office of Drinking Water policy.
Evaluation of Carcinogenic Potential
0 Assessment of the NTP Dioassav on o-DCB suggests that it was not
carcinogenic unier the conditions of the experiment.
= No adequate .iata are available to assess the potential cancer risk
associated witV. exposure to m-DCB.
83
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Orz'no-, Meta-, an5 P^ra-Dichlorobenzenes
March 31, 1 9" ~
-15-
° The IARC (1982) classified both p-DCB and o-DCB as Group 3 chemicais
with inadequate evidence for carcinogenicity in animals and humans.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986a), o-DCB and m-DCB may be classified
in Group D: Not classified. This category is for agents with inade-
quate animal evidence of carcinogenicity.
0 Because of positive evidence in two animal species, p-DCB may be
placed in category B2 (sufficient animal evidence, inadequate human
evidence) by these guidelines. However, consideration of the overall
weight of evidence could suggest the alternative view that p-DCB be
placed in Group C (limited animal evidence) by these guidelines, with
resDect to uncertainties with high doses and corn oil gavage and
diminished toxicological significance of the mouse liver tumor results.
The EPA has concluded that the overall weight of evidence favors
classification of p-DCB in Group C (U.S. EPA, 1987).
0 Because p-DC3 is considered a Group C agent, the DWEL would be divided
by an extra uncertainty factor of 10 to yield 0.375 mg/L.
0 Provisional cancer potency estimates for p-DCB were derived using the
multistage model and the liver tumor data on male mice in the chronic
feeding study by NTP (1986).
0 The 95% upper-limit carcinogenic potency factor for humans, q^*, is
2 x 10"' (mg/kg/day)~1 by the multistage model (U.S. EPA, 1986b).
For a 70 kg human drinking 2 L water/day, the water concentration
should be 17.5 ug/L in order to keep the upper-limit individual
lifetime cancer risk at 10"^. Water concentrations corresponding to
excess cancer risk of 10~4 and 10"6 are, therefore, 175 and 1.8 ug/L,
respectively. Maximum likelihood estimates by the multistage model
associate risks of 10~5 and 10"^ with exposures to 20.7 and 6.3 it:/'.,
respectively. There are not enough distinct data points to allow fits
to other no-dels tried (Weibull, logit, probit). While recognized as
statistically alternative approaches, the range of risks described bv
using any of these modeling approaches has little biological signifi-
cance unless data can be used to support the selection of one model
over another. In the interest of consistency of approach and in
providing an upper bound on the potential cancer risk, the EPA has
recommended use of the linearized multistage approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
® The OSHA standard for 1,2-dichlorobenzene is 50 ppm (300 mg/m3) (U.S.
EPA, 19S5a).
0 The 1982 AC3IH TLV is 50 ppir. (U.S. EPA, 1985a).
° The OSH^l standard for 1,4-dichlorobenzene is 75 ppm (450 mg/m3)
(U.S. EPA, 1985a).
84
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Ortno-, Meta-, and Para-DichloroDenzenes
March 31, 19?
-16-
0 The dicftlorobenzene isomers are designated as hazardous wastes under
the Resource Conservation and Recovery Act (RCRA) (U.S. EPA, 1985a).
0 Under the Federal Water Pollution Control Act, 1,2-di- and 1,4-dichloro-
benzenes are hazardous substances with reportable quantities of 100 lbs.
0 The ambient water quality criterion for dichlorobenzenes is 400 ug/L,
using a NOAEL of 13.4 nig/kg/day and an uncertainty factor of 1,000
(U.S. EPA, 1980).
° The WHO (1984) recommended an acceptable drinking water level of 1 ug/L
for 1,2- and 1,4-dichlorobenzenes based on odor threshold.
° The NAS (1983) calculated a chronic SNARL of 0.3 mg/L for o-DCB,
using a NOAEL of 60 mg/kg, 20% relative source contribution, and a
1,000-fold uncertainty factor.
0 The NAS (1977) calculated a chronic SNARL of 0.094 mg/L for p-DCB,
using a NOAEL of 13.4 mg/kg/day, a relative source contribution of
20%, and an uncertainty factor of 1,000.
0 The proposed RMCL for o-DCB is 0.62 mg/L (U.S. EPA, 1985b).
° The U.S. EPA Office of Drinking Water issued a final RMCL of 0.75 mg/L,
a proposed MCL of 0.75 mg/L, and a practical quantitation level of 5
ug/L for p-DC3 (U.S. EPA, 1985c). However, p-DCB is being considered
for repropos*! as a result of the recent positive NTP (1986) carcino-
genicity bioassay.
'II. ANALYTICAL METHOD"
0 Analysis of dichlorobenzene(s) is by a purge-and-trap gas chromato-
graphic procedure used for the determination of volatile organohalide-
in drinking water (U.S. EPA, I985d). This method calls for the
bubbling of an inert gas through the sample and trapping dichloro-
benzene(s) on an adsorbant material. The adsorbant material is
heated to drive off the dichlorobenzene(s) onto a gas chromatographic
column. The gas chromatograph is temperature programmed to separate
the method analytes which are then detected by a halogen specific
detector. This method is applicable to the measurement of dichloro-
benzene(s) over a concentration range of 0.05 to 1500 ug/L. Con-
firmatory analysis for dichlorobenzene(s) is by mass spectrometry
CJ.S. EPA, I985e). The detection limit for confirmation by mass
spectrometry is 0.3 ug/L.
II." TREATMENT TECHNOLOGIES
0 Granular activated carbon (GAC) adsorption and aeration for the
removal of ortho-, meta- and para-dichlorobenzene from water are
available and have been reported to be effective. Because ortho-,
meta- and para-dichlorobenzene are chemically similar, they can be
considered together ('J.S. EPA, 1985f).
85
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Ortho-, Meta-, and Para-Dichlorobenzenes
March 31, i9r
-17-
0 McCarty et al. (1979b) conducted a study at a 15-MGD advanced wast-?
treatment (AWT) plant which examined organics removal in air stripping
towers designed for ammonia removal. That study showed that 83 to 97
percent of trace quantities (ug/L range) of o-DCB, m-DCB and p-DCB were
removed.
0 In a laboratory study where water containing an average of 151 ug/L
of o-DCB, 229 ug/L of m-DCB and 225 ug/L of p-DCB was passed through a
diffused-air aerator using a 15:1 air to water ratio, there was a 74%
reduction in the o-DCB concentration, a 79% reduction of m-DCB and a
77% reduction in the p-DCB {Love et al., 1983). In another study of
well water contaminated with 3.0 ug/L o-DCB, 90% or more of the compound
was removed with air to water ratios of 47:1.
° Carbon adsorption also can be used to remove o-DCB, m-DCB and p-DCB from
contaminated water. According to Dobbs and Cohen (1980) at equilibnun
concentrations of 1 mq/L and 10 mg/L, activated carbon had adsorptive
capacities of 129 mg and 350 mg of o-DCB per gram of carbon, respec-
tively. Their data for prDCB show carbon capacities of 121 mg/gran
of carbon and 470 mg/gram of carbon, respectively, at the identical
equilibrium concentrations. Adsorption capacities for m-DCB are
slightly less than those for o-DCB and p-DCB (Love et ali, 1983).
° Data fron a GAC system containing Filtrasorb® 300 at an AWT Plant
demonstrated significant removals of o-DCB and p-DCB at trace concen-
trations (McCarty et al., 1979a).
c A colurr.r, study by EPA/ESE (ESE, 1981) examined removal of benzene,
nonocnlorobenzene, o-DCB and p-DCB from a wastewater stream by
regenerate". GAC. With influent concentrations of each in the mg/L
ranqe, o-DC3 and p-DCB did not break through during the study.
Estimats.i carbon usage rates for each could be expected to be less
than those obtained for benzene (10 lb/1,000 gallons). Although
experimental data from drinking water and wastewater experimentation
are markedly different, some comparisons can be made. Another ESE
field study (1973) at North Miami Beach using powdered activated
carbon addition to potable water demonstrated up to 97 percent removal
of dichlorobenzenes by 52 mg/L (434 lb/10® gallons) of PAC. This
concentration of PAC is much greater than that normally used.
86
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Ortho-, Meta-, an: Para-Dichlorobenzenes
March 31, 195"
-18-
REFERENCES
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Battelle's Columbus Laboratories. 1978e. Repeated dose toxicity study:
Para-dichlorobenzene (C54955), B6C3F1 mice. Unpublished Report.
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Battelle's CcluT.bus Lai)oratories. 197S5. Repeated dose toxicity study:
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87
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Ortho-, Meta-, and Para-Dichlorobenzenes
March 31, 195"
-19-
Battelle's Columbus Laboratories. 1978g. Re-run repeated dose toxicity
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Battelle's Columbus Laboratories. 1978i. Subchronic study: Ortho-
dichlorobenzene (C54944), Fischer 344 rats. Unpublished Report.
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Battelle's Columbus Laboratories. 1979a. Subchronic toxicity study: Para-
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Battelle's Columbus Laboratories. 1979b. Subchronic toxicity study:. Para-
dichlorobenzene (C54955), Fischer 344 rats. Unpublished Report.
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Battelle's Columbus Laboratories. 1980a. Re-run subchronic toxicity study:
Para-dichlorobenzene (C54955), B6C3F1 mice. Unpublished Report.
Subcontract No. 76-34-106002. Feb. 12, 1980.
Battelle's Columbus Laboratories. 1980b. Re-run subchronic toxicity study:
Para-dichlorobenzene (C54955), Fischer 344 rats. Unpublished Report.
Subcontract No. 76-34-106002. FeD. 12, 1980.
Dallas, C.E. , F.w. We.-.r, S. Feldman, L. Putcha and J.V. Bruckner. 1933.
The uptake and distribution of 1,1-dichloroethylene in rats during
innalatioi exposur-j. Toxicol. Appl. Pharmacol. 68:140-151.
Dobbs, R-.J., air J.v.. Cohen. 1980. Carbon isotherms for toxic organics.
United States Environmental Protection Agency. Cincinnati, Ohio.
Dowty, b., D. Carlisle, J. Laesleter and J. Storer. 1975. Halogenated
hydrocarbons m New Orleans drinking water and blood plasma. Science.
187:75-77.
E5E. 1978. Environmental Science and Engineering. Final data report for the
Sunny Isle Water Plant. North Miami Beach, Florida. EPA Contract.
ESE. 1981. Environmental Science and Engineering. Final report on pilot
operations on simulated wastewater from the production of chlorinated
benzenes. EPA Contract No. 68 03 2610.
Girard, R., F. Tolot, P. Martin and J. Bourret. 1969. Serious blood dis-
orders and exnosure to chlorine derivatives of benzene (a report of
seven cas = s). J. Med. Lyon. 5C ; 1 164):771-773.
Glaze, W.H., G.R. Peyton, F.Y. Huang, J.L. Burleson and P.C. Jones. 1980.
Oxidation of water supply refractory species by ozone with ultraviolet
radiation. United States Environmental Protection Agency, Cincinnati, OH.
-------
Ortno-, Meta-, and Para-Dichlorobenzenes
March 31, 1 9f
-20-
Guerin, M., P. Lazar and I. Chouroulinkov. 1971. Inhibitory action of
chemical carcinogens on mitosis of rat lung cell cultures. 2. Compara-
tive study of carcinogenic and non-carcinogenic substances. C.R. Seances
Co. Biol. Filiales. 165:2255-2258.
Gupta, K.C. 1972. Effects of some antimitotics on the cytology of fenugreek
roots in vivo and in vitro. Cytobios. 5(19):179-187.
Hallowell, M. 1959. Acute haemolytic anaemia following the ingestion of
paradichlorobenzene. Arch. Dis. Child. 34:74-75.
Hawkins, D.R., L.F. Chasseaud, R.N. Woodhouse and D.G. Cresswell. 1980.
The distribution, excretion and biotransformation of p-dichloro-[14]-
benzene in rats after repeated inhalation, oral and subcutaneous doses.
Xenobiotica. 10:81-95.
Hayes, W.C., T.R. Hanlev, Jr., T.S. Gushow, K.A. Johnson and .l.A. John. 1985.
Teratogenic potential of inhaled dichlorobenzenes in rats and rabbits.
Fund. Appl. Toxicol. 5:190-202.
Hodge, S. Palmer, J. Wilson and I.P. Bennett. 1977. Paradichloro-
benzene: Teratogenic!£/ study in rats. ICI Report No. CTL/P/340.
July 27, 1976. (Unpublished)
Hollingsworth, R.L., V.K. Rowe, F. Oyen, H.R. Hoyle and H.C. Spencer. 1956.
Toxicity of paradichlorobenzene: Determination on experimental animals
and human subverts. AMA Arch. Ind. Hlth. 14:138-147.
Hollingsworth, R.L., V.K. Row®, F. Oyen, T.R. Torkelson and E.M. Adams. 195®.
Toxicity of o-dichlorobenzene: Studies on animals and industrial experi-
ence. AMA Arch. Ind. Hlth. 17(1 ): 1 80-1 87.
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the evaluation of the carcinogenic use of chemicals to humans. Chemical
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Suppl. 4. Lyon, France, pp. 108-109.
Loeser, E., and M.H. Litchfield. 1983. Review of recent toxicology-studies
on p-dichlorober.zene. Food Chem. Toxicol. 21 :825-832.
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of volatile organic compounds in drinking water. United States Environ-
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EPA-600/6-83-019.
McCarty, P.L., 0. Argo and M. Reinhard. 1979a. Operational experiences with
activated carbon adsorbers at Water Factory 21. J. AWWA. 11: ,-683-689.
McCarty, P.L., K.K. Sutherland, J. Graydon and M. Reinhard. 1979b. Volatile
organic contaminants removal by air stripping. Presented at the Seminar
on Controlling Organics in Drinking Water, American Water Works Annual
Conference, San Francisco, CA.
89
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Orvio-, Meta-, and Para-Oichiorobenzenes
March 31, 19?."
-21-
Morita, M., and G. Ohi. 1975. Paradichlorobenzene in human tissue and atmos-
phere in Tokyo metropolitan area. Environ. Pollut. 8:267-274.
Morita, M., S. Mimura, G. Ohi, H. Yagyu and T. Nishizawa. 1975. A systematic
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NAS. 1977. National Academy of Sciences. Drinking Water and Health. Vol. 1.
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National Academy Press- Washington, D.C.
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mice (gavage study). NTP TR 235. NIH Publication No. 86-2511.
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B6C3F1 mice (gavage studies). Galley draft. NTP TR 319. NIH Publication
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Ostergren, G., and A. Levan. 1943. The connection between c-mitotic activity
and water solubility in some monocyclic compounds. Hereditas. 29:496-498.
Pagnatto, L.O., and J.E. Walkley. 1965. Urinary dichlorophenol as an index
of paradichlorobenzene exposure. Amer. Ind. Hyg. Assoc. J. 26:137-142.
Perocco, P., B. Silvans, and W. Alberghini. 1983. Toxic activity of seventeen
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Prasad, I., and D. Pra.mer. 1968. Mutagenic activity of some chloroanilines
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Para-dichlorobenzene: Long-term inhalation study in the rat. ICI Report
No. CTL/P/447. August, 1980. (Unpublished)
Sharma, A.K., and N.K. Battacharya. 1956. Chromosome breakage through para-
dichlorobenzene treatment. Cytologia. 21:353-360.
Sharma, A.K., and S.K. Sarkar. 1957. A study on the comparative effect of
chemicals on chromosomes of roots, pollen mother cells and pollen grains.
Proc. Ind. Acad. Sci. B. XLV(xxr):288-293.
Shimizu, M., Y. Yasui, and N. Matsumoto. 1933. Structural specifity of
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derivatives. Mutat. Res. 116:217-238.
90
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Ortho-, Meta-, and Para-Dichlorobenzenes
March 31, 193?
-22-
Simmon, v.F., E.S. Riccio and M.V. Peirce. 1979. In vitro microbiological
genotoxicity tests of chlorobenzene, m-dichlorobenzene, o-dichlorobenzen-=,
and p-dichlorobenzens. Unpublished report by SRI International for U.S.
EPA, Contract No. 68-02-2947. Final Report, May 1979.
Srivastava, L.M. 1966. Induction of mitotic abnormalities in certain genera
of tribe vicieae by paradichlorobenzene. Cytologia. 31:166-171.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water Related Environ-
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Standards, EPA-440/4-79-029.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water quality
criteria for dichlorobenzenes. Environmental Criteria and Assessment
Office for the Office of Water Regulations and Standards. EPA 440/5-80-039.
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occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Health assessment
document for chlorinated benzenes. Final Report. Office of Health and
Environmental Assessment. EPA/60018-84015F. January.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. National primary
drinking water regulations; Synthetic organic chemicals, inorganic chenicals
and microorganisms; Proposed rule. Federal Register. 50(219):46934-47022 .
Novembar 13.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. National primary
drinking water regulations: Volatioe synthetic organic chemicals; Fins I
and proposed rule. Federal Register. 50(219):46880-46933. November 13.
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Volatile naloqenat-id organic compounds in water by purge and trap qas
chromatography. Environmental Monitoring and Support Laboratory, Cin-
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U.S. EPA. 1985e. U.S Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass Spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268, June.
U.S. EPA. 1985f. U.S. Environmental Protection Agency. Draft. Technologies
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water supplies. Science and Technology Branch, Criteria and Standards
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September 24.
U.S. EPA. 1986b. U.S. Environmental Protection Agency. Risk estimates for
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March 31, 1987
1,2-OICHLOROETHANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. Riey are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered* unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
93
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1, 2-Dichloroethane
-2-
March 31, 1987
This Health Advisory is based on information presented in the Health
Assessment Document for 1,2-Dichloroethane (Ethylene Dichloride) (U.S. EPA,
1985a). Individuals desiring further information on the toxicological data
should use this document. Information on the Quantification of Toxicological
Effects (QTE) section is contained in the QTE Document (PB#86-118080). Both
documents are available for review at each EPA Regional Office of Drinking
Hater counterpart (e.g., Hater Supply Branch or Drinking Hater Branch), or
for a fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Road, Springfield, VA 22161. The toll-free number
is (800) 336-4700; in the Hashington, D.C. areat (703) 487-4650.
GENERAL INFORMATION AND PROPERTIES
CAS No. 107-06-2
Structural Formula
° Ethylene dichloride, EDC, 1,2-DCE
Uses (U.S. EPA, 1985a)
s The major use for EDC is in the production of vinyl chloride. In
addition, it is used as a starting material for the production of
other solvents, as an additive (lead scavenger) in gasolines and is
widely exported. Some of its minor uses include its use as a solvent
in metal degreasing and textile and PVC cleaning, in paints, coatings
and adhesives, as a grain fumigant, a varnish and finish remover,
in soaps and scouring compound, as a wetting and penetrating agent,
in ore flotation and as a chemical intermediate.
Properties (EPA, 1985a; Amoore and Hautala, 1983)
H H
CI - C - C - CI
H H
1,2-Dichloroethane
Synonyms
Chemical Formula
Molecular Height
Physical State
Boiling Point
Melting Point
Density (20#C)
Vapor Pressure
Water Solubility (20°C)
Log Octanol/Water Partition
c2h2c12
98.96
Clear, colorless, volatile, oily liquid
83.7«C
-35.3#C
1.2529 g/mL
64 torr (20°C)
8820 mg/L
1.48
Coefficient
Organoleptic Threshold (water)
Odor Threshold (air)
Conversion Factor
29 mg/L
3 ppm
1 ppm ¦ 4.05 mg/m3
94
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1,2-Dichloroethane
-3-
March 31, 1987
Occurrence
" Dichloroethane is a synthetic chemical with no natural sources.
s Production of dichloroethane was approximately 12 billion pounds in
1983 (U.S. ITC, 1984). However, the vast bulk of dichloroethane is
used as a feed stock for the production of other chlorinated compounds
and it is not readily released to the environment. Releases of
dichloroethane largely result from the approximately 3 million pounds
used as solvents and metal cleaners.
0 Releases of dichloroethane are largely to air, with smaller amounts
released to surface and ground waters. Because metal working opera-
tions are performed nationwide, dichloroethane releases occur in all
industrialized areas.
0 Dichloroethane released to the air slowly degrades over a few months.
Photooxidation is thought to be the predominant environmental process
determining the fate of 1,2-dichloroethane (U.S. EPA, 1979). Dichloro-
ethane released to surface waters migrates to the atmosphere in a few
days or weeks where it also degrades. Dichloroethane released to the
land does not sorb onto soil but migrates readily to ground water
where it is expected to remain for months to years.
0 Due to dichloroethane's limited releases, it is a relatively rare
environmental contaminant. Dichloroethane has been detected in both
ground and surface waters but, unlike other volatile organic compounds,
higher levels were reported in surface waters than in ground waters.
The Agency estimates that 0.3% of all ground water supplies contain
concentrations of dichloroethane ranging from 0.5 to 5 ug/L. Surface
waters contain higher levels, with 3% of all wells estimated to have
from 0.5 to 20 ug/L. Dichloroethane commonly occurs in air in urban
and suburban areas at concentrations of less than 0.2 ppb. No infor-
mation on the levels of dichloroethane in food have been reported.
0 For the majority of the U.S. population, the greatest source of
dichloroethane exposure is from air. Drinking water is the greatest
source only for populations with drinking water levels greater than
6 ug/L.
HI. PHARMACOKINETICS
Absorption
0 1,2-Dichloroethane is absorbed by humans and laboratory animals
through the lungs (Spencer et al., 1951; Urusova, 1953) gastro-
intestinal tract (Alumot e: al., 1976) and skin (Urusova, 1953).
e The proportions of a dose of 1,2-dichloroethane absorbed through the
skin and gastrointestinal tract are unknown. Wie nature of its other
chemical and physical properties would suggest that this substance
would be absorbed completely when ingested.
95
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1,2-Dichloroethane
-4.
March 31, 1967
Distribution
0 Forty-eight hours after the administration of a single oral dose of
150 mg/kg of 1,2-dichloroethane to rats, the liver and kidneys were
reported to have the highest concentration of the chemical. Success-
ively lower concentrations occurred in the forestomach, stomach and
spleen (Reitz et al*, 1980)*
* 1,2-Dichloroethane readily passes the blood/brain barrier. Distribu-
tion is also known to occur into milk (Urosova, 1953).
Metabolism
0 Following intraperitoneal administration to mice, 1, 2-dichloroethane
is metabolized to 2-chloroethanol, converted to alcohol and aldehyde
dehydrogenases, to monochloroacetic acid, and further dehalogenated by
enzyme interaction of monochloroacetate with glutathione or cysteine
to yield 5-carboxymethylcysteine and thiodiacetic acid (Yllner,
1971a,b).
0 Urinary metabolites of 1,2-dichloroethane intraperitoneally administered
to mice include chloroacetic acid, 2-chloroethanol, 5-carboxymethyl
cysteine, conjugated 5-carboxyi^ethyl cysteine, thiodiacetic acid and
5,5-ethylene-bis-cysteine (Yllner, 1971a,b).
* Following oral administration of 1,2-dichloroethane (750 mg/kg) or
2-chloroethanol (80 ag/Xg) to rats, the blood level of 2-chloroethanol
at four hours was 67.8 or 15.8 ug/mL, respectively (Kokarovtseva and
Kiseleva, 1978). These levels declined in accordance with first-order
kinetics with a half-life of about nine hours. The relatively low
blood concentrations found were postulated to be due to initial
sequestration of 1,2-dichloroethane in adipose and other tissues
with gradual diffusion redistribution as liver metabolism of 1,2-
dichloroethane to chloroethanol and chloroethanol to chloroacetic
acid proceeded.
Excretion
s Mice intraperitoneally injected with a dose of 0.05 to 0.17 g/kg of
1,2-dichloroethane excreted 11 to 46% of the dose, unchanged, via the
lungs; 5 to 13% of the dose was metabolized to carbon dioxide and
water; 50 to 73% of the dose was excreted as urinary metabolites
(Yllner, 1971a).
* Within 48 hours after dosing, 96% of the radioactivity of a single
oral dose of 150 mg/kg was eliminated from the body by rats (Reitz
et al., 1980).
96
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1,2-Dichloroethane
-5-
March 31, 1987
IV. HEALTH EFFECTS
Humans
• Clinical symptoms of acute 1,2-dichloroethax
usually appear within two hours after exposu**. -jjr .
headache, dizziness, general weakness, nausea, vomiting of blood and
bile, dilated pupils, heart pains and constriction, pain in the
epigastric region, diarrhea and unconsciousness* Pulmonary edema
and increasing cyanosis also may occur. These symptoms may disappear
if exposure is sufficiently brief (Wirtschafter and Schwartz, 193§;
McNally and Fostvedt, 1941).
• A 14-year-old male \ftio drank 15 ml (340 ag/kg) ot 1,2-dichloroethane
died six days later despite supportive treatment (Yodaiken and Babcock,
1973). During treatment, serum enzyme and calcium levels increased,
blood glucose decreased and blood clotting time increased. Autopsy
findings revealed extensive liver necrosis and epithelial cell damage
in the entire cortico-tubular structure of the kidneys accompanied by
degeneration in the proximal tubules.
0 While not all instances of 1,2-dichloroethane ingestion are fatal,
death has resulted in the majority of reported cases. Death is most
often attributed to circulatory and respiratory failure (Budanova,
1965; Yodaiken and Babcock, 1973; l
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1»2-Dichloroethane
March "31, 19S7
-6-
Reproductlve Effects
0 No reproductive effects, as measured by fertility, gestation, viability
or lactation indices, pup survival and weight gain, were indicated in
a multigeneration reproduction study using male and female ICR Swiss
mice receiving 0, 5, 15 or 50 mg/kg/day in drinking water* No effect
on the adult generations was evident after 25 weeks of dosing as
measured by body weight, fluid intake or gross pathology (Lane et al.,
1982).
Developmental Effects
s In a study in vh:ca male and female mice were exposed to 1,2-dichloro-
ethane in drinking water at doses of 0, 5, 15 or 50 mg/kg/day, no
statistically significant dose-related developmental effects were
observed, as indicated by incidence of fetal visceral or skeletal
anomalies (Lane et al., 1982).
Mutagenicity
0 1,2-Dichloroethane has been shown to be weakly mutagenic in Salmonella
typhimurium strains TA 1530, 1535 and 1538 and in DNA polymerase-defi-
cient Escherichia coli (Brem et al., 1974).
• 1,2-Dichloroethane has been found to be highly mutagenic in Salmonella
typhimurium strains TA 1530 and 1535 with S-9 activation (Rannug and
Beije, 1979).
* 1,2-Dichloroethane has been shown to induce sex-linked recessive
lethals in Drosophila melanogaster (Rapport, 1960; Shakarnis, 1969).
0 1,2-Dichloroethane was not mutagenic in Salmonella microsome assay
system (McCann et al., 1975).
Carcinogenicity
0 In an NCI (1978) bioassay, 1,2-dichloroethane was administered by
gavage at levels of 47 or 95 mg/kg body weight to Osborne-Mendel rats
five times per week for 78 weeks. Statistically significant increases
in the incidence of squamous cell carcinomas of the forestomach and
hemangiosarcomas of the circulatory system were observed in male
rats(p <0.04). Female rats had a statistically significant increased
incidence of adenocarcinoma of the mammary glands (p <0.002).
s In the same NCI (1978) bioassay, B6C3F^ mice received 1,2-dichloroethane
by gavage five times per week for 78 weeks; males were dosed at levels
of 97 or 195 mg/kg body weight and females at 149 or 299 mg/kg body
might. Statistically significant increases in the incidence of
mammary adenocarcinoma (p <0.04) and endometrial stromal polyps or
sarcocas (p <0.016) were seen in female mice. The incidence of
alveolar/bronchiolar adenomas was increased in both sexes (p <0.028).
98
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1,2-Dichloroethane
March 31, 1987
-7-
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncareinogenic end point of toxicity.
Die HAs for noncareinogenic toxicants are derived using the following formula:
HA ¦ (HOAEL or LOAEL) X (BW) _ Bg n ( yg/L)
(UF) x { L/day)
where:
NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect-Level
in nig/kg bw/day.
BW m assumed body weight of a child (10 kg) or
an adult (70 kg).
UF ¦ uncertainty factor (10, 100 or 1,000), in
accordance with NAS/OEW guidelines.
L/day « assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day and Ten-day Health Advisories
Appropriate data for the derivation of One-day and Ten-day HAs were not
located. It is recommended that the Longer-term HA of 0.74 mg/L for the
10 kg child be used as a conservative estimate for One-day and Ten-day
exposures.
Longer-term Health Advisory
A combination of three inhalational studies in which various animal
species were exposed to 1,2-dichloroethane for up to eight months are consid-
ered appropriate to use in calculating a Longer-term HA. In these studies,
exposures of rats and guinea pigs to air containing 100 ppm 1,2-dichloroethane
for 6 to 7 hours/day, 5 days/week resulted in no mortality and no adverse
effects as determined by general appearance, behavior, growth, organ function
or blood chemistry. However, similar exposures of rats, guinea pigs, rabbits,
and monkeys to air containing 400 or 500 ppm 1,2-dichloroethane resulted in
high mortality and varying pathological findings including pulmonary conges-
tion, diffused myocarditis, slight to moderate fatty degeneration of the
liver, kidney, adrenal, and heart, and increased plasma prothrombin time
(Heppel et al., 1946; Spencer et al., 1951; Hofmann et al., 1971).
The Longer-term HA is calculated as follows:
Step 1: Determination of Total Absorbed Dose (TAD)
TAD . (405 mg/s3) (1 m3/hr) (6 hr) (0.3) (5/7) _ 521 mg/day . 7.4 mg/kg/day
70 kg 70 kg 1
99
-------
1, 2-Dichloroethane March *3*t, 1967
-8-
where:
405 mg/m3 ¦ NQAEL of 100 ppm (1 ppm ¦ 4.05 mg/m3) for adverse effects
in rats and guinea pigs.
1 n>3/hr - respiratory rate of adult human (pulmonary rate/body
weight ratio assumed to be the same for humans and
test animals).
6 hr « exposure duration per day.
0.3 - fraction of test substance assumed to be absorbed.
5/7 - conversion of 5-day dosing regimen to full 7-day week.
70 kg » assumed body weight of an adult.
Step 2: Determination of the Longer-term HA
For a 1 0-kg child:
Longer-term HA - i7'* mgAg/day) (10 kg) . 0>74 ag/L (740 ug/L)
(100) (1 L/day)
For a 70-kg adults
Longer-term HA - (7.4 mg/kg/day) (70 kg) . 2.6 mg/L (2600 ug/L)
(100) (2 L/day)
where:
7.4 mg/kg/day = total absorbed dose (TAD).
10 kg ¦ assumed body weight of a child.
1 L/day ¦ assumed daily water consumption of a child.
70 kg ¦ assumed body weight of an adult.
2 L/day - assumed daily water consumption of an adult.
100 ¦ uncertainty factor, chosen in accordance with NAS/ODK
guidelines for use with a N0AEL from an animal study.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
100
-------
1,2-Dichloroethane
Mar en ji, iso <
-9-
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). Prom the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DUEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DUEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
No appropriate data are available for determining a reference dose and
drinking water equivalent level (DWEL) for 1,2-dichloroethane. A Lifetime
Health Advisory is not estimated for this chemical.
Evaluation of Carcinogenic Potential
0 1,2-Dichloroethane was shown to be carcinogenic in rats and mice
following gavage exposure in the NCI bioassay (NCI, 1978).
0 I ARC has not classified 1,2-dichloroethane (XARC, 1982).
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), 1,2-dichloroethane may.be
classified in Group B2: Probable Human Carcinogen. Ibis category is
for agents for which there is inadequate evidence from human studies
and sufficient evidence from animal studies.
° The most recent calculations by EPA's Carcinogen Assessment Group
(CAG) indicates the cancer risk estimate for 1,2-dichloroethane
corresponding to a 10-5 risk level is 3.8 ug/L, using the multistage
model (95% confidence limit) (U.S. EPA, 1985d).
0 The linear multistage model is only one method of estimating carcino-
genic risk. Using the 95% upper-bound estimate of risk at 1 mg/kg/day
for hemangiosarcomas in male rats, the following comparisons can be
made: Multistage, 6.0 x 10-2, Probit, 2.81 x 10-1; Weibull, 2.7 x 10-1
(U.S. EPA, 1985a). Each model is based on differing assumptions. Mo
current understanding of the biological mechanisms of carcinogenesis
is able to predict which of these models is more accurate than another.
° While recognized as statistically alternative approaches, the range of
risks described by using any of these modelling approaches has little
biological significance unless data can be used to support the selection
of one model over another. In the interest of consistency of approach
and in providing an upper bound on the potential cancer risk, the Agency
has recommended use of the linearized multistage approach.
101
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1»2-Dichloroethane
-1 0-
March 31, 1987
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 D.S. EPA (1985d) has promulgated a final Recommended Maximum Contami-
nant Level (RMCL) of zero for 1,2-dichloroethane in drinking water
based upon its carcinogenic potential and has proposed a Maximum
Contaminant Level (MCL) of 0.005 mg/L.
0 Due to the lack of appropriate data, the National Academy of Sciences
did not calculate a chronic Suggested-No-Adverse-Rasponse-Level
(SNARL) for 1,2-dichloroethane (NAS, 1980).
* ACGIH (1984) has'recommended a threshold limit value (TLV) of. 10 ppm
( 40 mg/m3) and a short-term exposure level (STEL) of 15 ppm (-•» 60
mg/m3) due to its hepatotoxic effects.
VII. ANALYTICAL METHODS
° Analysis of 1,2-dichloroethane is by a purge-and-trap gas chromato-
graphic procedure used for the determination of volatile organohalides
in drinking water (U.S. EPA, 1985b). This method calls for the
bubbling of an inert gas through the sample and trapping 1,2-dichloro-
ethane on the adsorbant material. The adsorbant material is heated
to drive off the 1,2-dichloroethane onto a gas chromatographic column.
The gas chromatograph is temperature programmed to separate the
method analytes which are then detected by a halogen specific detector•
This method is applicable to the measurement of 1,2-dichloroethane
over a concentration range of 0.2 to 1,500 ug/L. Confirmatory analysis
for 1,2-dichloroethane is by mass spectrometry (U.S. EPA, 1985c). The
detection limit for confirmation by mass spectrometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
° Treatment technologieswhich will remove 1,2-dichloroethane from
water include granular activated carbon (GAC) adsorption, aeration
and boiling.
0 Dobbs and Cohen (1980) developed adsorption isotherms for several
organic chemicals including 1,2-dichloroethane. It was reported
that Fibrasorb* 300 carbon exhibited adsorptive capacities of 3.5 mg
and 0.5 mg 1,2-dichloroethane/gm carbon at equilibrium concentrations
of 1,000 and 100 mg/L, respectively. Also, Love (1983) reported
that Witcarb* 950 carbon exhibited adsorptive capacities of 1.9 mg
and 0.6 mg 1,2-dichloroethane/gm carbon at equilibrium concentrations
of 100 and 10 mg/L, respectively. USEPA-DWRD installed pilot-scale
adsorption columns in New Jersey to treat contaminated groundwater
(Love and Eilers, 1982). A Witcarb* 950 carbon column removed 1,2-
dichloroethane from a concentration as high as 8 mg/L to 0.1 mg/L.
Breakthrough occurred at 1,700 bed volumes (BV) with an empty bed
contact time (EBCT) of 18 minutes. Similar studies in Louisiana
showed removal of 1,2-dichloroethane from a concentration of 8 mg/L
102
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1, 2-Dichloroethane
March 31, 1987
-11-
to less than 0.1 mg/L after 39 days of continuous operation by a
full-scale GAC column containing Nuchar® WF-G activated carbon (Love,
1983).
0 1,2-Dichloroethane is amenable to aeration on the basis of its Henry's
Law Constant of 61 ata (Kavanaugh and Trussell, 1980). In a pilot-
scale diffused air aeration column, removal efficiency of 42% of
1,2-dichloroethane was achieved at an air-to-water ratio of 4:1
(Love and Eilers, 1982). In a pilot-scale packed tower aeration
study removal efficiencies of 85 to 98.5% for 1,2-<3ichloroethane were
achieved on air-to-water ratios of 5-45, respectively (BSE, 1985).
° Boiling also is. effective in eliminating 1,2-dichloroethane from water
on a short-term, emergency basis. Studies have shown that 5 to 10
minutes of vigorous boiling will remove 88 to 98% of 1,2-dichloroethane
originally present (Love, 1983).
• Air stripping is an effective, simple and relatively inexpensive
process for removing 1,2-dichloroethane and other volatile organics
from water. However, use of this process then transfers the contaminant
directly to the air stream. When considering use of air stripping as
a treatment process, it is suggested that careful consideration be
given to the overall environmental occurrence, fate, route of exposure
and various other hazards associated with the chemical.
103
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1(2-Dichloroethane
-12-
March 31, 1987
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11 2-Dichloroethane
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Acta Hiarmacol. et. Toxicol. 30:69-80.
Yllner, S. 1971b. Metabolism of chloroacetate-14C in the mouse. Acta Phar-
macol. et. Toxicol. 30:257-265.
Yodaiken, R.E., and J.R. Babcock. 1973. 1,2-Dichloroethane poisoning.
Arch. Environ. Health. 26:281-184.
106
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1 /2-Dichloroethane March 31, 1987
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Zhizhonkov, N.Y. 1976. Acute dichloroethane poisoning. Vrach Oelo.
6t 127-128.
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March 31, 19£~
1,1-DICHLOROETHYLENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employinc a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
1
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,1-Dichloroethylene
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March 31, 19?"'
This Health Advisory is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for the dichloro-
ethylenes (U.S. EPA, 1984a). The HA and CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Hater
counterpart (e.g., Water Supply Branch or Drinking/Water Branch), or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB #86-117785/AS.
The toll-free number is (800) 336-4700; in the Washington, D.C. area: (703)
487-4650.
GENERAL INFORMATION AND PROPERTIES
CAS No. 75-35-4
Chemical structure
CI
I
Cl-CC-H
Synonyms
° Vinylidene chloride, 1,1-DCE, dichloroethene
Uses
0 1,1-Dichloroethylene has been used as a chemical intermediate and in
the manufacture of polyvinylidene copolymers.
Properties (Irish, 1963; Windholz et al., 1976)
Chemical Formula C2H2CI2
Molecular Weight 96.95
Physical State (room temp.) clear, colorless liquid
Boiling Point 31.5 °C
Melting Point -122.2 °C
Density
Vapor Pressure 591 torr (20°C)
Specific Gravity 1.3
Water Solubility 250 mg/L (20°C)
Log Octanol/Water Partition 5.37
Coefficient
Taste Threshold (water)
Odor Threshold (water)
Odor Threshold (air) 2000-5500 mg/m3
Conversion Factor
Occurrence
1,1-Dichloroethylene (1,1-DCE) is a synthetic chemical with no known
natural sources (U.S. EPA, 1983).
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March 31, 19c"
0 Approximately 200 million pounds of 1,1-DCE were produced in 1980.
The major use of 1,1-DCE is as a co-monomer in the production of a
number of polymers. Polymers of 1,1-DCE and vinyl chloride are used
as food wrap (CEH, 1983).
0 The major releases of 1,1-DCE to the environment are during its
production and its use in the manufacture of polymers. Due to its
volatile nature, the majority of releases are expected to be to air.
Small amounts of 1,1-DCE may be released to water and land in
industrial effluents and from the disposal of solid wastes (U.S. EPA,
1983). 1,1-Dichloroethylene may be a degradation product of trichloro-
ethylene and perchlsroethylene. While laboratory studies are currently
inconclusive, 1,'1-DCE has been found to co-occur in ground water with
trichloroethylene and tetrachloroethylene and their other degradation
products, cis- and trans-1,2-dichloroethylene and vinyl chloride.
0 There is relatively little information on the behavior of 1,1-DCE in
the environment. However, the behavior of this chemical has been
estimated based upon the information on similar chlorinated compounds
(U.S. EPA, 1979). 1,1-Dichloroethylene released to the atmosphere is
expected to chemically degrade in hours; when released to surface
waters, it is expected to volatilize rapidly. 1,1-DCE is chemically
stable in water and mobile in soils and is expected to migrate with
ground water. 1,1-Dichloroethylene is not believed to bioaccumulate
in plants or animals.
® Available data suggest that 1,1-DCE is not a common contaminant of
drinking water. It has not been reported to occur at levels higher
than 0.1 ug/L in surface water. However, 1,1-DCE has been reported
to occur at levels up to 40 ug/L in wells contaminated with other
chlorinated solvents.
0 No information is available on the occurrence of 1,1-DCE in food.
While 1,1-DCE is used in the manufacture of food wrap, residual levels
are expected to be very low because of its high volatility. Due to
limited release and rapid degradation, little or no contamination of
food by 1,1-DCE is expected.
0 1,1-Dichloroethylene contamination of air has been reported to occur
in urban and suburban areas in the low ppt range. Levels in the ppb
range have been reported in the areas where 1,1-DCE and its
polymers are manufactured (U.S. EPA, 1983).
III. PHARMACOKINETICS
Absorption
0 1,1 -Dicnloroet'nylene is completely absorbed after gavage, since 96 to
100% of a single dose is excreted within 72 hours (Jones and Hathway,
1978a; McKenna et al., 1978b).
11C
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1,1-Dichloroethylene March 31, 1&:~
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Distributlon
• Distribution in rats following a single oral dose of 25 mg of 1,1-DCE/kg
resulted in high concentrations in the liver and kidneys after 30
minutes with more general distribution throughout other soft tissues
after 1 hour (Jones and Hathway, 1978a).
° Single oral doses of 14C-1,1-DCE, at 1 or 50 mg/kg, were administered
to rats (McKenna et al., 1978a,b). At 72 hours after dosing, the
greatest percentage of radioactivity was found in the liver.
Metabolism
a The metabolic end products of chlorinated ethylenes are predominately
alcohols and carboxylic acids. The known metabolites of 1,1-DCE are
chloroacetic acid, chloroacetyl chloride and dichloroacetaldehyde
(Liebler and Guengerich, 1983; Liebler et al., 1984). Toxic inter-
mediates that are formed may interact with tissue macromolecules.
Excretion
° The rate of excretion is relatively rapid, since most of a dose is
eliminated within the first 24-72 hours after administration (Jaeger
et al., 1977). At low doses, a greater percentage of the metabolites
are eliminated via renal and biliary excretion. Carbon dioxide
formed during metabolism is expired through the lungs.
As maximal metabolic capacity is approached at the higher dose levels,
proportionally less of the compound is removed from the blood as it
passes through the liver. As a result, increasing amounts of unchanged
1,1-DCE are"eliminated via the lungs (McKenna et al. 1977).
IV. HEALTH EFFECTS
Humans
° At high concentrations (2. 4000 ppm; 15,880 mg/m3), inhalation of
1,1-DCE results in rapid onset of CNS depression, with unconsciousness
following if exposure is continued (Irish, 1963).
0 Reports of effects on workers exposed to this chemical in combination
with other vinyl compounds include liver function abnormalities,
headaches, vision problems, weakness, fatigue and neurological sensory
disturbances (NIOSH, 1979).
Animals
Short-term ExDosure
° Reported oral LD50S in adult rats range from 200 to 1800 mg/kg (NIOSH,
1978; Ponomarkov and Tomatis, 1980). Young or fasted rats are more
sensitive to the acute effects of 1,1-DCE, with LD50S of approximately
50 mg/kg (Andersen and Jenkins, 1977).
Ill
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1,1-Dichioroethyiene
March 3i, l»
-5-
0 The oral LDggs in the mouse and the dog were reported to be 200 mg/kg
(Jones and Hathway, 1978b) and 5750 mg/kg (NIOSH, 1978), respectively.
° The most sensitive end-point of 1,1-DCE toxicity is liver damage,
ranging from fatty infiltration to necrosis (Reynolds et al., 1975;
Chieco et al., 1982). In rats, after doses of 50 to 700 mg of
1,1-DCEAg» the liver toxicity of 1,1-DCE followed a complex dose-
response pattern, with a threshold level, a^rapid increase in effect
and an extended plateau where increasing doses caused slight increases
in effect (Anderssr. and JenkinB, 1977).
0 After a 90 day continuous exposure to 1,1-DCE (189 mg/m^) liver and
kidney lesions have been demonstrated (Prendergast et al., 1967).
° Since glutathione depletion increases toxicity (Jaeger et al., 1974;
Andersen et al., 1980), the acute toxicity of the chemical is probably
the result of a toxic metabolite.
Long-term Exposure
0 As with acute exposure, the liver appears to be the principal target
of 1,1-DCE toxicity following extended periods of exposure. Chronic
exposure of rats to 0 to 200 ppm (0 to 26 mg/kg) in drinking water
resulted in fatty changes and hypertrophy of liver cells in females
and males at the highest dose (Rampy et al., 1977; Quast et al.,
1983).
Reproductive Effects
• In a three-generation rat reproductive study, Nitschke et al. (1983)
reported that, at concentrations of 0, 50, 100 or 200 ppm (0 to 26
mg/kc) in the drinking water, 1,1-DCE did not affect rat reproductive
capacity.
Developmental Effects
0 At levels producing no maternal toxicity (inhalation; 20 ppm in rats
and 80 ppm in rabbits and ingestion; 200 ppm in rats) 1,1-DCE did not
produce teratogenic effects in rats or rabbits following exposure of
dams during organogenesis (Murray et al., 1979).
Mutagenicity
0 With S-9 activation, 1,1-DCE was mutagenic in the Ames Salmonella
test at concentrations of 3.3 x 10-4 to 3.3 x 10-2 m (Bartsch et al.,
1975)- or when exposed to an atmosphere containing 5% 1,1-DCE for 3
hours (Simmon et al., 1977). The chemical had no mutagenic activity
in the absence of the S-9 fraction.
0 1,1-Dichioroethyiene was mutagenic to E. coli K12 at a concentration
of 2.5 mM with, but not without, microsomal activation (Greim et al.,
1975).
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March 31, 1 9£T
0 In mammalian assay systems, a mutagenic effect was not observed.
Using the dominant lethal assay, it was reported that exposure to
1,1-DCE at 55 ppm for 6 hr/day for 11 weeks (Short et al., 1977) or
to 10 to 50 ppm for 6 hr/day for 5 days (Anderson et al., 1977) did
not produce germinal mutation. In addition, using V79 Chinese hamster
ovary cells, exposed to 1,1-DCE at concentrations of 2 or 10%, Drevon
and Kuroki (1979) did not observe any adverse effects.
° 1,1-Dichloroethylene binds with DNA to a slight degree in the liver
and kidneys of both rats and nice after inhalation exposure to 10 or
50 ppm for 6 hours. However, aassive tissue damage also occurred.
In mice, the kidneys seem to be a more sensitive indicator of tissue
damage than the liver (Reitz et al., 1980).
e The International Agency for Research on Cancer (IARC) concluded that
there is sufficient evidence to state that 1,1-DCE is mutagenic
(IARC, 1982).
* 0 For a recent review of this area, the reader is referred to the
article by Jacobson-Kram (1986).
Carcinogenicity
° The results of most studies of the carcinogenic potential of this
substance fail to support a significant, treatment-related increase
in tumor incidence (U.S. EPA, 1984a). Mo oral study has resulted
in a significant tumor response (NTP, 1982; Quast et al., 1983).
Some, but not all, of the inhalation studies have reported significant
tumor increases (e.g., mammary tumors in female rats and mice and
kidney adenocarcinomas in mice) (Maltoni et al., 1985).
0 1,1-Dichloroethylene was inactive as a whole mouse skin carcinogen
when administered subcutaneously (Van Duuren et al., 1979). It was
active as a skin tumor initiator following several topical applications
of phorbol ester, as a promotor.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA ¦ (NOAEL or LOAEL) x (BW) „ mq/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL ° No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
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BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF « uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day • assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The study by Chieco and coworkers (1981) has been selected to derive the
One-day HA. The authors reported that when 200 mg/kg of 1,1-DCE was given in
water containing 0.5% Tween 80, the chemical caused only a slight increase in
the plasma levels of alanine, but not aspartate, transaminase. In addition,
the pathological changes observed in the liver were limited to a few scattered
microfoci of necrosis. Accordingly, the 200 mg/kg is taken to be the LOAEL.
The One-day HA for the 10 kg child is calculated as follows:
One-day HA « (200 mg/kg/day) (10 kg) „ 2.0 ag/L <2,000 ug/L)
(1,000) (1 L/day)
where:
200 mg/kg/day = LOAEL based on hepatic effects.
10 kg = assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with nas/odk
guidelines for use with a LOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Ten-day Health Advisory
Appropriate studies for the calculation of the Ten-day HA are not available.
However, evaluation of all toxicological data for 1,1-DCE suggests that the
Longer-term Health Advisory for the 10-kg child of 1,000 ug/L would provide
sufficient protection over a ten-day period.
Longer-term Health Advisory
A Longer-term HA can be calculated from a 90-day subchronic^ study in which
rats of both sexes were given 1.,_DCE at nominal concentrations of 0, 50, 100
or 200 ppm (0 to 20 mgAg bw/day) in their drinking water (Rampy, et al.,
1977). v Except for a decreased kidneysbody weight ratio in males at the low
dose, there were no statistically significant differences in organ weights or
in organ:body weight ratios at the termination of the study. The only abnormal
histopathology noted was an increased cytoplasmic vacuolization of hepatocytes
114
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1,1-Dichloroethylene
March 21, 1S"
-8-
in the livers of both sexes exposed to the highest dose. A NOAEL of 100 ppm
(10 to 12.6 mg/kg) was identified.
A Longer-term HA for the 10-kg child is calculated as follows:
Longer-term HA = (10 mgAg/day) (10 kg) . 1.0 mg/L (1,000 ug/L)
(100) (1 L/day) *
where:
10 mg/kg/day ¦ NOAEL based on the absence of liver effects.
10 kg « assumed body weight of a child.
100 ¦ uncertainty factor, chosen in accordance with NAS/ODW
guidelines foruse with a NOAEL from an animal study.
1 L/day « assumed daily water consumption of a child.
A Longer-term HA for the 70-kg adult is calculated as follows:
Longer-term HA ¦ CO mgAg/day) (70 kg) _ 3>5 Bg/L (3 500 ug/L)
(100) (2 L/d%y)
where:
10 mg/kg/day = NOAEL based on the absence of liver effects.
70 kg » assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines foruse with a NOAEL from an animal study.
2 L/day » assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADZ). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived fron
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 1. A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
115
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,1-Dichloroethylene
March 31, 196"
-9-
adult. The Lifetime MA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The Lifetime HA can be calculated from the 2-year chronic study in rats
(Quast et al., 1983). 1,1-Dichloroethylenfe, at nominal concentrations of 0,
50, 100 or 200 ppm (0 to 20 mgAg/day) in drinking water, was administered to
animals of both sexes. Mo consistent treatment-related biochemical changes
were observed in any parameter measured. The only abnormal histopathology
observed was mid-zonal fatty accumulation in the livers of both sexes
receiving the highest dose. No liver degeneration was noted. A LOAEL of
100 ppm (10 mg/kg) was identified, based upon a trend towards increased fatty
deposition in the liver.
A Drinking Water Equivalent Level (DWEL) and Lifetime HA for the 70-kg
adult are calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = no mg/kg/day) = o.01 mgAg/day
(1,000)
where:
10 mg/kg/day = LOAEL for hepatic effects.
1,000 = uncertainty factor, chosen in accordance with NAS/ODK
guidelines for use with a LOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.01 mg/kg/day) (70 kg) . 0.35 mg/L (350 ug/L)
(2 L/day)
where:
0.01 mgAg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (0-35 mg/L) (20\) B 0,007 mg/L (7 ug/L)
(10)
11
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1,1-Dichloroethylene
-10-
March 31, 156"
where:
0.35 mg/L » DWEL.
20% = assumed relative source contribution from water.
10 ¦ additional uncertainty factor for class C carcinogens.
!
Evaluation of Carcinogenic Potential
0 Qualitative and quantitative assessment of the carcinogenic potential
of 1,1-DCE is complicated by the fact that there is only one positive
bioassay (Maltoni et al., 1985) among the 18 oncogenic studies (U.S.
EPA, 1985c).
0 IARC (1982) reported that the data were inadequate to assess the
carcinogenic potential in humans, but that it would reevaluate the
assessment after reviewing the rat drinking water study (Rampy et al.,
1977; Quast et al., 1983) and the NTP gavage bioassays (NTP, 1982).
At the present time, this has not been done.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), 1,1-dichloroethylene may be
classified in Croup C: Possible human carcinogen. Group C includes
agents with limited evidence of carcinogenicity in animals in the
absence of human data.
I. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 In June, 1984, EPA proposed a Recommended Maximum Contaminant Level
(RMCL) of zero for 1,1-dichloroethylene in drinking water (U.S. EPA,
1984b). In 1985, a RMCL of 7 was promulgated for 1,1-dichloroethylene»
This value also was proposed for the MCL (U.S. EPA, 1905a).
e In 1980, EPA estimated a-range of excess cancer risks for lifetime
exposure to 1,1-dichloroethylene when developing ambient water quality
criteria (U.S. EPA, 1980a). This range was 23 ug/L, 2.3 ug/L and
0.23 ug/L, respectively, for risks of 10~4, 10~5 and 10~6, assuming
consumption of 2 liters of water and 6.5 grams of contaminated fish
per day by 70-kg adult.
° The National Academy of Sciences calculated a chronic SNARL (Suggested-
No-Adverse-Response-Level) of 100 ug/L, based upon non-carcinogenic
effects only (NAS, 1983). The Academy identified a NOAEL of 2 mg/kg
from the 1982 NTP bioassay in mice. An uncertainty factor of 100
was applied. It was assumed that a 70 kg adult consumes .2 liters of
water daily and 20% of the exposure of most individuals would be
from drinking water. In addition, a factor of 5/7 to correct from
5- to 7-day/week exposure was used.
0 The World Health Organization has established a guideline for 1,1-DCE
in drinking water of 0.3 ug/L, set on evidence of carcinogenicity
(WHO, 1984).
117
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t,l-Dichloroethylene
March 31, Mi
-11-
0 The threshold limit value (TLV) for 1,1-DCE in occupational settings
is 5 ppm (20 mg/m3) (ACGIH, 1982).
VII. ANALYTICAL METHODS
° Analysis of 1,1-DCE is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile orgapohalides in drinking water
(U.S. EPA, 1985). This method calls for the bubbling of an inert gas
through the sample and trapping 1,1-DCE on an adsorbant material.
The adsorbant material is heated to drive off the 1,1-DCE onto a gas
chromatographic column. This method is applicable to the measurement
of 1,1-DCE over a concentration range of 0.03 to 1500 ug/L. Confirma-
tory analysis for 1,1-DCE is by mass spectrometry (U.S. EPA, 1985b).
The detection limit for confirmation by mass spectometry is 0.2 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Granular activated carbon (GAC) adsorption and aeration treatment
technologies are available for the removal of 1,1-DCE from water
and have been reported to be effective. Selection of individual or
combinations of technologies to achieve chemical reduction must be
based on a case-by-case technical evaluation and an assessment of the
economics involved.
' Aeration has been shown to be effective in removing 1,1-DCE from
water, based upon its carbon adsorption isotherm (Henry's Law
Constant <= 498 atm) and pilot and full-scale testing. The chemical
was removed successfully from contaminated ground water at 12-14°C in
an EPA pilot packed tower aerator containing 18 feet of 1-inch plastic
saddle packing (ESE, 1984). The average percent removal varied with
air-to-water volume ratio, from 90.6% to 99.99% at ratios of 5 to 8C,
respectively. Similarly, the concentration of 1,1-DCE in contaminates
well water decreased from 122 ug/L to 4 ug/L (97%) using diffused
aeration (ESE,- 1984). Aeration was conducted in a pilot (1.5 inch
diameter, 4-foot long) countercurrent glass column, using a 10-minute
contact time and an air-to-water ratio of 4.
° Air stripping is an effective, simple and relatively inexpensive
process for removing 1,1-DCE from water. However, the use of this
process transfers the contaminant directly to the air stream. When
considering use of air stripping as a traetment process, it is
suggested that careful consideration be given to the overall
environmental occurrence, fate, route of exposure and various hazards
associated with the chemical.
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1,1-Dichioroethyiene
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IX. REFERENCES
ACGIH. 1982. American Conference of Government Industrial Hygienists.
TLVs. Threshold limit values for chemical substances in work air.
Andersen, M.E., and L.R. Jenkins, Jr. 1977. Oral toxicity of 1,1-dichioro-
ethyiene in the rat: Effects of sex, age and fasting. Environ. Health
Perspect. 21:157-163.
Andersen, M.E., O.E. Thomas, M.L. Gargas, R.A. Jones and L.J. Jenkins, Jr.
1980. The significance of multiple detoxification pathways for reactive
metabolites in the toxicity of 1,1-dichioroethyiene. Toxicol. Appl.
Pharmacol. 52:422-432.
Anderson, D. 1977, Dominant lethal studies with the halogenated olefins
vinyl chloride and vinylidene chloride in male CD-1 mice. Environ.
Health Perspect. 21:71-78.
Bartsch, H., C. Malaveille, R. Hontesano and L. Tomatis. 1975. Tissue-
mediated mutagenicity of vinylidene chloride and 2-chlorobutadiene in
Salmonella typhimurium. Mature. 255:641-643.
CEH. 1983. Chemical Economics Handbook, Stanford Research Institute,
Menlo Park, California.
Chieco, P., M.T. Moslen and E.S. Reynolds. 1981. Effect of administrative
vehicle on oral 1,1-dichioroethyiene toxicity. Toxicol. Appl. Pharmacol.
57: 146-155.
Chieco, P., M.T. Moslen and E.S. Reynolds. 1982. Histochemical evidence that
plasma and mitochondrial membranes are primary foci of hepatocellular
injury caused by 1,1-dichioroethyiene. Lab. Invest. 46:413-421.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/80-023. MERL, Cincinnati, OH.
Drevon, C., and T. Kuroki. 1979. Mutagenicity of vinyl chloride, vinyli-
dene chloride and chloroprene in V79 Chinese hamster cells. Mutat. Res.
67:173-182.
ESE. 1984. Environmental Science and Engineering. Draft technologies
and costs for the removal of volatile organic chemicals from potable
water supplies. ESE No. 84-912-0300. Prepared for the U.S. EPA,
Science arid Technology Branch, CSD, ODW, Washington, DC.
Greim, H., G. Bonse, Z. Radwan, D. Reichert and D. Henschler. 1975.
Mutagenicity iri vitro and potential carcinogenicity of chlorinated
ethylenes as a function of metabolic oxirane formation. Biochem.
Pharmacol. 24:2013-2017.
119
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1,1-Dichloroethylene
March 31, 198T
-14-
McKenna, M.J., P.G. Watanabe and P.J. Gehring. 1977. Pharmacokinetics of
vinylidene chloride in the rat. Environ. Health Perspect. 21:99-105.
McKenna, M.J., J.A. Zempel, E.O. Madrid and F.J. Gehring. 1978a. The
pharmacokinetics of <14C) vinylidene chloride in rata following
inhalation exposure. Toxicol. Appl. Pharmacol. 45:599-610.
McKenna, M.J., J.A. Zempel, E.O. Madrid, W.H. Braun and P.J. Gehring. 1978b.
Metabolism and pharmacokinetic profile of vinylidene chloride in rats
following oral administration. Toxicol. Appl. Pharmacol. 45:821-835.
Murray, T.J,, X.D. Nitschke, L.W. Rampy and B.A. Schwetz. 1979. Kwbryo-
toxicity and fetotoxicity of inhaled or ingested vinylidene chloride
in rats and rabbits. Toxicol. Appl. Pharmacol. 49:189-202.
NAS. 1983. National Academy of Sciences. Drinking Water and Health.
Volume 5. National Academy Press, Washington, DC.
N30SH. 1978. National Institute for Occupational Safety and Health.
1,1-Dichloroethylene. Registry of toxic effects of chemical substances,
p. 563.
NIOSH. 1979. [ C.D. for Occupational Standard]
Nitschke, K.D., F.A. Smith, J.F. Quast, J.M. Morris and B.A. Schwetz. 1983.
A three-generation rat reproductive toxicity study of vinylidene chloride
in the drinking water. Fund. Appl. Toxicol. 3:75-79.
NTP. 1982. National Toxicology Program. Carcinogenesis bioassay of vinylide
chloride (CAS No. 75-35-4) in F344 rats and B6C3F1 mice (gavage study).
U.S. HHS. PHS. NIH NTP-80-2 NIH Publication No. 82-1784.
Ponomarkov, V., and L. Tomatis. 1980. Long-term testing of vinylidene
chloride and chloroprene for carcinogenicity in rats. Oncology
37:136-141.
Prendergast, J.A., R.A. Jones, L.J. Jenkins, Jr. and J. Siegel. 1967.
Effects on experimental animals of long-term inhalation of trichloro-
ethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoro-
methane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270-285
Quast, J.F., C.G. Humiston, C.E. Wade, J. Ballard, J.E. Beyer, R.W. Schwetz
and J.M. Norris. 1983. A chronic toxicity and oncogenicity study in
rats and subchronic toxicity study in dogs on ingested vinylidene
chloride. Fund. Appl. Toxicol. 3:55-62.
Rampy, L.W., J.F. Quast, C.G. Humiston, M.F. Blamer and B.A. Schwetz. 1977.
Interim results of two-year toxicological studies in rats of vinylidene
chloride incorporated in the drinking water or administered by repeated
inhalation. Environ. Health Perspect. 21:33-43.
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1,1-Dichloroethylene
-15-
March 31, 19c"
Reitz, R.H., P.G. Watanabe, M.J. McKenna, J.F. Quast and P.J. Gehring. 1980.
Effects of vinylidene chloride on DNA synthesis and DNA repair in the
rat and mouse: A comparative study with dimethylnitrosamine. Toxicol.
Appl. Pharmacol. 52:357-370.
Reynolds, E.S., M.T. Moslen, S. Szabo, R.J. Jaeger and S.D. Murphy. 1975-.
Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Amer. J.
Pathol. 81:219.
Short, R.D., J.L. Minor, J.M. Winston and C.C. Lee. 1977. A dominant lethal
study in male rats after repeated exposure to vinyl chloride or vinylidene
chloride. J. Toxicol. Environ. Health. 3:965-968.
Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of
chemicals identified in drinking water. Dev. Toxicol. Environ. Sci.
2:249-258.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Hater Related Environ-
mental Fate of 129 Priority Pollutants. Office of Hater Planning and
Standards, EPA-440/4-79-029, December.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water quality
criteria for dichloroethylenes. Office of Hater Regulations and Standards.
Criteria and Standards Division. Washington, D.C. EPA 440/5-80-041.
UoS. EPA. 1983. U.S. Environmental Protection Agency. Vinylidine chloride
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1934a. U.S. Environmental Protection Agency. Draft criteria
document for the dichloroethylenes. Criteria and Standards Division,
Office of Drinking Water, Washington, DC.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. National primary
drinking water regulations; Volatile synthetic organic chemicals;
Proposed rulemaking. Federal Register 49(114):24330-24355. June 12.
U.S. EPA. 1984c. U.S. Environmental Protection Agency. Method 501.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Final RMCL,
proposed MCLs for VOCs. November 13, 1985.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio. June.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Health assessment
document for vinylidene chloride. August.
121
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1 , l-Dichloroethylene
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March 31, 19E~
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185):33992-34003.
September 24.
U.S. ITC. 1982. United States International Trade Commission. Synthetic
organic chemicals United States production. 1983 USITC Publication-
1422, Washington, D.C. 20436.
Van Ouuren, B.L., B.M. Goldschmidt, G. Loewengart, A.C. Smith, S. Melchionne,
I. Seldman and D. Roth. 1979. Carcinogenicity of halogenated olefinic
and aliphatic hydrocarbons in mice. J. Natl. Cancer Inst. 63:1433-1439.
WHO. 1984. World Health Organization. Guidelines for drinking water
quality. Volume 1. Recommendations. Geneva, Switzerland.
Windholz, M., ed. 1976. The Merck Index. 10th edition. Merck and Co., Inc.
Rahway, NJ.
122
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March 3", 19""
CIS-1,2-DICHLOROETHYLENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA} Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
123
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cis-1,2-Dichloroethylene
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March 3* , 19.7
This Health Advisory is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for the Dichloro-
ethylenes (U.S. EPA, 1984a). The HA and CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Hater
counterpart (e.g., Hater Supply Branch or Drinking Hater Branch), or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB #86-117785/AS.
The toll-free number is (800) 336-4700; in the Hashington, D.C. area: (703)
487-4650.
II. GENERAL INFORMATION and PROPERTIES
CAS No. 156-59-2
Chemical Structure
CI CI
I I
H-C*>H
Synonyms
1,2-DCE; cis-1,2-DCE; 1,2-dichloroethene
Uses
In a mixture with the trans-1,2- isomer, as a captive intermediate
in the manufacture of other chlorinated solvents
Properties (Irish, 1963; Windholz et al., 1976)
Chemical Formula C2H2CI2
Molecular Weight 96.95
Physical State clear, colorless liquid
Freezing Point -80.5°C
Boiling Point 60°C
Melting Point
Density
Vapor Pressure 208 mm Hg (25°C)
Specific Gravity 1.27 (25°C)
Water Solubility 3500 ug/L (208C)
Log Octanol/Water Partition —
Coefficient
Taste Threshold Not available
Odor Threshold Not available
Conversion Factor
Occurrence
® The 1,2-dichloroethylenes are synthetic chemicals with no known natural
sources (U.S. EPA, 1983).
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cis-1,2-Dichloroethylene
-3-
Marc'n 31, 13!"
0 There is little information on the current production and use of the
1,2-dichloroethylenes. The production volume for 1,2-dichloroethylene
(mixed isomers) was 1,000 lbs or less in 1978 (U.S. EPA, 1978).
0 The major releases of the 1,2-dichloroethylenes are from the manufac-
turing plants in the Gulf Coast region of the U.S., where they are used
as a captive intermediate. Releases are expected to be small. The T,2-
dichloroethylenes, particularly the cis- isomer, have been identified
as the degradation products of trichloroethylene and tetrachloroethylene
in ground water (Parsons et al., 1984; Vogel and McCarty, 1985).
# There is little dire;t information on the fate of the 1,2-dichloro-
ethylenes in the environment. However, the behavior of the compounds
has been estimated based upon the information on similar chlorinated
compounds (U.S. EPA 1979), 1,2-Dichloroethylenes released to the
atmosphere are expected to chemically degrade in a matter of hours;
when released, to surface waters, they are expected to volatilize
rapidly to air. 1,2-Dichloroethylenes are chemically stable in water
and mobile in soils. Once released to land the 1,2-dichloroethylenes
are expected to migrate with ground water. 1,2-Dichloroethylenes
have been shown to biologically degrade to vinyl chloride in some
groundwaters. These compounds are not expected to bioaccumulate in
plants or animals. Based upon their similar physical properties,
the two isomers of 1,2-dichloroethylene are not expected to behave
differently in the environment.
0 Monitoring studies have found that the 1,2-dichloroethylenes occur as
widespread bat relatively rare contaminants of ground waterr. The
cis- isomer has been reported to occur at higher levels than the
trans- isomer. The majority of the 1,2-dichloroethylenes has been
found to co-occur with trichloroethylene. Levels of the 1,2-dichloro-
ethylenes in approximately 1 % of all ground waters are greater thar.
0.5 ug/L. Levels as high as 300 ug/L have been reported for the
trans- isomer, while levels of 800 ug/L have been reported for the
cis- isomer. The 1,2-dichloroethylenes occur in surface water at
lower amounts. Levels of 1,2-dichloroethylenes in air are in the ppt
range except near production sites where they may reach levels in the
low ppb range. Based upon these compounds' volatility and limited
use, levels of 1,2-dichloroethylenes in food are expected to be
negligible (U.S. EPA, 1983).
0 The major source of exposure to the 1,2-dichloroethylenes is from
contaminated water except in the areas near production sites where
air exposures may dominate.
III. PHARMACOKINETICS
Absorption
* cis-1,2-Oichloroethylene is a neutral, low molecular weight, lipid
soluble material which would be expected to be readily absorbed
following exposure by any route (oral, inhalation, dermal) at the
levels expected to be encountered in contamination incidents (U.S.
EPh, 1984a).
125
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cis-1,2-Dichloroethylene
March 31, 19
-4-
Distribution
* Kinetic data to define the tissue distribution of cis-1,2-dichloro-
ethylene after oral exposure are not available. If this isomer,
however, follows the same absorption and distribution pattern as
observed for 1,1-dichloroethylene, the highest concentrations would
be expected to be found in the liver and kidney (McKenna et al..
1978).
Metabolism
• The metabolic end products of chlorinated ethylenes are predominantly
alcohols and carboxvlic acids. Perfusion of cis-1,2-dichloroethylene
through isolated rat liver yielded dichloroethanol and dichloro-
acetic acid, possibly indicating the initial formation of dichloro-
acetaldehyde (Bonse et al., 1975).
° The position of the chlorine moeity on the chlorinated ethylenes appears
to play an important role in their metabolism. Cis-1,2-dichloroethylene
was metabolized at a faster rate than trans-1,2-dichloroethylene
(which possesses a relatively greater degree of asymmetry) in an
in vitro hepatic microsomal system (Costa, 1983).
° Using isolated rat liver microsomes, Freundt and Macholz (1978)
reported that cis-1,2-dichloroethylene showed competitive and
reversible interaction with the mixed function oxygenase system,
resulting in decreased drug metabolism.
Excretion
° No data concerning the excretion of cis-1,2-dichloroethylene are
available. If it is similar to 1,1-dichloroethylene, then the rate
of elimination would be expected to be relatively rapid, with most of
a single dose being excreted in the urine within 24 to 72 hours after
cessation of expos-ure (Jaeger et al., 1977).
IV. HEALTH EFFECTS
Humans
° At high concentrations, the dichloroethylenes, like other chlorinated
ethylenes, possess anesthetic properties, cis-1,2-Dichloroethylene
was used as an anesthetic with some success prior to introduction of
newer anesthetic gases, and appeared to be safe (Irish, 1963).
Animals
Short-term Exposure
0 No cis- isomer-specific LD50S have been reported. An oral LD50
of 770 mgAg of the isomer mixture was reported for rats
(NIOSH, 1978).
126
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cis-1 ,2-Dichioroethyier.e
-5-
e At high exposure levels, general anesthetic and narcotic effects
are observed (Irish, 1963).
0 Administration of a single dose of cis-1,2-dichloroethylene at 400
mg/kg to rats caused a significant elevation of liver alkaline
phosphatase (Jenkins et al., 1972).
Long-term Exposure
# No information was found in the available literature on the effects
of long-tern exposures to cis-1,2-dichloroethylene.
Reproductive Effects
* No information was found in the available literature on the potential
of cis-1,2-dichloroethylene to produce reproductive effects.
Developmental Effects
0 No information was found in the available literature on the potential
of cis-l,2-dichloroethylene to produce developmental effects.
Mutagenicity
0 cis-1,2-Dichloroethylene was not mutagenic, with or without metabolic
activation, when assayed in E. coli XI2 at a medium concentration of
2.9 mM (Sreim et al., 1975)
0 Gaili et al. (1982a) reported that cis-1,2-dichloroethylene did not
induce point mutation, mitotic gene conversion or mitotic recomb-natior.
in yeast. In addition, they (1982b) reported that cis-1,2-dichloro-
ethylene was not mutagenic in an in vivo (intravenous host-mediated
assay) test. (Both manuscripts are in Italian.)
Carcinogenicity
0 No information was found in the available literature on the carcinogenic
potential of cis-1,2-dichloroethylene.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) M ag/L ( /L)
(UF) x ( L/day)
127
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cis-1,2-Dichloroethyiene March 31, 19?'
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW o assumed body weight of a child (10 kg) or
an adult (70 kg).
OF « uncertainty factor (10, 100 or 1,000), in
accordance with NAS/OOW guidelines.
L/day ¦ assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
There are few animal studies which provide dose-response data on the
effects of cis-1,2-dichloroethylene (Irish, 1963; Jenkins et al., 1972;
Freundt and Macholz, 1978). Only the study by Jenkins et al. provides
sufficient information from which a One-day Health Advisory can be calculated.
These authors monitored levels of liver glucose-6-phosphatase, liver alkaline
phosphatase, liver tyrosine transaminase, plasma alkaline phosphatase and
plasma alkaline transaminase and observed that a single, oral dose of 400 mg/kg
to the rat produced a significant change only in liver alkaline phosphatase.
The LOAEL of 400 mg/kg reported by Jenkins et al. (1972) will be used for the
one-day calculations.
The One-day Health Advisory for the 10 kg child is calculated as follows:
One-day HA = (400 mg/kg/day) (10 kg) _ 4 mg/Ij (4 OOO ug/L)
(1,000) (1 L/day)
where:
400 mgAg/day = LOAEL based on increase in liver alkaline phosphatase.
10 kg ¦ assumed body weight of a child.
1,000 » uncertainty factor, chosen in accordance with NAS/ODK
guidelines for use with a LOAEL from an animal study.
1 L/day « assumed daily water consumption of a child.
Ten-day Health Advisory
Appropriate studies Cor the calculation of a Ten-day Health Advisory
are not available. Evaluation of the available toxicological data on cis-1,2
dichloroethylene and 1,1-dichloroethylene suggests that the Longer-term
Health Advisory of 1 ir.g/L should provide adequate protection over a 10-day
exposure period as well.
128
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cis-*,2-DichloroethyleSe
March 3", 1&S~
-7-
Longer-term Health Advisory
A Longer-term HA for cis-1,2-dichloroethylene cannot be derived directly
from compound-specific data since appropriate data do not exist at this time.
The available information from shorter-term exposure to 1,1-dichloroethylene
and cis- and trans 1,2-dichloroethylene suggests that the non-carcinogenic
effects induced by the 1,2- isomers is likely to be no more, and conceivably
less, severe than those induced by 1,1-dichloroethylene. Since the non-carcin-
ogenic end-points of toxicity for all three isomers appear to be essentially
identical, adopting the Longer-term HA derived for 1,1-dichloroethylene for
use as the Longer-term HA for cis-1,2-dichloroethylene may even result in an
added margin of safety.
The Longer-term HA will be derived from a 90-day subchronic study in which
rats of both sexes were administered 1,1-dichloroethylene at nominal concen-
trations of 0, 50, 100 or 200 ppm (0-25.6 mg/kg/day) in their drinking water
(Rampy et al., 1977). Except for a decreased kidneysbody weight ratio in
males at the low dose, there were no statistically significant differences in
organ weights or organ:body weight ratios at the end of the study. The only
histopathology noted was an increased cytoplasmic vacuolization of hepatocytes
in the livers of both sexes exposed to the highest dose. A NOAEL of 100 ppm
(10 to 12.6 mg/kg) was identified.
The Longer-term HA for the 10-kg child is calculated as follows:
Longer-term HA = (10 mg/kg/day) (10 kg) m ^ mg/L (1000 ug/L)
(100) (1 L/day)
where:
10 mg/kg/day = NOAEL based on the absence of liver effects.
1 0 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODv;
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for the 70-kg adult is calculated as follows:
Longer-term HA = (10 mg/kg/day) (70 kg) s 3<5 ng/L (3500 ug/L)
(100) (2 L/day) y/
where:
10 mg/kg/day
70 kg
1 00
2 L/day
129
» NOAEL based on the absence of liver effects.
= assumed body weight of an adult.
= uncertainty factor, chosen in accordance with NAS/ODK
guidelines for use with a NOAEL from an animal study.
= assumed daily water consumption of an adult.
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cis-1,2-Dichloroethylene
-8-
March 31, 19=
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfO), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Hater Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinkinc
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Lifetime toxicity data for cis-1,2-dichloroethylene do not exist.
Data from the chronic drinking water study in rats as used for the Lifetime
Health Advisory for 1,1 -dichloroethylene will be used instead. The same
caveats and assumptions as were described above for the Longer-term HA also
apply here.
The Lifetime HA can be calculated from the 2-year chronic study in rats
(Quast et al., 1963). 1,1-Dichloroethylene, at nominal concentrations of 0,
50, 100 or 200 ppr. (0 to 20 mg/kg/day) in drinking water, was administered
to animals of both sexes. No consistent treatment-related changes were
observed in any parameter measured. The only histopathology observed was in
the livers of both sexes receiving the highest dose, changes characterized
by a minimal amount of mid-zonal fatty accumulation. ' No liver degeneration was
noted. A LOAEL of 100 ppm (10 mg/kg) was identified, based upon a trend
towards increased fatty deposition in the liver.
A Drinking Water Equivalent Level (DWEL) and Lifetime HA for the 70-kg
adult are calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - (10 mg/kg/day) „ 0.01 mgAg/day
(1,000)
where:
10 mg/kg/day = LOAEL based on adverse liver effects.
130
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cis — 1 , 2-Dichloroet.r.y lene
March 31, 199 7
-9-
1,000 = uncertainty factor, chosen in accordance with NAS/OD'n
guidelines for use with a LOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.01 mg/kg/day) (70 leg) « 0e35 mg/L (35o Ug/L)
(2 L/day)
where:
0.01 mgAg/day » RfD.
70 kg a assumed body weight of an adult.
2 L/day * assumed daily water consumption of an adult.
Step 3: Deterr.ination of Lifetime Health Advisory
Lifetime HA = (0.35 mg/L) (20%) » 0.07 mg/L (70 ug/L)
where:
0.35 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
° There are no data available on the carcinogenic potential of cis-1,2-
dichloroethylene.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), cis-1,2-dichloroethylene is
classified m Group D: Not classified. This category is for agents
with inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
° The Threshold Limit Value (TLV) in the occupational setting for the
1,2-dichloroethylene isomer mixture is 200 ppm (790 mg/m3) (ACGIH, 1962).
VII. ANALYTICAL METHODS
0 Analysis of cis-1,2-dichloroethylene is by a purge-and-trap gas
chromatographic procedure used for the determination of volatile
organohalides in drinking water (U.S. EPA, 1984b). This.method calls
for the bubbling of an inert gas through the sample and trapping
1,2-dichioroethylene on an adsorbant material. The adsorbant material
is heated to drive off the 1,2-dichloroethylene onto a gas chromato-
graphic column. This method will differentiate between the two
isomers of 1,2-dichloroethylene. This method is applicable to the
131
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cis-1, ^-uicmcroethyiene
March 3", 13£~
-1 0-
measurement of 1,2-dichloroethylene over a concentration range of
0.03 to 1500 ug/L. Confirmatory analysis for 1,2-dichloroethylene is
by mass spectrometry (U.S. EPA, 1985a). The detection limit for
confirmation by nass spectometry 0.2 ug/L.
III. TREATMENT TECHNOLOGIES
# Treatment technologies which will remove cis-1,2-dichloroethylene
from water include granular activated carbon (GAC) adsorption,
aeration and boiling.
• Dobbs and Cohen -(1930) developed adsorption isotherms for cis-1,2-
dichloroethylene It was reported that Filtrasorb* 300 carbon exhibited
adsorptive capacities of 1.3 mg and 0.26 mg cis-1,2-dichloroethylene/gm
carbon at equilibrium concentrations of 100 and 10 ug/L, respectively.
0 USEPA-DWRD installed pilot-scale adsorption columns at three locations
in New England (U.S. EPA, 1985b,c). Cis-1,2-dichloroethylene was
present in the contaminated groundwater at concentrations ranging froir.
2 to 18 ug/L. The raw water was passed through a Filtrasorb *400 GAC
column until breakthrough concentration of 0.1 ug/L was achieved
which after approximately 10 weeks of continuous operation.
0 cis-1,2-Dichloroethylene is amenable to removal by aeration on the
basis of its Henry's Law Constant of 225 atm (U.S. EPA, 1965b,c). In
a pilot-scale diffused air aeration column, removal efficiency of 85%
was achieved from original concentrations of 18 to 118 ug/L at an .
air-to-water ratio of 30:1. At an air-to-water ratio of 5:1 and the
same operating conditions, 58% of cis-1,2-dichloroethylene was removed
from the same source water (Love, 1983). In another pilot-scale
study, a countercurrent diffused air aeration column removed 80% of
cis-1,2-dichloroethylene from well water with 0.5 ug/L, at an air-to-
water ratio of 4:1 (Love and Eilers, 1982). Numerous packed column
air stripping plant studies have been performed by EPA. All of the
studies (using identical column size) indicated that packed column
aeration is effective in removing cis-1,2-dichloroethylene from
drinking water supplies at different concentrations. The best removal,
i.e., 99%+, was achieved at an optimum air-to-water ratio of 80-85:1
(U.S. EPA, 1985b,c; ESE, 1985).
8 Boiling also is effective in eliminating cis-1,2-dichloroethylene
from water on a short-term, emergency basis. Studies have shown that
five minutes of vigorous boiling will remove 96% of cis-1,2-dichloro-
ethylene present in the water (Love and Eilers, 1982).
0 Air stripping is an effective, simple and relatively inexpensive
process for removing cis-1,2-dichloroethylene and other volatile
organics from water. However, this process transfers the contaminant
directly into the air stream. When considering this method as a
treatment process, it is suggested that careful consideration be
given to the overall environmental occurrence, fate, route of exposure
and various hazards associated with the chemical.
132
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cis-1 ,2-Dichloroethy ler.e
-11-
March 31, 1 95?
IX. REFERENCES
ACGIH. 1982. American Council of Governmental Industrial Hygienists. TLVs.
Threshold limit values for chemical substances and physical agents in the
workroom environment. Cincinnati, Ohio. p.
Bonse, G., T. Urban, R. Montessano and L. Tomatis. 1975. Chemical reactivity,
metabolic oxirane formation and biological reactivity of chlorinated
ethylenes in the isolated perfused rat liver preparation. Biochem.
Pharmacol. 24:1829-1834.
Costa, A.K. 1983. The chlorinated ethylenes: Their hepatic metabolism and
carcinogenicity. Diss. Abst. Int [B]. 44(6)s1791-B.
Dobbs, R.A. and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
chemicals. Cincinnati, Ohio. EPA-600/8-80-023.
ESE. 1985. Environmental Science and Engineering. Technologies and costs
for the removal of volatile organic chemicals from potable water supplies.
ESE No. 84-912-300. Prepared for U.S. EPA Science and Technology Branch,
CSD, PDVt, Washington, DC.
Freundt, J.J., and J. Macholz. 1978. Inhibition of mixed function oxidases
in rat liver by trans-and cis-1,2-dichloroethylene. Toxicology.
10:131-135.
Galli, A., C. Bauer, G. Breruetti, C. Corsi, R. Del Carratore, R. Nieri and
M. Paolini. 1982a. (a) Studio in vitro. Attivita genetica dell'
1,2-dxchloroetilene. Boll. Soc. It. Biol. Sper. 58:860-863.
Galli, A., C. Bauer, G. Brenzetti, C. Corsi, R. Del Carratore,~R. Nieri and
M. Paolini. 1982b. (a) Studio in vivo. Attivita genetica dell'
1,2-dic'nloroetilene. Boll. Soc. It. Biol. Sper. 58:864-869.
Greim, H., G. Bonse, Z. Radwan, D. Reichert and D. Henschler. 1975.
Mutagenicity in vitro and potential carcinogenicity of chlorinated
ethylenes as a function of metabolic oxirane formation. Biochem.
Pharmacol. 24:2013-2017.
Irish, D.D. 1963. Vinylidene chloride. In: F.A. Patty (ed), Industrial
Hygiene and Toxicology. 2nd ed. Vol. II. John Wiley and Sons, Inc.,
New York. pp. 1305-1309.
Jaeger, R.J., L.G. Shoner and L.J. Coffman. 1977. 1,1-Dichloroethylene
hepatotoxicity: Proposed mechanism of action of distribution and binding
of 14c radioactivity following inhalation exposure in rats. Environ.
Health Perspect. 21:113-119.
Jenkins, L.J., Jr., K.J. Trabulus and S.D. Murphy. 1972. Biochemical effects
of 1,1-dichloroethylene in rats: Comparison with carbon tetrachloride
and 1,2-dichloroethylene. Toxicol. Appl. Pharmacol. 23:501-510.
133
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cis-i,^-uicnioroethyiene
March 31, 19
-12-
ove, D.T., Jr. 1983. Treatment of volatile organic compounds in drinking
water. U.S. Dept. of Commerce. NTIS.
ove, D.T., Jr., and R.G. Eilers. 1982. Treatment of drinking water containing
trichloroethylene and related industrial solvents. J.A.W.W.A. 74:413-425.
eKenna, M.J., J.A. Zempel, E.O. Madrid and P.J. Gehring. 1978. The pharmaco-
kinetics of (14c) vinylidene chloride in rats following inhalation
exposure. Toxicol. Appl. Pharmacol. 45:599-610.
IOSH. 1978. National Institute for Occupational Safety and Health.
1,2-Dichloroethylene. Registry of toxic effects of chemical substances,
p. 563.
arsons, F., P.R. Wood and J. DeMarco. 1984. Transformation of tetrachloro-
ethene and trichloroethene in microcosms and groundwater. J.A.W.W.A.
76:56.
uast, J.F., C.G. Humiston, C.E. Wade, J. Ballard, J.E. Beyer, R.W. Schwetz
and J.M. Norris. 1983. A chronic toxicity and oncogenicity study in rats
and subchronic toxicity study in dogs on ingested vinylidine chloride.
Fund. Appl. Toxicol. 3:55-62.
ampy, L.W., J.F. Quast, C.G. Humiston, N.F. Blamer and B.A. Schwetz. 1977.
Interim results of two-year toxicological studies in rats of vinylidene
chloride incorporated in the drinking water or administered by repeated
inhalation. Environ. Health Perspect. 21:33-43.
.S. EPA. 1978. U.S. Environmental Protection Agency. TSCA Inventory-
Non-confidential portion. Office of Toxic Substances.
.S. EPA. 1979. U.S. Environmental Protection Agency. Water related environ-
mental fate of 129 priority pollutants. Office of Water Planning and
Standards. EPA-440/4-79-029. December.
.S. EPA. 1963. U.S. Environmental Protection Agency. 1,2-Dichloroethylene
occurrence in drinking water, food, and air. Office of Drinking Water.
.S. EPA. 1984a. U.S. Environmental Protection Agency. Draft health effects
criteria document for the dichloroethylenes. Criteria and Standards
Division, Office of Drinking Water. Washington, DC. December.
.S. EPA. 1984b. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June.
.S. EPA. 1985a. U.S. "nvironmental Protection Agency. Method 524.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography/raass spectrometry. Environmental Monitoring and Support
Laboratory, Cincinnati, Ohio 45268. June.
134
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cis-1,2-Dichloroethylene
March 31, 1 S" ~
-13-
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Office of Drinking
Water Health Advisory Program. Prepared by ICAIR, Life Systems, Inc.
for the U.S. EPA Office of Drinking Water, Criteria and Standards Division.
U.S. EPA. 1985c. U.s Environmental Protection Agency. Draft technologies ana
costs for the removal of synthetic organic chemicals from potable water
supplies. Science and Technology Branch, CSD, ODW, Washington, D.C.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Pederal Register. 51(185):33992-34003.
September 24.
U.S. ITC. 1983. United Slates International Trade Commission. Synthetic
organic chemicals. United States production. 1982 U.S. ITC Publication
1422, Washington, D.C. 20436.
Vogel, T.M., and P.L. McCarty. 1985. Biotransformation of tetrachloroethylene
to trichloroethylene, dichloroethylene, vinyl chloride, and carbon dioxide
under methanogenic conditions. Appl. Environ. Microbiol. 49:1080-1083.
windholz, M., ed. 1976. The Merck Index. 10th edition. Merck & Co., Inc.
Rahway, fJJ.
135
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TRANS-1,2-DICHLOROETHYLENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. Hiey are not to be
construed as legally enforceable Federal standards. Hie HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogeni
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. Tnis provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
1
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trans-1,2-Dichloroetr.ylene
Marc:-. 3 i, IS!" *
-2-
This Health Advisory is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for the Dicfiloro-
ethylenes (U.S. EPA, 1984a). The HA and CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Water
counterpart (e.g., Water Supply Branch or Drinking Water Branch), or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB #86-117785/AS.
The toll-free number is (800) 336-4700; in the Washington, D.C. area: (703)
487-4650.
II. GENERAL INFORMATION and PROPERTIES
CAS No. 156-60-5
Structural Formula
CI H
I I
C « C
I I
H CI
Synonyms
0 1,2-DCE; trans-1,2-DCE; 1,2-dichloroethene
Uses
0 In a mixture with the cis-1,2- isomer, as captive intermediates ir.
the production of other chlorinated solvents.
Properties (Irish, 1963; Windholz et al., 1976)
Chemical Formula
Molecular Weight
Physical State
Freezing Point
Boiling Point
Melting Point
Density
Vapor Pressure
Specific Gravity
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold (water)
Odor Threshold (water)
Odor Threshold (air)
1 mg/L
1 ppn
C2H2CI2
96.95
clear, colorless liquid
-49.4#C
47°C
265 mm Hg (25°C)
1.27 (25°C)
6300 ug/L (25° )
Not available
Not available
1,100 ppm (Lehmann and Schmidt-Kehl, 1936)
252 ppm (25°c and 760 Torr.)
3.97 mg/m3 (25°c and 760 Torr.)
137
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trans-1, 2-ricr.lorof
¦"iene
March 3'
-3-
Occurrence
0 The 1,2-dichloroethylenes are synthetic chemicals with no known natural
sources (U.S. EPA, 1983).
0 There is little information on the current production and use of the
1,2-dichloroethylenes. The production volume for 1,2-dichloroethylene
(mixed isomers) was 1,000 lbs or less in 1978 (U.S. EPA, 1978).
8 Ihe major releases of the 1,2-dichloroethylenes are from the manufac-
turing plants in the Gulf Coast region of the U.S., where they used
as captive intermediates. Releases are expected to be small. The 1,2-
dichloroethylenes, particularly the cis- isomer, have been identified
as degradation products of trichloroethylene and tetrachloroethylene
in ground water (Parsons et al., 1984; Vogel and McCarty, 1985).
° There is little direct information on the fate of the 1,2-dichlo-
roethylenes in the environment. However, the behavior of these
compounds has been estimated based upon the information on similar
chlorinated compounds (U.S. EPA, 1979). 1,2-Dichloroethylenes
released to the atmosphere are expected to degrade chemically in
a matter of hours; when released to surface waters, they are expected
to volatilise rapialy to air. 1,2-Dichloroethylenes are chemically
stable in water and mobile in soils. Once released to land, 1,2-di-
chloroethylenes are expected to migrate with ground water. 1,2-Di-
chloroetnylenes have been shown to degrade biologically to vinyl
chloride in some groundwaters. These compounds are not expected
to bioaccumalate in plants or animals. Based upon their similar
physical properties, the two isomers of 1,2-dichloroethylene are not
expected to De'nave differently in the environment.
0 Moni.tonnc studies have found that the 1,2-dichloroethylenes occur
as widespread, but relatively rare, contaminants of ground water.
Tne cis- isoner has been reported to occur at higher levels than the
trans- isomer. Tne majority of the 1,2-dichloroethylenes has been
found to co-occur with trichloroethylene. Levels of the 1,2-dicnioro-
ethylenes are greater than 0.5 ug/L in approximately 1 % of all
ground waters. Levels as high as 300 ug/L have been reported for t.ie
trans- isoner, while levels of 800 ug/L have been reported for the
cis- isomer. The 1,2-dichloroethylenes occur in surface water at
lower amounts. The 1,2-dichloroethylenes in air are in the ppt range
except near production sites where they may reach the low ppb range.
Based upon their volatility and limited use, levels of 1,2-dichloro-
ethylenes in food are expected to be negligible (U.S. EPA, 1983).
° Tne major source of exposure to the 1,2-dichloroethylenes is fror.
contaminated water except in the areas near production sites where
air exposures may dominate.
138
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trans-1,2-Dicnloroethylene-
March 21, 19;
-4-
III. PHARMACOKINETICS
Absorption
0 trans-1,2-Dichloroethylene is a neutral, low molecular weight, lipid
soluble material which should be readily absorbed by any route (oral,
inhalation, dermal) at the levels expected to be encountered in
contamination incidents (U.S. EPA, 1984a).
Distribution
0 Kinetic data to define the tissue distribution of trans-1,2-dichloro-
ethylene after oral exposure are not available. If this isomer follows
the same absorption and distribution pattern as 1,1-dichloroethylene,
the highest concentrations would be expected to be found in the liver
and kidney (McKenna et al., 1978).
Metabolism
0 The metabolic end products of chlorinated ethylenes are predominantly
alcohols and carboxylic acids. In rat liver microsomal preparations,
supplemented with NADPH, trans-1,2-dichloroethylene was transformed to
2,2-dichloroethanol and 2,2-dichloroacetic acid (Costa and Ivanetich,
1982), Presumably, these products were formed by reduction or oxidation
of 2,2-dichloroacetaldehyde.
0 The positions of the chlorine moieity on the chlorinated ethylenes
appear to play an important role in metabolism. Trans-1,2-dichloro-
ethylene (which possesses a relatively greater degree of asymmetry)
was metabolized at a slower rate than cis-1,2-dichloroethylene in an
in vitro hepatic microsomal system (Costa, 1983).
Excretion
0 No data concerning the excretion of trans-1,2-dichloroethylene are
available. If it is similar to 1,1-dichloroethylene, then the rate
of elimination will be relatively rapid, with most of a single dose
being excreted in the urine within 24 to 72 hours after cessation of
exposure (Jaeger et al., 1977).
IV. HEALTH EFFECTS
Humans
° At high concentrations, the dichloroethylenes, like other chlorinated
ethylenes, possess anesthetic properties (Irish, 1963). It appears that
the trans- isomer is about twice as potent as the cis- isomer in
depressing the central nervous system (Albrecht, 1927).
139
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trans-1, 2-Dichloroethyiene March 3", li1;'
-5-
Animals
Short-term Exposure
0 The oral LD50 in the 200 g rat was 1/300 mq/kg (Freundt et al., 1977).
When administered intraperitoneal!./, the LD5q was six-fold higher
{7,800 mg/kg).
0 At high exposure (8^000 to 16,000 ppm) levels, trans-i,^rdichloroethylene
can cause narcosis and death in rats in four hours (Torkelson and Rowe,
1981).
0 No significant immunological effects were observed in male mice
exposed by gavage to 22 or 220 mg/kg for 14 consecutive days (Munson
et al., 1982). In addition, no changes in body or organ weights
(liver, kidney, thymus and lung) were observed.
Long-term Exposure
0 Freundt et al. (1977) exposed Wistar rats to air containing trans-1,2-
dichloroethylene at 0, 200, 1,000 or 2,000 ppm (0 to 7,940 mg/m3).
Brief (8-hour) or prolonged (8 hours/day, 5 days/week for 1, 2, 8 or
16 weeks) exposure at 200 ppm produced slight degeneration of the
liver lobule and lipid accumulation in the Kupffer cells. At 8 and
16 weeks of exposure, severe pneumonic infiltration was observed.
Exposure at 1000 ppm for 8 hours resulted in significant reductions
in serur. albumin, urea, nitrogen and alkaline phosphatase. Eight-hour
exposures at both 200 and 1,000 ppm produced a significant decrease
in the number of leucocytes.
Reproductive Effects
° No information was found in the available literature on the potential
of trans-1,2-dichloroethylene to produce reproductive effects.
Developmental Effects
0 No information was found in the available literature on the potential
of trans-1,2-dichloroethylene to produce developmental effects.
Mutagenicity
° trans-1,2-Dichloroethylene at a medium concentration of 2.3 mM was
not mutagenic, with or without microsomal activation, when assayed
in Z. coli K12 (Greim et al., 1975).
° trans-1,2-Dichloroethylene did not cause point mutation, mitotic gene
conversion or mitotic recombination in a diploid strain of Saccharomyces
cerevisiae, with or without microsomal activation (Galli'et al. (19S2a;.
Tney also reported that it had no genetic effects in an in vivo (intra-
venous host-mediated assay) mutagenicity study (Galli et al., 19S2o).
140
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trans-1,2-Dichloroethylene
March 3", 19
-6-
Carcinogenicity
° No information was found in the available literature on the carcinogen!:
potential of trans-1,2-dichloroethylene.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify^ sensitive noncarcinogenic end point of toxicity.
Die HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) „ mg/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
Freundt et al. (1977) reported the effects of trans-1,2-dichloroethyler.e
after inhalation by mature female Wistar rats (180 to 200g) at 200 ppsr. (6GC
mg/m3, the currently established TLV/MAC in many countries) or at 1000 or
3000 ppm (4000 or 12000 mg/m3, respectively). A brief (8 hour) exposure at
200 ppm did net result in significant adverse effects on the liver. Tnere
was slight pulmonary capillary hyperemia and distention of the alveolar
septum. This effect was, most likely, transitory in nature and would not
occur after oral administration.
A number of biochemical and hematological parameters also were tested.
No changes in serum cholesterol, albumin, uric acid, urea nitrogen, glucose,
alkaline phosphatase, SG0T or SGPT were observed after the single 8-hour
exposure at 200 ppm. Exposure at 1,000 ppm for 8 hours resulted in significant
reductions in serum albumin, urea nitrogen and alkaline phosphatase. Eight-
hour exposures at both 200 and 1,000 ppm caused a significant decrease in the
number of leucocytes. Since leucocyte count may be affected by external
stimuli [physical exertion, stress and food intake (Lentner, 1984)], the
number of leucocytes in this study (2.5 x 103) appears to be lower than normal
for rats [6 to 17 x 10^/mm3 (Harkness and Agner, 1983)] and there is no dose
response noted in the 200 and 1,000 ppm groups, it is difficult to evaluate
141
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trans-1,2-Dichloroethylene
March 3",
-7-
the reported decrease in leucocytes. Accordingly, this parameter will not be
used in setting the NOAEL. Clinico-chemical parameters were not studied at
the 3,000 ppm exposure level.
A NOAEL of 200 ppm over a single 8-hour exposure was identified for
trans-1,2-dichloroethylene based upon the normal biochemical parameters and
on the slight liver effects in only 1 of 6 rats.
3he One-day Health Advisory for the 10-kg child is calculated as follows:
Step 1: Determination of the total absorbed dose (TAD)
TAD = 200 x 3.97 (mg/m3) x 0.006 (m3/hr) x 8 = 200
(0.19 kg)
where:
200 x 3.97 (mg/m3) = total absorbed dose converted from ppm to mg/m3.
0.006 = conversion factor to obtain m3/hr for 190 g rats,
i.e., 100 ml/min x 60 min/hr divided by 1,000,000
(ml to m3).
8 = duration of exposure in hours.
0.19 = average weight in kg of exposed rats.
Step 2: Determination of a One-day Health Advisory
One-dav HA = (200 mg/kg/day) (10 kg) = 2o.O mg/L (20,000 ug/L)
(100; (1 L/day)
where:
200 mg/kc/day = tAD.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Ten-day Health Advisory
Appropriate- studies for the calculation of the Ten-day HA are not available.
The Longer-term HA for a 10 kg child (1.43 mg/L) is recommended as a conservative
estimate for a ten-day exposure.
142
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trans-1,2-Dichloroethylene
March 31, 1*
-8-
Longer-term Health Advisory
Freundt et al. (1977) also studied the effects of administering trans-
1»2-dichloroethylene at 200 ppm (8 hr/day for 5 days/week) for 16 weeks.
They found slight to severe fatty infiltration in the parenchymal and Kupffer
cells of the liver (5 of 6 rats) and severe pneumonic infiltration (3 of 6
rats}.
Based on the liver and lung effects, a LOAEL of 200 ppm was identified
for trans-1,2-dichloroethylene.
The Longer-term HA is calculated as follows:
Step 1: Determination of the total absorbed dose (TAD)
TAD = 200 mgAg (see One-day HA)
Step 2: Determination of a Longer-term HA for a 10-kg child
Longer-term HA = (200 mg/kg/day) (5) (10 kg) = 1.43 mg/L (1,430 ug/L)
(1,000) (7) (1 L/day)
where:
200 mg/kg/day = LOAEL for hepatic and pulmonary effects.
5/7 = correction factor for 5 day/week dosing regimen.
10 kg = assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
A Longer-terr, HA for a 70-kg adult is calculated as follows:
Longer-ter-. HA = (200 mg/kg/day) (5) (70 kg) a 5 mg/L (5,000 ug/L)
(1,000) (7) (2 L/day)
where:
200 mg/kg/day = LOAEL for hepatic and pulmonary effects.
5/7 = correction factor for 5 day/week dosing regimen.
7 0 kg = assumed body weight of an adult.
1,000 = uncertainty factor, chosen in accordance with NAS/ODv;
guidelines for use with a LOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
143
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trans-1, 2-Dichlorost'-/Ieni
Karcn !¦,
-9-
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADD. The RfD is an esti-
mate of a daily exposure to the human population tfyat is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). Fran the RfD, a Drinking Water Equivalent Level '
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure l«:vel, assuming 100% exposure from that medium, at
which adverse, ncncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals'. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Lifetime toxicity data for trans-1,2-dichloroethylene do not exist
at this time. Data fron the chronic drinking water study in rats as used
for the Lifetime Health Advisory for 1,1-dichloroethylene will be used in-
stead. The same caveats and assumptions as were described above for the
Longer-term HA also apply here.
The Lifetime HA is calculated from a 2-year chronic study in rats (Quast
et al., 1 983). i, 1 -Dichloroethylene, at concentrations of 0, 50, 100 or 20 ;¦
ppm (0 to 20 ngA'-g/day) in drinking water, was administered to animals of
both sexes. No consistent treatment-related changes were observed in any
parameter measured. The only histopathology observed was in the livers of
both sexes receiving the highest dose, changes characterized by a minimal
amount of mid-zonal fatty change. No liver degeneration was noted. A LOAEL
of 100 ppm (10 mgAg) was identified, based upon a trend towards increased
fatty deposition in the liver.
A Drinking Water Equivalent Level -(DWEL) and Lifetime HA for the 70-kg
adult are calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
Rfri = HO mgAg/day) _ 0.01 mg/)cg/day
(1,000)
144
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trans-1,2-Dichloroethylene March 31, 1r "
-10-
where:
10 mg/kg/day = LOAEL.
1,000 » uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL « (0.01. mgAg/day) (70 kg) m 0>35 /L (3S0 Ug/L)
(2 L/day)
where:
0.01 mg/kg/day ¦ RfD.
70 kg = assumed body weight of an adult.
2 L/day «• assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (0.035 mg/L) (20%) ¦ 0.07 mg/L (70 ug/L)
where:
0.35 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
c There are no data available which describe the carcinogenic potential
of trans-1,2-dichloroethylene.
" Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), trans-1,2-dichloroethylene is
classified in Group D: Not classified. This category is for agents
with inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The Threshold Limit Value (TLV) in the occupational setting for the
1,2-dichloroethylene isomer mixture is 200 ppm (790 mg/m^) (ACGIH, 19S2)
145
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trans -1,2-Dicnloroet.viene
March 3 t, 19c7
-11-
VII. ANALYTICAL METHODS
0 Analysis of trans-1,2-dichloroethylene is by a purge-and-trap gas
chromatographic procedure used for the determination of volatile
organohalides in drinking water (U.S. EPA, 1984b). This method calls
for the bubbling of an inert gas through the sample and trapping of
1,2-dichloroethylenes on an adsorbant material, Die adsorbant material
is heated to drive off the 1,2-dichloroethylene onto a gas chromato-
graphic column. This method will differentiate between the two
isomers of 1,2-dichloroethylene. TCiis method is applicable to the
measurement of 1,2dichloroethylene over a concentration range of
0.03 to 1500 ug/L. Confirmatory analysis for 1,2-dichloroethylene is
done by mass spectrometry (U.S. EPA, 1985a). Bie detection limit
for confirmation by mass spectometry is 0.2 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Very few data are available concerning the removal of trans-1,2-
dichloroethylene from drinking water. However, the available data
suggest that both granular activated carbon (GAC) adsorption and
aeration will be somewhat effective in reducing the levels of this
chemical in water.
0 Dobbs and Cohen (1980) developed adsorption isotherms for trans-1,2-
dichloroethylene. It was reported that Filtrasorb® 300 carbon
exhibited adsorptive capacities of 0.95 mg, 0.29 mg and 0.09 nc
trans-1,2-dichloroethylene/gm carbon at equilibrium concentrations of
100, 10 and 0.1 ug/L, respectively. No field data are available on
the adsorption of trans-1,2-dichloroethylene from contaminated water.
° Theoretical considerations indicate that trans-1,2-dichloroethylene
is amenable to treatment by aeration on the basis of its Henry's La*-
Constant of 225 atm (U.S. EPA 1985b,c). In a laboratory study,
distilled water containing 217 ug/L of trans-1,2-dichloroethyleri£,
was- passed through a diffused-air aeration column'. A 97% reduction
of the compound was reported in a countercurrent operation at ar.
air-to-water ratio of 15:1 (U.S. EPA, 1985b,c).
0 Air stripping is an effective, simple and relatively inexpensive
process for removing trans-1,2-dichloroethylene and other volatile
organics from water. However, the use of this process then transfers
the contaminant directly into the air stream. When considering use
of air stripping as a treatment process, it is suggested that careful
consideration be given to the overall environmental occurrence, fate,
route of exposure and various hazards associated with the chemical.
146
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trans-1,2-Dichloroethylene
-1 2-
IX. REFERENCES
Albrecht, P. 1927. Arch. Klin. Chir. 146:273.
ACGIH. 1982. American Council of Government Industrial Hygienists. TLVs.
Threshold limit values for chemical substances and physical agents in
the workroom environment. Cincinnati, OH.
Bonse, G., T. Urban, R. Montessano and L. Tomatis. 1975. Chemical reactivity,
metabolic oxirane formation and biological reactivity of chlorinated
ethylenes in the isolated perfused rat liver preparation. Biochem.
Pharmacol. 24:1829-1834.
Costa, A.K. 1983. The chlorinated ethylenes: Their hepatic metabolism and
carcinogenicity. Diss. Abst. Int. [B]. 44(6);1797-B.
Costa, A.K. and K.M. Ivanetich. 1982. The 1,2-dichloroethylenes: Their
metabolism oy hepatic cytochrome P-450 in vitro. Biochem. Pharmacol.
31:2093-2102.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon absorption isotherms for toxic
chemicals. Cincinnati, Ohio. EPA-600/3-80-023.
Filser, J.G., and H.M. Bolt. 1979. Pharmacokinetics of halogenated ethylenes
in rats. Arch. Toxicol. 42:123-136.
Freundt, J.J., G.P. Liebaldt and E. Lieberwirth. 1977. Toxicity studies on
trans-1,2-dichloroethylene. Toxicology. 7:141-153.
Freundt, J.J., and J. Macholz. 1978. Inhibition of mixed function oxidases
i-n rat liver by trans-and cis-1,2-dichloroethylene. Toxicology.
10:1 31-1 39.
Galli, A., c. Bauer, G. Brenzetti, C. Corsi, R. Del Carratore, R. Nieri and
M. Paolmi. 1982a. (a) Studio in vitro. Attivita genetica dell'
1,2-dichloroetilene. Boll. Soc. It. Biol. Sper. 58:860-863.
Galli, A., C. Bauer, G. Brenzetti, C. Corsi, R. Del Carratore, R. Nieri and
M. Paolini. 1982b. (a) Studio in vivo. Attivita genetica dell'
1,2-dichloroetilene. Boll. Soc. It. Biol. Sper. 58:864-869.
Greim, H. G. Bonse, Z. Radwan, D. Reichert and D. Henschler. 1975. Mutagen-
icity in vitro and potential carcinogenicity of chlorinated ethylenes as
a function of metaboliG oxirane formation. Biochem. Pharmacol.
24:2013-2017.
Hardie, D.W.F.,1964. Dichloroethylene. In: Mark, H.F., J.J. McKetta, Jr.,
D.F. Othmer, eds. Kirk-Othmer encyclopedia of chemical technology, 2nd
ed., Wiley-Interscience, New York, Vol. 5. pp. 178-183.
Harkness, J.E., and J.U. Agner. 1983. The biology and medicine of rabbits
and rodents. 2nd Ed., Lea and Fibiger, Philadelphia, p. 46.
147
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trans-1,2-Dichloroethylene
March 31, 191
-1 3-
Irish, D.D. 1963. Vinylidene chloride. _In_: F.A. Patty (ed), Industrial
Hygiene and Toxicology. 2nd ed. Vol. II. John Wiley and Sons, Inc.,
New York. P. 1305-1309.
Jaeger, R.J., L.G. Shoner and L.J. Coffman. 1977. 1,1-Dichloroethylene
hepatotoxicity: Proposed mechanism of action of distribution and binding
of 14C radioactivity following inhalation exposure in rats. Environ.
Health Perspect. 21:113-119.
Jenkins, L.J., Jr., M.J. Trabulus and S»D. Murphy. 1972. Biochemical effects
of 1,1-dichloroethylene in rats; Comparison with carbon tetrachloride and
1,2-dichloroethylene. Toxicol. Appl. Pharmacol. 23:501-510.
Lehmann, K.B. and L. Schmidt-Kehl. 1936. Study of the most important chloro-
hydrocarbons from the standpoint of industrial hygeine. Arch. Hyg.
Bakteriol. 116:131-268.
Lentner, C. 1984. Geigy Scientific Tables. Vol. 3, 8th Ed. Ciba-Geigy, Ltd.,
Basel, p. 209.
McKenna, M.J., j.a. Zempel, E.O. Madrid and P.J. Gehring. 1978. The pharmaco-
kinetics of (14C) vinylidene chloride in rats following inhalation exposure.
Toxicol. Appl. Pharmacol. 45:599-610.
Manson, A.E., V.M. Saunders, K.A. Douglas, L.E. Sain, B.M. Kauffraan and
K.L. White, Jr. 1982. _In vivo assessment of immunotoxicity. Environ.
Health Perspect. 43:41-52.
Parsons, F., P.R. Wood and J. DeMarco. 1984. Transformation of tetrachloro-
ethene and trichloroethene in microcosms and groundwater. J.A.W.w.A.
76:56.
Quast, J.F., C.G. Huniston, C.E. Wade, J. Ballard, J.E. Beyer, R.W. Schwetz
and J.M. Karris. 1983. A chronic toxicity and oncogenicity study in rats
and subc'nronic toxicity study in dogs on ingested vinylidine chloride.
Fund. Appl. Toxicol. 3:55-62.
Rampy, L.W., j.f. £uast, C.G. Humiston, M.F. Blamer and B.A. Schwetz. 1977.
Interim- results of two-year toxicological studies in rats of vinylidene
chloride incorporated in the drinking- water or administered by repeated
inhalation. Environ. Health Perspect. 21:33-43.
Torkelson, T.R., and V.K. Rowe. 1981. Halogenated aliphatic hydrocarbons.
In: G.D. Clayton and F.E. Clayton (eds.). Patty's Industrial Hygiene
and Toxicology. 3rd ed. Vol. 2B. John Wiley and Sons, Inc., New York,
pp. 3550-3553.
U.S. EPA. 1978. U.S Environmental Protection Agency. TSCA Inventory —
Non-confidential portion. Office of Toxic Substances.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water related environ-
mental fate of 129 priority pollutants. Office of Water Planning and
Standards. EPA-440/4-79-029. December.
148
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trans-1,2-Oicnloroethylene
Ma r ch 3 '<, 1 9
-14-
U.S. EPA. 1983. U.S. Environmental Protection Agency. 1,2-Dichloroethylene
occurrence in drinking water, food, and air. Office of Drinking Water,
ST3.
U.S. EPA. 1984a. U.S. Environmental Protection Agency. Draft health effects
criteria document for the dichloroethylenes. Criteria and Standards
Division, Office of Drinking Hater. Washington, DC. December.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Method 524.1 Volatile
halogenated organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Office of Drinking
Water Health Advisory Programs, Prepared by ICAIR, Life Systems, Inc.
for the U.S. EPA Office of Drinking Water, Criteria and Standards Division.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Draft technologies
and costs for the removal of synthetic organic chemicals from potable
water supplies. Science and Technoloby Branch, CSD, ODW, Washington, D.C.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185)33992-34003.
September 24.
U.S. ITC. 1983. United States International Trade Commission. Synthetic
organic chemicals. United States production. 1982 U.S.ITC Publication
1422, Washington, D.C. 20436.
Vogel, T. v.., and P.L. McCarty. 1985. Biotransformation of tetrachloroethyie.ne
to trichloroethylene, dichloroethylene, vinyl chloride, and carbon dioxide
under methanogenic conditions. Appl. Environ. Microbiol. 49:1080-1083.
Windholz, M., S. Budvari, L.Y. Stroumtsos and M.N. Fertig. (eds.) 1976. The
Merck Index, 9tn ed. Merck & Co., Inc., Rahway, N.J.
149
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DICKLOROMETHANE
Health Advisory
Office of Drinking Hater
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Hater (ODH), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
150
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-2-
This Health Advisory is based upon information presented in the Office
of Health and Environment Assessment Criteria Document (CO) for Dichloromethane
(U.S. EPA, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for a fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB85 191559. The toll-
free number is (800) 336-4700? in the Washington, 'D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 75-09-2
Structural Formula
CI
I
H-C-Cl
I
H
Synonyms
0 Methylene chloride, methylene dichloride, methylene bichloride, DCM
Uses
0 Solvent for insecticides, paints, varnish and paint removers and in
food processing; degreasing and cleaning fluids.
Properties (Verschueren, 1977; Windholtz, 1983)
Chemical Formula CH2CI2
Molecular Weight 84.94
Physical State Colorless liquid
Boiling Point 408C (760 mm Hg)
Melting Point -95 to -976C
Density 1-.3255 (20/4#C)
Vapor Pressure 349 mm Hg (20°C)
Water Solubility 20 g/L (20#C)
Log Octanol/Water Partition —
Coefficient
Odor Threshold
Taste Threshold
Conversion Factor —
Occurrence
0 Dichloronethane (DCM) is a synthetic chemical with no known natural
sources.
0 Production of DCM was approximately 600 million lbs in 1983 (U.S.
ITC, 1964).
151
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uicr.xor urae uione
-3-
e The major sources of DCM released to the environment are from its
industrial uses where the majority of all DCM produced is released.
Most of the releases occur to the atmosphere by evaporation. However,
large amounts of DCM are disposed of by burial in landfills or dumping
on the ground or into sewers. Because DCM is involved in industrial
operations performed nationwide, releases occur in all urban areas.
Releases of DCM during its production are relatively minor in comparison
to releases during its use*
* Dichloromethane released to the air is degraded in a matter of a few
days. Dichloromethane released to surface waters migrates to the
atnosphere in a few days or weeks where it also degrades. Volatiliza-
tion is the major transport process for Its removal from aquatic
systems (U.S. EPA, 1979). Dichloromethane which is released to the
land does not sorb onto soil and migrates readily to ground water
where it is expected to remain for months to years. Dichloromethane,
unlike some other chlorinated compounds, does not bioaccumulate in
individual animals or food chains.
0 Because of the large and dispersed releases, DCM occurs widely in the
environment. It is ubiquitous in the air with levels in the ppt
range and is a common contaminant in ground and surface waters with
higher levels found in ground water.
0 Very limited information is available on the occurrence of dichloro-
methane in food. Dichloromethane has been reported to occur in fish.
It is used as an extraction solvent for the decaffination of coffee
and other food processing operations. Low levels of DCM have been
reported to occur in some foods from these operations.
° The major sources of exposure to DCM are from contaminated water.
Air and food are only a minor sources (U.S. EPA, 1980c).
III. PHARMACOKINETICS
Absorption
0 Dichloromethane is expected to be absorbed completely when ingested.
A single oral dose of 1 or 50 mgAg 14C-DCM administered to male rats
(3/dose) was exhaled as unchanged DCM (12.3 or 72.1%, respectively)
within 48 hours (McKenna and Zempel, 1981).
Distribution
0 Tissue distribution after administration of 1 or 50 mgAg of '4c-dcm
in water by gavage to male rats (3/dose) was measured by McKenna and
Zempel (1981). The highest concentration of radioactivity was present
in liver and the lowest in fat, 48 hours after either dose.
152
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March 31, 1967
-4-
Metabolism
° The major metabolites of DCM are carbon monoxide and carbon dioxide.
McKenna and Zempel (1981) studied the metabolism of 14c-DCM after
gavage administration to groups of three male Sprague-Dawley rats
dosed at 1 or 50 mgAg* They metabolized about 88 or 28% of the
dose, respectively. The major metabolites exhaled after 48 hours
were carbon monoxide (30.9 and 11*9% of the 1 or 50 mg/kg doses,
respectively) and carbon dioxide (35.0 and 6.3% of the 1 or 50 ag/kg
doses, respectively).
Excretion
* Metabolites of DCM are excreted in urine. McKenna and Zempel (1981)
reported that, in rats given 1 or 50 mgAg 14C-DCM, 4.52 ±0.05% or
1.96 ±0.05% of the dose, respectively, was excreted in the urine
within 48 hours. The fecal elimination of DCM after oral or intra-
peritoneal administration of DCM is low (<1.0%) (DiVincenzo and
Hamilton, 1975; McKenna and Zempel, 1981).
IV. HEALTH EFFECTS
Humans
0 Bonventre et al. (1977) described a fatal intoxication with DCM
which was being used as a paint remover. Postmortem examination
revealed the presence of DCM in the liver (14.4 mg/100 g tissue),
blood (51 mg/dL or 510 mg/L) and brain (24.8 mg/100 g tissue).
The carboxyhemoglobin content was 3% saturated.
Animals
Short-term Exposure
0 Oral LD50s for DCM were reported as 1,987 mgAg' for mice and 2,121
mgAg for rats (Kimura et al. 1971; Aviado et al. 1977).
0 Kimura et al. (1971) administered single oral doses of DCM to young
adult Sprague-Dawley rats and determined that an approximate dose
of 1.3 gAg body weight was the lowest dose to induce the first
observable signs of toxicity (dyspnea, ataxia, cyanosis and/or coma).
Long-term Exposure
0 Bornmann and Loeser (1967) administered DCM in drinking water at
2.25 g/18L (or 125 mg/L) to 30 male and 30 femaie Wistar rats for 13
weeks. This is equivalent to a dose of about 15 mgAg/day assuming
that 10 mL of water is consumed daily. The animals wereC examined
for changes in behavior, body weight, blood and urine chemistries,
reproductive function, organ to body weight ratios and histology.
No treatment-related effects were observed, even though some rats
may have consumed as much as 250 mg DCM (36.6 mgAg/day) during this
153
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Di ch1o r one tn a ne
-5-
experiment. The urine albumin test was frequently positive; however,
the authors did not attach any biological significance to this obser-
vation. From this study, a NOAEL of 125 mgA9/day was identified.
• Hazelton Labs (1982) reported on the toxicity and carcinogenicity of
DCM in a chronic two-year drinking water study in Fischer 344 rats.
Two control groups (85 and 50 rats/sex/group) received deionized
drinking water. Four groups of animals (85 rats/sex/group) were
given DCM in drinking water at target doses of 5, 50, 125 and 250
mg/kg/day. A high-dose recovery group (25 rats/sex) was given DCM
in drinking water at a target dose of 250 mgAg/day for the initial
78 weeks and deionized drinking water subsequently for the remainder
of the study. At i6, 52 and 78 weeks of treatment, there were incre-
mental sacrifices of 5, 10 or 20 rats/sex/group, respectively. At
104 weeks of exposure, all survivors were sacrificed. Survival,
body weight gains, total food consumption, water consumption, clinical
observations, ophthalmoscopic findings, clinical pathology, absolute
and relative organ weights and gross and microscopic pathology were
examined to evaluate any compound-related effects. The dose o£
5 mg/kg was identified as the no-effect level based on the absence of
effects on body weight, hematological parameters and histopathological
changes in the liver (incidence of foci/areas of cellular alteration
and/or fatty char.gts ).
Developmental Effects
0 No positive conclusion can be drawn regarding the potential for
developmental effects of DCM.
• Maternal exposure of rats and mice to DCM (4337 mg/m3) on days 6
through 15 of gestation was associated with soft tissue abnormalities
in the offspring of rats and skeletal changes in the offspring of
both rsts ani mice (Schwet2 et al., 1975).
" Other workers have found no increased incidence of gross external,
skeletal or soft tissue anomalies in offspring after maternal expos-re~
of rats tc DCM at 15,615 mg/m3 (6 hours/day, 7 days/wk) before and
during gestation. (Hardin and Manson, 1980).
Mutagenicity
0 DCM has been reported to be mutagenic in several bacterial and yeast
test systems, as well as in mammalian test systems. DCM was also
reported to be positive in a mammalian transformation test (U.S. EPA,
1985a).
Carcinogenicity
° In a pulmyna.y '..jiLr response assay, DCM administered intraperitoneally
did not produre an increased incidence of lung tumors in mice (Theiss
et al. 1977).
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March 31, 19E?
-6-
9 An inhalation bioassay conducted in male and female F344/N rats and
B6C3F1 mice indicated clear evidence of carcinogenicity in male and
female mice as shown by increased incidences of lung (alveolar/
bronchiolar adenoma and/or carcinoma) and liver (hepatocellular
adenoma and carcinoma combined) tumors (NTP, 1985, as cited in U.S.
EPA, 1985c). Some evidence of carcinogenicity in male rats and
sufficient or clear evidence of carcinogenicity in female rats was
indicated by an increased incidence of benign neoplasms of the mammary
gland. These animals were exposed at concentrations of 0, 1,000,
2,000 and 4,000 ppm for rats and 0, 2,000 and 4,000 ppm for mice,
6 hours/day, 5 days/week for 102 weeks.
0 Hazelton Laboratories (1982) studied the carcinogenicity of DCM in a
chronic two-year drinking water study in Fischer 344 rats, using the
protocol as described under longer-term exposure. Hepatic histological
alteration detected in the 50 to 250 mgAg/day dose groups (both
sexes) included an increased incidence of foci/areas of cellular
alteration. Fatty liver changes were detected in the 125 and 250
mg/kg/day groups after 78 and 104 weeks of treatment. The authors
stated that DCM did not induce carcinogenicity under the conditions
of the study.
° The U.S. EPA (1985b) performed an independent assessment of the data
from the Hazelton Laboratories (1982) study and determined that
incidences of hepatic neoplastic nodules and carcinomas (combined
in females exposed to 50 mg/kg/day (4.8%), 250 mg/kg/day (7.1%) and
250 mgAg/day, recovery group (8.0\) were significantly (P<0.05)
higher than that in matched controls (0*). No significant increase
in liver tumors was evident in any of the male dose groups. The U.S.
EPA (1985b) considered data on historical control values and concluded
that the 250 mgAg/day dose was borderline for carcinogenicity in
Fischer 344 rats.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA - (NOAEL or LOAEL) x (BW) . ^ ( /L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW ¦ assumed body weight of a child (10 kg) or
an adult (70 kg).
155
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Dichloromethane
ria lui j i , i d
-7-
UF ¦ uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day * assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The study by Kimura et al. (1971) has been selected to serve as the
basis for the One-day HA for the 10 kg child because no other acute oral
studies of appropriate duration or design were located in the literature.
This study identified a LOAEL in young adult Sprague-Dawley rats on the basis
of the first observable gross signs of toxicity (i.e., dyspnea, ataxia,
cyanosis and/or coma) following administration of a single oral dose of DCM
by gavage. The authors implied that multiple dose levels were administered
to define dose-response, although details were not reported. The calculations
for a One-day HA for a 10-kg child are given below:
One-day HA = 1'326 mg/kg/day) (10 kg). » 13.3 ng/L (13,300 ug/L)
(1,000) (1 L/day)
where:
1 , 326 mg/kg/day = LOAEL, based on the first observable gross signs of
toxicity in rats.
10 kg = assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with ODW/NkS
guidelines for use with a LOAEL from an animal stody.
1 L/day = Assumed daily water consumption of a child.
Ten-day Health Advisory
The study by Bornmann and Loeser (1967) in which DCM was administered
in drinking water at 125 mg/L to Wistar rats for 13 weeks, has been selected
to serve as the basis for the Ten-day HA for the 10-kg child because it was
the most comprehensive short-term oral toxicity study located.
CTie Ten-day HA for a 10 kg child is calculated as follows:
Ten-day HA * (15 mg/kg/day)(10 kg) « 1<5 mg/L (1 500 ug/L)
(100) (1 L/day)
where:
15 mg/kg/day = NOAEL, based on absence of effects on body weight gain,
blood and urine chemistries, reproductive function,
organ/body weight ratios, or histopathological changes
in Wistar rats.
10 kg s assumed body weight of a child.
156
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uuic waiaue
March 31, 1987
-8-
100 » uncertainty factor, chosen in accordance with 0DK/NA3
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Exposure
There were no suitable data available from which to calculate Longer-Term
Health Advisories.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADZ). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from .
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water'is based cn actual exposure data or, if data are not available,, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised i.i
assessing the risks associated with lifetime exposure to this chemical.
Dichloromethane may be classified in Group B2: Probable Human Carcinoaer.,
according to EFA's guidelines for assessment of carcinogenic risk (U.S. EFA,
1986). Because of this, caution must be exercised in making a decision on
how to deal with possible lifetime exposure to this substance. The risk
manager must balance this assessment of carcinogenic potential against the
likelihood of occurrence of health effects related to non-carcinogenic end-
points of toxicity. In order to assist the risk manager in this process,
drinking water concentrations associated with estimated excess lifetime cancer
risks over the range of one in ten thousand to one in a million for the 70-kg
adult, drinking 2 liters of water per day, are provided in the following
section. In addition, in this section, a Drinking Water Equivalent Level
(DWEL) is derived. A DWEL is defined as the medium-specific (in this case,
drinking water) exposure which is interpreted to be protective for non-
carcinogenic er.d-points of toxicity over a lifetime of exposure. The DWEL
is determined for the 70-kg adult, ingesting 2 liters of water per day. Also
provided is an estimate of the excess cancer risk that would result if exposure
were to occur at the DWEL over a lifetime.
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Di ch lc r one th-a ne
natcn :i, 1.5:
-9-
Neither the risk estimates nor the DWEL take relative source contribution
into account. The risk manager should do this on a case-by-case basis,
considering the circumstances of the specific contamination incident that has
occurred.
The study by Hazelton Laboratories (1982) is most appropriate from which
to derive the DWEL because it is an oral chronic (two year) study that admini-
stered DCM in drinking water in multiple dose levels to rats. This is the
most comprehensive chronic oral study available* There were sufficient
numbers of animals in the dose groups and a dose-response was demonstrated.
A NOAEL of 5 mg/kg/day was identified in this study.
The DWEL for a 70-kg adult is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - (5 mg/kg/day) . 0.05 mgAg/day
(100)
where:
5 mgAg/day * NOAEL based on the absence of liver and blood effects
in rats.
100 = uncertainty factor, chosen in accordance with NAS/ODK
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL *= (0.05 mg/kg/dav) (70 kg) = 1>75 mg/L (1,750 Ug/L)
(2 L/day)
where:
0.05 mgAg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption by an adult.
Step 3: Determination of the Lifetime Health Advisory
Dichloromethane is classified in Group B2: Probable Human Carcinogen.
A Lifetime HA has not been calculated for DCM.
The estimated excess cancer risk associated with lifetime exposure to
drinking water containing DCM at 1,750 ug/L is approximately 3.7 x 10-4.
This estimate represents the upper 95% confidence limit from extrapolations
prepared by EPA's Carcinogen Assessment Group using the linearized, multistage
model. The actual risk is unlikely to exceed this value, but there is consid-
erable uncertainty as to the accuracy of risks calculated by this methodology.
1
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n&rcn ji, 1 9£7
-10
Evaluation of Carcinogenic Potential
0 IARC (1982} has classified DCM in group 3: Limited evidence of
carcinogenicity in animals.
° Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), DCM nay be classified in Group B2:
Probable human carcinogen. This category is for agents for which
there is inadequate evidence from human studies and sufficient evidence
from animal studies.
* More recently, EPA's CA6 (U.S. EPA, 1985c) estimated that the upper-
bound incremental unit carcinogenic risk for drinking water containing
1 ug/L DCM for a lifetime was 2.1 x 10-7 (ug/L)-1. Thi3 risk estimate
was the mean of the derived carcinogenic risk estimates based on the
finding of liver tumors (not based on lung tumors) in the NTP (1985)
draft inhalation study in female mice and the suggestively positive
finding of liver tumors in the Hazelton (1982) unpublished ingestion
study in male mice. Since the extrapolation model is linear at low
doses, additional lifetime cancer risk is directly proportional to
the water concentration of DCM. Thus, levels of 10~4, 10"5 and 10-6
are 0.46, 0.C48 and 0.005 mg/L, respectively.
6 The linear multistage model is only one method of estimating carcino-
genic risk. Using the 10-6 risk level, the following comparisons in
micrograms/L may be made: Multistage, 4.8; Probit, 74,000; Logit,
4,000; Weibull, 10. Each model is based on differing assumptions.
No current understanding of the biological mechanism of carcinogenesis
is able to predict which of these models is more accurate than another.
While recognized as statistically alternative approaches, the range of
risks described by using any of these modeling approaches has little
biological significance unless data can be used to support the
selection of one model over another. In the interest of consistency
of approach and in providing an upper bound on the potential cancer
risk, the Agency has recommended use of the linearized multistage
approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
° ACGIH (1984) has recommended a time-weighted average threshold limit
value (TVJA-TLV) of 100 ppm ( 360 mg/m^) in the absence of occupa-
tional exposure to carbon monoxide and is based upon experimental
data obtained from nonsmoking males at rest. A short-term exposure
level (STEL) of 500 ppm is also recommended.
° The Occupational Health and Safety Administration (OSHA, 1979) has
established occupational exposure standards as follows: * an eight-hour
time-weighted-average (TWA) of 1,737 mg/m^t an acceptable ceiling
concentration of 3,474 mg/m3; and an acceptable maximum peak above
the ceiling of 6,948 mg/m3 (five minutes in any two hours).
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Dichloromethane
March Ji, 1*6
-11-
0 Due to the metabolic formation of carboxyhemoglobin and the additive
toxicity with carbon monoxide, the National Institute of Occupational
Safety and Health (NIOSH, 1976) has recommended a ten-hour TWA exposure
limit of 261 mg/m3 and a 1737 mg/m3 peak (15 minute sampling), in the
presence of carbon monoxide concentrations less than or equal to 9.9
mg/m3 (TWA). Proportionately lower levels of DCM are required in the
workplace when carbon monoxide concentrations greater than 9.9 mg/m3
are present.
c Based on noncarcinogenic risks, a water quality criterion of 12.4 mg/L
is the acceptable concentration of DCM in drinking water (U.S. EPA,
1960a). Ihis calculation was performed by the U.S. EPA as part of the
overall process for developing a U.S. EPA Hater Qiality Criteria for
halomethanes as a group and uses a limit of 200 ppm (694 mg/m3) for
protection against excessive carboxy-hemaglobin formation. In that
calculation, the EPA assumed that the average person consumes approxi-
mately two liters of water and eats 6.5 g of contaminants in fish and
seafood per day, and that the estimated coefficient of absorption via
inhalation versus ingestion is 0.5.
0 The original U.S. EPA Suggested-No-Adverse-Response-Levels (SNARLs,
now referred to as Health Advisories) for DCM were set at 13, 1.5
and 0.150 mg'L in drinking water for One-day, Ten-day and Longer-term
exposures, respectively (U.S. EPA, 1980b). The U.S. EPA-SNARLs were
established for a 10 kg body weight child and did not consider the
possible carcinogenic risk that may result from exposure to a chemical.
0 The NAS (1960) calculated one-day and seven-day NAS-SNARLs for DC.M
in drinking water based on the minimal-effect acute oral dose in rats
reported by Kimura et al. (1971). The NAS concluded that data on.the
no-effect dose do not exist. Using the 1 mlAg U.3 gAg) minimal-
effect acute oral dose in the rat, assuming two liters/day of drinking
water as the only source (consumed by a 70 kg adult) and employing a
safety factor of 1,000, the NAS (1980) calculated the one-day SNARL.
Since no appropriate data were available for the seven-day SNARL, the
one-day SNARL was divided by a factor of seven (days). However, the
NAS (1980) erroneously reported a value of 35 mg/L for the one-day
and 5 mg/L for the seven-day calculation. Re-examination of calcula-
tions indicated that the one-day and seven-day adult NAS-SNARLs
should be 45.5 mg/L and 6.5 mg/L, respectively.
VII. ANALYTICAL METHODS
° Analysis of DCM is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile organohalides in drinking water
(U.S. EPA, 1985d). This method calls for the bubbling of an inert
gas through the sample and trapping DCM on an adsorbant material.
The adsorbant. material is heated to drive off the DCM onto a gas
chromatographic column. This method is applicable to the measurement
of DCM over a concentration range of less than 1 to 1500 ug/L; however,
measurement of DCM at low concentrations is difficult due to problems
with contamination. Dichloromethane vapors readily penetrate tubing
160
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* Viliui WUIC
id ;it
March 31, 196 7
-l
during the purge/trap procedure. Confirmatory analysis for DCM is
by mass spectrometry. (U.S. EPA 1985e). The detection limit for
confirmation by mass spectrometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Limited information is available concerning the removal of dichloro-
me thane from drinking water. However, evaluation of physical and
chemical properties and some experimental data suggest that adsorp--
tion by granular activated carbon (GAC) and aeration are feasible
technologies to remove this contaminant in drinking water supplies.
0 Dobbs and Cohen (1960) developed adsorption isotherms for several
organic chemicals, including DCM. This study reported that Filtrasorb®
300 exhibited adsorptive capacities of 1.3 ag and 0.09 mg DCM per gm
carbon at equilibrium concentrations of 1,000 mg/L and 100 mg/L,
respectively.
0 Another study reported activated carbon usage of 3.9 lb/1,000 gal of
treated water to maintain an effluent DCM concentration below 1 ug/L
from a raw water influent concentration above 20 ng/L (ESE, 1982).
This particular treatment scheme employed two activated carbon columns
operating in series with extremely long empty bed contact time (262
minutes).
0 The calculated Henry's Law constant for DCM is 2.5 x 10-3 atm-m3/mole
(ESE, 1982). In a bench-scale study, distilled water which was
spiked with 225 ug/L of DCM was passed through a diffused air aerator.
The results showed 82 percent reduction in DCM at an air-to-water
ra^io of 15:1 (Love, 1983). Dichloronethane will, therefore, be
amenable to air stripping treatment. Actual field performance data,
however, have not been reported for this compound.
0 Air stripping is an effective, simple and relatively inexpensive
process for removing DCM and other volatile organics from water.
However, use of this process then transfers the contaminant directly
to the air stream. When considering use of air stripping as a treatment
process, it is suggested that careful consideration be given to the
overall environmental occurrence, fate, route of exposure and various
hazards associated with the chemical.
° Treatment technologies for the removal of DCM from water have not
been extensively evaluated except on an experimental level. Selection
of individual or combinations of technologies to attempt DCM reduction
must be based on a case-by-case technical evaluation, and an assessment
of the economics involved.
161
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uicnioromeinane
-13-
IX. REFERENCES
ACGIH. 1984. American Conference of Governmental Industrial Hygienists.
Documentation of the threshold limit values. 4th ed. 1980-1984 supplement,
pp. 275-276.
Aviado, D.M., S. Zakhari and T. Watanabe. 1977. Methylene chloride. In:
Non-fluorinated propellants and solvents for aerosols, L. Goldberg, ed.,
CRC Press, Inc., Cleveland, Ohio, pp. 19-45.
Bonventre, J., 0. Brennan, D. Jason, A. Henderson and M.L. Bastos. 1977.
Two deaths following accidental inhalation of dichloromethane and 1,1,1-
trichloroethane. J. Anal. Toxicol. 1:158-160.
Bornmann, G., and A. Loeser. 1967. Zur Frage einer chronisch-toxischen
Wirkung von Dichloromethan. Z. Lebensm.-Unters. Forsch. 136:14-18.
DiVincenzo, G.D., and M.L. Hamilton. 1975. Fate and disposition of carbon-14
labelled methylene chloride in the rat. Toxicol. Appl. Pharmacol.
32:385-393.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600-8-80-023. Office of Research and Development, MERL,
Wastewater Treatment Division, Cincinnati, Ohio.
ESE. 1982. Environmental Science and Engineering. Review of organic con-
taminants in 0DW data base for summary of all available treatment tech-
niques, compound dichloromethane. Prepared for U.S. EPA, Office of
Drinking Water, EPA-68-01-6494.
Hardin, B.D., and J.M. Manson. 1980. Absence of dichloromethane teratogenicity
with inhalation exposure in rats. Toxicol. Appl. Pharmacol. 52:22-25.
Hazelton Laboratories America, Inc. 1982. National Coffee Association
(prepared for the twenty-four month chronic toxicity and oncogenicity stud/
of methylene chloride in rats). Final Report, Vols. I-IV. Vienna, Va.:
2112-101. August 11, 1982.
IARC. 1982. IARC monographs on the evaluation of the carcinogenic risk of
chemicals to humans. Supplement 4, Lyon, France.
Kimura, E.T., D.M. Ebert and P.W. Dodge. 1971. Acute toxicity and limits of
solvent residue for sixteen organic solvents. Toxicol. Appl. Pharmacol.
19:699-704.
Love, O.T., Jr. 1983. Treatment of volatile organic compounds in drinking
water. NTIS, U.S. Department of Commerce.
McKenna, M.J., and J.A. Zempel. 1981• ttie dose-dependent metabolism of
I14C]methylene chloride following oral administration to rats. Fd.
Cosmet. Toxicol. 19:73-78.
162
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Dichloromethane
-14-
March 3', 19?"
NAS. 1980. National Academy of Sciences. Drinking Water and Health.
Vol. 3. National Academy Press, Washington, D.C.
NTP. 1985. National Toxicology Program. NTP technical report on the toxicology
and carcinogenesis studies of dichloromethane (methylene chloride)
in F344/N rats and B6C3F1 mice (inhalation studies) NTP TR 306. Draft.
Research Triangle Park, N.C. 94 pp. As cited in U.S. EPA, 1985c.
NZOSH. 1976. National Institute for Occupational Safety and Health. Criteria
for a recommended standard...occupational exposure to methylene chloride.
U.S. Department of Health, Education and Welfare (NZOSH). Washington,
D.C., pp. 1-3, 76-138, 142.
OS HA. 1979. Occupational Safety and Health Administration. General industry
standards. (OSHA) 2206, Revised January, 1978. U.S. Dept. of Labor,
Washington, D.C.
Schwetz, B.A., B.J. Leong and P.J. Gehring. 1975. Wie effect of maternally
inhaled trichloroethylene, perchloroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice and rats.
Toxicol. Appl. Pharmacol. 32:84-96.
Theiss, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisberger. 1977. Test for
carcinogenicity of organic contaminants of United States drinking waters
by.pulmonary tumor response in Strain A mice. Cancer Res. 37:2-717-2720.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water Related Environ-
mental Fate of 129 Priority Pollutants. Office of Water Planning and
Standards. EPA-440/4-79-029.
U.S. EPA. 1980a. U.S. Environmental Protection Agency. Ambient water
quality criteria for halomethanes. Office of Water Regulations and
Standards. Criteria and Standards Division. Washington, D.C.
EPA 440/5-80-051.
U.S. EPA. 1980o. U.S. Environmental Protection Agency. Advisory opinion
for dichloromethane (methylene chloride) (Draft). Office of Drinkmc
Water. Washington, D.C.
U.S. EPA. 1960c. U.S. Environmental Protection Agency. Dichloromethane
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Health assessment
document for dichloromethane (methylene chloride). Office of Health and
Environmental Assessment. EPA-600/8-82/004F.
U.S. EPA. 19S5b. U.S. Environmental Protection Agency. Health assessment
document for dichloromethane (methylene chloride) (Final report). Office
of Healtr and Environmental Assessment. Washington, D.C.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Addendum to health
assessment document for dichloromethane (methylene chloride) (Final
report). Office of Health and Environmental Assessment. Washington, D.C.
EPA 600/8-82-004FA.
163
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U.S. EPA. 1985d. U.S. Environmental Protection Agency. Method 502.1.
Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas
Chromatography, Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268.
U.S. EPA. 1985e. U.S. Environmental Protection Agency. Method 524.1.
Volatile Organic Compounds in Water by Purge and Trap Gas Chromatography/
Mass Spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185)s33992-34003.
September 24.
U.S. ITC. 1984. United States International Trade Commission. Synthetic
Organic Chemicals United States Production. USITC Publication 1422,
Washington, D.C. 20436.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
2nd ed. Van Ncstrand Reinhold Company, NY. pp. 451-452.
Windholz, M. 1983. The Merck Index. 10th Edition. Merck and Co., Inc.,
Rahway, NJ. p. 869.
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March 31, 15=7
p-DIOXANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. Ihey are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based or. data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogeni
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or E carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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p-Dioxane March 31, 196?
-2-
This Health Advisory is based upon information presented in the Office
of Drinking Water's Health Advisory Document for p-Dioxane (U.S. EPA, 1981)-
The 1961 Health Advisory is available for review at each EPA Regional Office
of Drinking Water counterpart (e.g., Water Supply Branch or Drinking Water
Branch).
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 123-91-1
Structural Formula
/ \
\_/
Synony ms
0 1,4-Dioxane; 1,4-Diethylene dioxide
Uses
° Solvent for cellulose acetate, resins, oils and waxes.
Properties (Windholtz, 1983, Verschueren, 1977)
Chemical formula
Molecular weight
Physical state
Boiling point
Melting point
Vapor pressure
Density
Solubility
Taste/odor threshold
c4h8o2
88.10
Colorless liquid
101.1°C
11.8°C
30 mm (20#C)
1.033 g/ml (20°C)
miscible in water at all concentratio:
Occurrence
0 1,4-Dioxane is a synthetic organic compound with no known natural
sources. Production of dioxane in 1979 was 6 million lbs.
9 Based upon dioxane's physical properties, it is expected to volatilize
from soil and surface waters. Dioxane also is expected to be mobile
in soil. No information on the biodegradation of dioxane has been
identified.
° Dioxane has not been included in Federal and State surveys of drinking
water supplies. However, it has been reported to occur"in both surface
and ground water (U.S. EPA, 1979). No information on the occurrence
of dioxane in food or air has been identified.
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March 31, 1987
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III. PHARMACOKINETICS
0 Dioxane has been reported to be absorbed readily through the lungs,
skin and gastrointestinal tracts of mammals.
0 There is evidence that dioxane is absorbed after ingestion. Several
investigators administered dioxane in water to rats and observed
systemic adverse health effects (Argus et al., 1965; Hoch-Ligeti
et al., 1970; Kociba et al., 1974). However, the quantities absorbed
following ingestion are not known. Based on the physico-chemical
properties of this compound, and for the purpose of HA estimation,
100% absorption will be assumed after ingestion.
Distribution
" Woo et al. (1977b) studied the binding of H3-dioxane to tissue
macromolecules of animals. Male Sprague-Dawley rats, weighing 95 to
130 g, were administered a single intraperitoneal dose of H^-dioxane
at 500 uCi/100 g body weight, and sacrificed after 1, 2, 6 or 16
hours. Cystolic, microsomal, mitochondrial and nuclear fractions
were examined. The percent covalent binding was highest in the
nuclear fraction followed by mitochondrial and microsomal fractions
and tne whole homogenate. The binding of dioxane to the macromolecules
in the c/toscl was mainly noncovalent. Pretreatment of rats with
inducers of microsomal enzymes had no significant effect on the
covalent binding of dioxane to the various subcellular fractions of
the liver.
Metabolisr/Ixcretl cr.
0 Dioxar,c has been reported to be metabolized in animals to 2-hydrcx-. -
etnoxyacetic acid and 1,4-dioxan-2-one. After a single oral dose of
1,000 mg/kg bw of 1,4-(1)dioxane to rats, Braun and Young (1977)
recovered from the urine 85% of the dose as -hydroxyethoxyaceti:
acid (HEAA) anc most of the remainder as unchanged dioxane. Woo et al.
(1977a) isolated and identified p-dioxane-2-one from the urine of
rats given intraperitoneal doses of 100 to 400 mg dioxane/kg bod/
weight; the amount of p-dioxane-2-one excreted increased with the
dose level administered.
° Humans exposed to 50 ppm dioxane for six hours eliminated it from the
body primarily by metabolism to HEAA, which was subsequently eliminated
rapidly in the urine (Young et al., 1977).
IV. HEALTH EFFECTS
Humans
0 Tne lowest oral lethal dose for humans has been recorded as 500 mc/kc
(NIOSK, 1978).
L 6 7
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larch 31, 195?
-4-
0 Johnstone (1959) described a fatal case of dioxane poisoning. The
estimated exposure by inhalation in this case was 470 ppm (1,690 mg/rr-S
for one week; the extent of dermal exposure was not known. Postmorter
examination revealed hepatic and renal lesions as well as demyelinatic-.
and edema of the brain.
Animals
Short-term Exposure
0 Oral LD^q values for experimental anioals are 4200 mg/kg (rat), 5700
mg/kg (mouse), 2000 mg/kg (cat), 2000 mg/kg (rabbit) and 3150 mg/kg
(guinea pig) (NIOSH, 1978)•
0 Fairley et al. (1934) intravenously injected four rabbits with a
single dose of either 1, 2, 3 or 5 mL of 80% dioxane diluted with
saline to a total volume of 10 mL. Three other rabbits each were
given two 5 mL intravenous injections of dioxane mixed with 5 mL of
saline with an interval of 48 hours between injections. One rabbit,
used as a control, received 10 mL of saline. Die immediate effect of
dioxane injection in all of the rabbits was violent struggling, which
began as soon as the first few drops were injected. With doses of
4 or 5 mL dioxane, the struggling was followed by convulsions and
collapse; the rabbits then rapidly returned to normal. The four
rabbits given the single doses of 80% dioxane were killed 1 month
later. Degeneration of the renal cortices with hemorrhages was
observed by microscopic examination. In the rabbit administered the
3 mL dioxane dose, the degenerative changes extended into the medulla
and the liver showed extensive cellular degeneration starting at the
periphery of the lobules. No abnormality was found in other organs.
The livers of the rabbits given the 1- and 5 mL doses' showed no
microscopic abnormalities; areas of cloudy swelling were seen in the
liver of the rabbit given 2 mL of dioxane.
Longer-terr Exposure
0 Kociba et al. (1974) reported liver and kidney damage in male and
female Sherman strain rats. The animals were given drinking water
containing 0, 1.0, 0.1 or 0.01% dioxane for up to 716 days. Toxico-
logical analysis included changes in body weights, survival rates,
blood chemistry (packed cell volume, total erythrocyte count, hemo-
globin, total and differential white blood cell counts) and complete
histopathological examination. There was no evidence of toxicity witn
regard to the tested parameters in animals receiving 0.01% dioxane in
drinking water; however, liver and kidney damage was observed at 0.1%
dosage level. Decrease in body weight gains, survival rates, water
consumption and an increase in the incidence of tumors (hepatocellular
and nasal carcinomas) was observed at 1% dosage level.
Reproductive Effects
0 No reports were available on the reproductive effects of 1,4-dioxane
in humans or other mammalian species.
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p-Oioxane
:ch 31, 19S"
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Developinerital Effects
0 No reports were available on the developmental effects of 1,4-dioxane
in humans or other mammalian species.
Mutagenicity
0 No reports were available on the mutagenic potential of 1,4-dioxane.
Carcinogenicity
' Hoch-Ligeti et al. (1970) and Argus et al. (1973) observed a linear
relationship between the total dose of 1,4-dioxane in drinking water
and the incidence of liver neoplasms in rats. The levels of 1,4-
dioxane in the drinking water were 0.75, 1.0, 1.4 and 1.8% for 13
months. A minimum effective tumor dose (TD5), 50% tumor dose (TD50),
and maximum effective dose (TD95) were calculated for 1,4-dioxane.
These were 72, 149 and 260 g, respectively.
0 In a two-year study in Sherman strain rats (60/sex/level) given
1,4-dioxane in drinking water, Kociba et al. (1974) reported that the
group receiving 1% 1,4-dioxane (calculated to be equivalent to approxi-
mately 1015 mg/kg/day and 1599 mg/kg/day for male and female rats,
respectively) showed a significant increase compared to controls in
the incidence of hepatocellular carcinomas and squamous cell carcinomas
of the nasal cavity. At 0.01% (9.6 and 19.0 mg/kg/day, respectively
for males and females) and 0.1% (94.0 and 148.0 mg/kg/day, respec-
tively), there was no significant difference in the incidence of
neoplasrr,s between the control and the experimental groups.
0 In a 90-week study in B6C3Fi mice (50/sex/level) on the oncogenic
effects of reagent-grade 1,4-dioxane in drinking water, a significant
increase in hepatocellular carcinomas over controls was reported in
both tne 0.5 and 1% groups of both sexes (NCI, 1978). Tne average
daily low dose (0.5% v/v) was 720 (530 to 990) "mg/kg/day for males
and 380 (180 to 620) mgAg/day for females; at the 1% level, the
doses were 530 (680 to 1150) and 860 (450 to 1560) mg/kg/day,
respectively .
0 In the NCI (1978) study, Osborne-Mendel rats (35/sex/level) exposed
to 1,4-dioxane in drinking water exhibited a dose-related, statisti-
cally significant incidence of squamous cell carcinomas of the nasal
turbinates in both sexes. Hepatocellular adenomas were observed in
female Osborne-Mendel rats at both dose levels. Average doses for
110 weeks for males were 240 (130 to 380) and 530 (290 to 780) mg/kg
body weight; for females, the doses were 350 (200 to 580) and 640
(500 to 940) mg/kg boty weight.
Effects on Immunologic Status and Competence
0 Thurman et al. (1978) reported on the in vitro effects of 1,4-dioxane
on the mitogenic stimulation of murine lymphocytes. At 2.5 and 5
g/L, 1,4-dioxane greatly enhanced lipopolysaccharide stimulation of
169
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p-Dioxar.e
Ma r ch 31, 19c"
¦6-
lymphocytes as well as depressing phytohemagglutinin stimulation of
lymphocytes. These results were interpreted to indicate stimulation
of B-cell proliferation and suppression of T-cell responses. The
authors did not discuss the implications of the results in human
lymphocytes which appeared to be opposite to the findings with murine
lymphocytes. In vitro, at 25 g/L of 1,4-dioxane, a slight enhancemen
of phytohemagglutinin stimulation of human lymphocytes was seen, indi
eating a stimulation of T-cell responses and an enhancement of the
immune response; little or no effect was seen at lower concentrations
More data confirming this initial finding in murine lymphocytes are
necessary before any valid conclusions can be made on the immuno-
suppressive effects of 1,4-dioxaife.
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years} and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity
The HAs for noncarcinogenic toxicants are derived using the following formula
HA = (NOAEL or LOAEL). x (BW) „ mg/L ( ug/L)
(UF) x < L/day )
where:
NCAEL or LOAiL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
A study by Fairley et al. (1934) has been selected for calculating a One
day HA. In this study, a single dose of 1, 2, 3 or 5 mL of 1,4-dioxane was
given intravenously to rabbits. Even though one rabbit was used per dose
level, the dose-response data generated by this study provide more useful
information concerning the toxic effects of dioxane than the other available
studies. Rabbits sacrificed one month later had degeneration of the renal
cortices with hemorrhages as observed by microscopic examination, with the
increasing do5& levels, the degenerative change extended into the medulla
and the liver e.lso showed extensive and gross cellular degeneration.
170
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A One-day HA for a 10 kg child is calculated as follows:
LOAEL {mg/Jcg/day ) •= (1 ml/day ' t1'03 ^m^)(0'80> (1 °°° m<3/q) = 412 nig A g/day
Where:
1 ml/day = Administered dose of p-dioxane (LOAEL)
1.03 g/ml = Density of dioxane
0.80 ¦ Percent composition of dioxane solution
1000 mg/g = Conversion factor for grams to milligrams
2 kg ¦ Assumed body weight of rabbit
One-day HA = (412 mg/kg/day ) (10 kg) „ 4.12 mg/i, (4,120 ug/L)
(1 L/day) (1,000)
Where:
412 mg/kg/day = LOAEL for liver and kidney effects in the rabbit
10 kg = Assumed weight of a child
1 L/day = Assumed volume of water consumed daily by a child
1,003 = uncertain!ty factor, chosen in accordance with NAS/0
guidelines for use with a LOAEL from an animal stusy
Ten-day h'ealtr. Advisory
In the absence of an acceptable study for the calculation of a Ten-da.
HA, the One-day HA value is divided by ten; therefore, the Ten-day HA is
estimated as 0.412 mg/L (412 ug/L).
Longer-term Health Advisory
No suitable data are available to determine a Longer-term HA. Kociba
et al. (1974) observed a no effect level of 9.6 mg/kg/day based on a two-yea
drinking water study in rats. This study, although scientifically sound,
should not be used for estimating a Longer-term HA because of the carcinogen
potential of p-dioxane. p-Dioxane has been reported to be carcinogenic in
both sexes of rats and mice by several independent investigators. This may-
be compared with trichloroethylene where only one species responded to the
carcinogenic effects of the chemical. Another reason for not calculating a
Longer-term HA for dioxane is its potential of being chlorinated in water,
thus producing a highly toxic chemical. Woo et al. (1980) showed that
chlorination of dioxane increased the toxicity by as much as 1,000 fold.
-------
p-Dioxane
_^March 31, 1 5 £ 7
-8-
Lifetime Health Advisor/
The Lifetime HA represents that portion of an individual's total exposure
Lhat is attributed to drinking water and is considered protective of noncar-
rinogenic adverse health effects over a lifetime exposure. The Lifetime HA
Ls derived in a three step process. Step 1 determines the Reference Dose
[RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
nate of a daily exposure to the human population that is likely to be without
ippreciable risk of deleterious effects over a lifetime, and is derived from
Jie NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
V an uncertainty factor(s), From the RfD, a Drinking Hater Equivalent Level
DWEL) can be determined (Step 2). A DUEL is a medium-specific (i.e., drinkinc
rater) lifetime exposure level, assuming 100% exposure from that medium, at
rhich adverse, noncarcinogenic health effects would not be expected to occur.
3ie DWEL is derived from the multiplication of the RfD by the assumed bod/
reight of an adult and divided by the assumed daily water consumption of an
dult. The Lifetime HA is determined in Step 3 by factoring in other sources
if exposure, the relative source contribution (RSC). The RSC from drinking
rater is based on actual exposure data or, if data are not available, a
¦alue of 20% is assumed for synthetic organic chemicals and a value of 10%
s assumed for inorganic chemicals. If the contaminant is classified as a
iroup A or B carcinogen, according to the Agency's classification scheme of
arcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
ssessing the risks associated with lifetime exposure to this chemical.
Because of its suspected carcinogenicity, a Lifetime Health Advisory for
-dioxane is not recommended.
valuation of Carcinogenic Potential
0 A nurr.ber of studies show that p-dioxane is carcinogenic in more than
one animal species.
0 IARC has classified 1,4-dioxane in Group 2B, indicating sufficient
evidence of its carcinogenicity in animals (IARC, 1982).
0 EPA has not classified this chemical.
0 Drinking water concentrations estimated by EPA to increase the risk
by one excess cancer per million (10~6) would be 7 micrograms per
liter, assuming consumption of 2 liters of water per day by a 70-kg
adult over a 70-year lifetime and using the linearized multistage
model. The drinking water concentrations associated with a risk of
10~4 and 10~5 would be 700 and 70 ug/L, respectively.
0 The linearized multistage model is only one method of estimating car-
cinogenic risk. Using the 10~6 risk level, the following comparisons
in micrograms/L can be made: Multistage, 7j Logit, 10~7; and Weibull,
10~7. Each model is based on differing assumptions. No current
understanding of the biological mechanisms of carcinogenesis is able to
predict which of these models is more accurate than another.
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p-Oioxane
March 31, 19£T
-9-
0 While recognized as statistically alternative approaches, the range
of risks described by using any of these modelling approaches has
little biological significance unless data can be used to support
the selection of one model over another. In the interest of consistenc/
of approach and in providing an upper bound on the potential cancer
risk, the Agency has recommended use of the linearized multistage
approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 NIOSH has recommended an exposure standard of 1 ppm/30 M in air
(NIOSH, 1977).
0 TLV = 25 ppm; STEL = 100 ppm (ACGIH, 1980).
'VII. ANALYSIS
0 There is no standardized method for the determination of p-dioxane
in drinking water. However, p-dioxane can be determined iy the purge
and trap gas chromatographic-mass spectrometric (GC-MS) procedure
used for determination of volatile organic compounds in industrial
and municipal discharges (U.S. EPA, 1984). In this method, a 5 ml
water sample is spiked with an internal standard of an isotopicaliy
stable analog of p-dioxane and purged with an inert gas. The volatile
compounds are transferred from the aqueous phase into the gaseous
phase where the/ are passed into a sorbent column and trapped. After
purging is completed, the trap is backflushed and heated to desorb
the compounds on to a gas chromatograph (GC). The compounds are
separated by the GC and detected by a mass spectrometer (MS). The
labeled compound serves to correct the variability of the analytical
technique. Tr.e method detection limit is dependent upon the nature
of interferences.
VIII. TREATMENT
0 Treatment technologies which are capable of removing p-dioxane fron
drinking water include adsorption by granular activated carbon (GAC) or
powdered activated carbon (PAC). The only data available demonstrating
removal of p-daoxane are for carbon adsorption. Further studies are
required to determine the effectiveness of O3 or O3-UV oxidation.
The available adsorption data are from laboratory bench-scale studies.
Field pilot studies or plant-scale data on p-dioxane are not available.
0 McGuire et al. (1978) developed isotherms for a number.of organic
chemicals, including dioxane. Based on the isotherm data, they
reported that the activated carbon Filtrasorb® 400 exhibited adsorptive
capacities of 0.6 mg dioxane/g carbon and 3.5 mg dioxane/g carbon at
equilibrium concentrations of 1 mg/L and 10 mg/L. They also tested
the effectiveness of PAC treatment at 50 mg/L with 5-hour contact
time. Tne results showed poor removal efficiency. However, it was
173
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p-Dioxa/ie
March 31, 19S7
10
concluded that greater removal of 1,4-dioxane could be achieved using
PAC at higher dosages.
# Suffet et al. (1978) used a pilot-scale test column packed with an
experimental polymeric resin and compared its performance to granular
activated carbon, ftie resins showed poor performance with respect
to p-dioxane removal.
0 A batch laboratory study to demonstrate oxidation of p-dioxane by 100
og/L chlorine and 100 mg/L permanganate showed no reductions after
12-hour and 3-hour contact times, respectively (McGuire et al.,
1978). A batch laboratory study showed diffused aeration to be
ineffective, achieving less than 3% removal at an 80:1 air-to-water
ratio over a 2.4-hour period (McGuire et al., 1978).
8 Treatment technologies for the removal of 1,4-dioxane from drinking
water have not been extensively evaluated (except on an experimental
level). An evaluation of some of the physical and/or chemical
properties of 1,4-dioxane indicates that the following techniques
wojld be candidates for further investigation: adsorbtion by activate:
carbon and oxidation by ozone or ozone/ultraviolet light. Individual
or combinations of technologies selected to attempt 1,4-dioxane
reduction must be based on a case-by-case technical evaluation, and
an assessment of the economics involved.
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.ioxane
March 31, 19 = 7
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REFERENCES
ACGIH. 1980. American Conference of Governmental Industrial Hygienists.
Documentation of the threshold limit values• 4th ed. Cincinnati, OH.
pp. 154-155.
Argus, M.F., J.C. Arcos and C. Hoch-Ligeti. 1965. Studies on the carcino-
genic activity of protein-denaturing agents: Hepatocarcinogenicity of
dioxane. J. Nat. Cancer Inst. 35:949-953.
Argus, m.f., R.S. Sohal, G.M. Bryant, C. Hoeh-Ligesti and J.C. Arcos. 1973.
Oose-response and ultrastructural alterations in dioxane carcinogenesis.
Influence of methylcnolanthrene on acute toxicity. Eur. J. Cancer.
9(4):237-243.
Braun, W.H. and J.D. Young. 1977. Identification of -hydrojQ'ethoxyacetic
acid as the major urinary metabolite of 1,4-dioxane in the rat. Toxicol.
Appl. Pharmacol. 39:33-38.
Fairley, A., E.C. Linton and A.H. Ford-Moore. 1934. Ihe toxicity to animals
of 1,4-dioxane. J. Hyg. 34:486-501.
Hoch-Ligeti, C., M.F. Argus and J.C. Arcos. 1970. Induction of carcinomas
in the nasal cavity of rats by dioxane. Brit. J. Cancer. 24( 1 ):164-167
IARC.. 1982. International Agency for Research on Cancer. IARC monographs
on the evaluation of the carcinogenic risk of chemicals to humans.
Supplement 4. IARC, Lyon, France.
Johnstone, R.T. 1959. Death due to dioxane? AMA Arch. Ind. Health.
20:445-447.
Kociba, R.J., S.B. McCollister, C. Park, T.R. Torkelson and P.J. Gehring.
1974. 1,4-Dioxane. I. Results of a 2-year ingestion study in rats.
Toxicol. Appl. Pharmacol. 30(2):275-286.
McGuire, M.J., I.H. Suffet and J.V. Radziul. ¦ 1978. Assessment of unit
processes for the removal of trace organic compounds from drinking water
JAWWA. 10:565-572.
NCI. 1978. National Cancer Institute. Bioassay of 1,4-dioxane for possible
carcinogenicity. Washington, D.C.: U.S. Department of Health, Educatio
and Welfare, National Institute of Health. DHEW Pub. No. (NIH) 78-1330.
NIOSH. 1977. National Institute of Occupational Safety and Health. Criteri
for a recommended standard — occupational exposure to dioxane. Washing
ton, D.C.: U.S. Department of Health, Education and Welfare. DHEW
(NIOSH) Pub. 77-226.
NIOSH. 1978. National Institute of Occupational Safety and Health. Registry
of toxic effects of chemical substances. U.S. Department of Health,
Education and Welfare. Washington, D.C.
L
-------
March 31, T9S7
¦12-
Suffet, I.H., L. Brenner, J.T. Coyle and P.R. Cairo. 1978. Evaluation of
the capability of,granular activated carbon and XAD-2 resin to remove
trace organics from treated drinking water. Environmental Science and
Technology. 1(12):1315-1322.
Thurman, G.B., B.G. Simms, A.L. Goldstein and O.J. Kilian. 1978. The
effects of organic compounds used in the manufacture of plastics on the
responsivity of murine and human lymphocytesr Toxicol. Appl. Pharmacol.
44:617-641.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Chemical Hazard
Information Profile: Dioxane,^Office of Toxic Substances.
U.S. EPA. 1981. U.S. Environmental Protection Agency. Health advisory
document for p-dioxane. Draft. Office of Drinking Water.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Method 1624 Revision
B, Volatile Organic Compounds fcy Isotope Dilution GC/MS. Federal Register.
49(2095:433407-433415.
Verschueren, K. 1977. Handbook of environmental data on organic chemicals.
1st ed. Van Nostrand Reinhold Compaiy, N.Y. p. 377.
Windholz, M., ea. 1983. Merck Index, 10th ed. Merck and Company, Inc.
Rahwa/, NJ. pp. 481-482.
Woo, Y-T, J.C. Arcos and M.F. Argus. 1977a. Metabolism in vivo of dioxane:
Identificatior. of p-dioxane-2-one as the major urinary metabolite.
Biocher,. Pharmacol. 26:1535-1538.
Woo, y-T, M.F. Argus and J.C. Arcos. 1977b. Tissue and subcellular distri-
bution of 3h"-cioxane in the rat and apparent lack of microsome-catalyzed
covalent bmdmc in the target tissue. Life Sci. 21 (10): 1447-1456.
Woo, Y-T, B.J. Nejb'jrger, J.C. Arcos, M.F. Argus, K. Nishiyama and G.W. Gnf£:r..
1960. Enhancement of toxicity and enzyme-repressing activity of p-dioxane
by cnlormaticn: Stereo-selective effects. Toxicol. Letts. 5:65-75.
Young, J.D., W.H. Braun, L.W. Rampy, M.B. Chenoweth and G.E. Blau. 1977.
Pharmacokinetics of 1,4-dioxane in humans. J. Toxicol. Environ. Heajth.
3(3) :'507-52G.
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March 31, 198"
2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk tc
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
177
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2,3,1, 8-Tetrachlorodibenzo-p-Dioxin
March 31, IS?"
2-
This Health Advisory (HA) is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for 2, 3,7,8-tetra-
chlorodibenzo-p-dioxin (U.S. EPA, 1985a). The HA and CD formats are similar
for easy reference. Individuals desiring further information on the toxico-
logical data base or rationale for risk characterization should consult the
CD. The CD is available for review at each EPA Regional Office of Drinking
Water counterpart (e.g., Water Supply Branch or Drinking Water Branch), or
for a fee from the National Technical Information,Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB #86-117983/AS. The
toll-free number is (800) 336-4700; in the Washington, D.C. area: (703) 487-465
GENERAL INFORMATION AND PROPERTIES
CAS No. 1746-01-6
Structural Formula
0 Dioxin; TCDBD; TCDD; 2,3,7,8-tetrachlorodibenzodioxin, 2,3,7,8-tetra-
chlorodibenzor-1,4-dioxin; 2, 3,7,8-TCDD.
Uses
0 There are no commercial uses for TCDD. (U.S. EPA, 1985a).
Properties (U.S. EPA, 1985a)
Synonyms
Molecular Formula
Molecular Weight
c12H4ci4°2
321 .9
colorless solid, needle shape
Physical State
Boiling Point
Melting Point
Vapor Pressure
303 - 305°C
3.5 x 10-9 mm Hg* at 30.1°C
7.9 x 10-3 Ug/L«*
1.4 x 106
Water Solubility
Log Octanol/Water Partition
Coefficient
Odor Threshold
Taste Threshold
not available
not available
Conversion Factor
* Cheng et al. (1983-1984). Converted from 4.68 x 10"7 pascals
**Adams and Blaine (1985).
Occurrence
° TCDD is a synthetic chemical which has no natural sources. TCDD is
not produced directly but is formed as a by-product in the manufac-
ture of a number of chlorinated phenolic compounds. It can also be
present in fly ash and flue gases of incinerators.
178
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2,3,1,S-Tetrachlorodibenzo-p-Oioxin
March 31, 198?
-3-
° TCDD is extremely resistant to degradation once adsorbed onto soil
with a reported half-life of 10-12 years. TCDD has a very low water
solubility and binds readily to soil. TCDD has been shown to migrate
very slowly in soil. TCDD also has been demonstrated to bioaccumulate
in fish and mammals.
0 TCDD has not been included in drinking water surveys. Given its
limited solubility, it is not expected to occur at detectable levels
in either ground or surface water. TCDD has been reported to occur
at low levels in some surface waters where it is probably bound to
suspended materials. TCDD has been found in a number of freshwater
fish at levels ranging from 1-695 ngAg« TCDD also has been reported
to occur at low levels in rice treated with phenolic herbicides and
in the fat of animals that grazed on pasture treated with phenolic
herbicides. Due to TCDD's physical characteristics, diet is expected
to be a greater route of exposure than drinking water; however, the
available data are insufficient to evaluate the actual levels of
either route (U.S. EPA, 1984a).
III. PHARMACOKINETICS
Absorption
0 Gavage treatment with single or repeated doses of 2,3,7,8-TCDD in oil
has resulted in absorption of approximately 50% of the dose
(unspecified) administered to guinea pigs (Nolan et al., 1979) and
approximately 70-83% of the dose administered to rats (1 or 50 ug/kc)
(Rose et al., 1976; Piper et al., 1973) or to hamsters (650 ug/kg)
(Olson et al., 1980a). Absorption of a single oral dose of 1.14 ng
3h-2,3,7,8-TCDD/kg in corn oil by a male volunteer has been estimated
to be 88.5% (Poiger and Schlatter, 1986).
0 Dietary administration of 0.5 or 1.4 ug 2,3,7,8-TCDD/kg/day for 42
days resulted in somewhat reduced gastrointestinal absorption by rats
(approximately 50-60% of the administered dose was absorbed) (Frres
and Marrow, 1975).
0 Percutaneous absorption of 2,3,7,8-TCDD (26 ng) has been estimated ir.
rats to be approximately 40% of the absorption of an equivalent dose
orally administered (Poiger and Schlatter, 1980).
0 Inhalation absorption of 2,3,7,8-TCDD has not been studied (U.S. EPA,
1985a).
c Diamond Shamrock (1985) noted greater oral absorption of 2,3,7,8-
TCDD in animals given contaminated soil containing oil than without
oil.
Distribution
0 In the Poiger and Schlatte: (1986) study, concentrations of 3.0 and
2.8 ppt of ^h-2,3,7,8-TCDD were detected in adipose tissue 10 and 63
days, respectively, after treatment.
179
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i, i, /,8-Tetrachlorodibenzo-p-Dioxin
March 31, 195"
-4-
0 Tissue distribution following oral or intraperitoneal (i.p.) admini-
stration of 2,3,7,8-TCDD to rats appears to be preferentially to the
liver and adipose tissue (Fries and Marrow, 1975; Rose et al., 1976;
Van Miller et al., 1976; Kociba et al., 1978). Other tissues showed
substantially lower concentrations of 2,3,7,8-TCDD. Soon after treat-
ment, the liver may have concentrations about three (Kociba et al.,
1978a) to five (Rose et al., 1976) times that in adipose tissue.
It was suggested that male rats accumulate 2,3,7,8-TCDD in the liver
more efficiently than female rats (Fries and Marrow, 1975). Tissue
distribution in mice (Manara et al«, 1982) and hamsters (Olson
et al., 1980a) seems to be similar to that in rats.
0 Monkeys, however, appear to accumulate 2,3,7,8-TCDD preferentially
in adipose tissue to a greater extent than in the liver (Van Miller
et al., 1976; McNulty et al., 1982). Two years after a single oral
dose to a monkey, adipose tissue contained 100 ppt and the liver 15
ppt 2,3,7,8-TCDD (McNulty et al., 1982). Prolonged tissue retention
of the compound was thus demonstrated. Tissue distribution in guinea
pigs appears to be similar to that in monkeys (Gasiewicz and Neal,
1979; Nolan et al., 1979) since tissue levels in adipose tissue
exceed those in the liver.
0 Evidence tnat 2,3,7,8-TCDD accumulates in the adipose tissue of
exposed humans was presented by Young et al. (1983) who reported
levels of 3 to 99 ppt in the adipose tissue of armed forces veterans
claiming health problems related to Agent Orange.
° Fetal distribution of 2,3,7,8-TCDD has been studied in rats (Moore
et al., 1976) and mice (Nau and Bass, 1981; Nau et al., 1982).
Levels of 2,3,7,8-TCDD were low in rat fetuses on gestation days 14
and 18 of gestation and appeared to be evenly distributed in all fetal
tissues. On day 21 of gestation, the fetal liver showed a marked
affinity for 2,3,7,8-TCDD (Moore et al., 1976). 2,3,7,8-TCDD was
distributed to the fetuses of mice following oral, i.p. or subcu-
taneous (s.c.) administration (Nau et al., 1982). Maximunr fetal
concentrations occurred on days 9 and 10 of gestation; lower fetal
concentrations were observed on gestation days 11 through 18, coinci-
dent with placentation. Hie fetal liver had less affinity for the
compound than did the maternal liver.
° Ryan et al. (1985) reported 2,3,7,8-TCDD levels of 5-10 ppt in
adipose tissue samples from humans taken at autopsy across Canada.
Higher levels of other dioxins were also found.
Metabolism
0 In an early metabolism study, Vinopal and Casida (1973) reported that
in vivo or rn vitro studies with mice showed that polar metabolites
of 2, 3,7, f?-TCD0 were not produced by this species. In rats, however,
hydroxyl^tion and conjugation with glucuronide and sulfate have been
demonstrated (Poiger and Schlatter, 1979; Poiger et al., 1982;
Olson et al., 1983). Glucuronide conjugates tended to predominate
in the bile (Poiger and Schlatter, 1979) and sulfate conjugates were
located in the urine (Olson et al., 1983).
180
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2,3,7,8-Tetrachlorodibenzo-p-Dioxin
March 31, 19C"
-5-
0 Poiger and Schlatter (1979) stated tjiat metabolism of 2,3,7,8-TCDD
proceeds slowly in the liver. Neal et al. (1982) demonstrated
that the rate of hepatic metabolism was enhanced by activated cyto-
chrome P-450 mono-oxygenase. It was suggested that metabolism of
2,3,7,8-TCDD proceeds by the formation of reactive epoxide intermedi-
ates (Poland and Glover, 1979). Dechlorination also was demonstrated
by Olson et al. (1983) and Sawahata et al. (1982), who identified
tri- and dichlorodibenzo-£-dioxins as metabolites in in vitro rat
hepatocyte systems. From the bile of dogs, six major metabolites
have been identified (Poiger et al., 1982); hydroxylated conjugates
of tetra-, tri- and dichlorodibenzo-£-dioxin predominated.
0 Although metabolite profiles are consistent with an arene oxide
intermediate, the covalent interaction of 2,3,7,8-TCDD with cellular
macromolecules is minimal.
Excretion
° When the excretion data are plotted serai-logarithmically, a straight
line results, suggesting that elimination of 2,3,7,8-TCDD is a first-
order phenomenon, especially in rats. Excretion in the guinea pig
may be a zero-order process (Gasiewicz and Neal, 1979). The half-life
for body elimination varied considerably with estimated ranges of 10
to 15 days in the hamster (Olson et al., 1980a), the species least
sensitive to the toxic effects of 2,3,7,8-TCDD, 11 to 24 days in the
mouse (Gasiewicz et al., 1983a,b), 17 to 31 days in the rat (Piper,
et al., 1973; Allen et al., 1975; Rose et al., 1976) and 22 to 30
days in the guinea pig (Gasiewicz and Neal, 1979; Nolan et al.,
1979). One strain of mice, DBA/2J, had a half-life for elimination
of approximately 24 days, about twice as long as in other strains
tested by Gasiewicz et al. (1983a,b). These authors also noted that
this strain of mice had a greater tendency to accumulate 2,3,7,8-TCDD
in adipose tissue than did other strains and that this phenomenon
probably resulted in slower body elimination. Half-lives for body
elimination of 2,3,7,8-TCDD have not been calculated for the monkey,
but it was suggested that the tendency of this species to accumulate
2,3,7,8-TCDD in adipose tissue may also result in slow body elimination
(Van Miller et al., 1976).
° Recently, Olson and Bittner (1983) examined the elimination of 2,3,7,6-
TCDD in rats over a longer period than in the studies previously
summarized and determined that biphasic elimination occurred. They
estimated a half-life of approximately 7 days for the initial rapid
phase and a half-life of approximately 75 days for the slower phase,
probably related to release from stores of body fat. McNulty et al.
(1982) estimated the half-life for elimination from the fat of monkeys
to be approximately 1 year.
0 In the Poiger and Schlatter (1986) study, 11.5% of the 3H-TCDD was
excreted in feces during tr.^ first three days after treatment, and
no 3h activity was found in urine. These investigators estimated an
elimination half-life of 4.95 years for the 3H-TCDD.
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0 The fecal route seems to be the major pathway for the elimination of
2,3,7,8-TCDD-derived radioactivity in rats (Piper et al., 1973;
Allen et al., 1975; Rose et al., 1976j Van Miller et al., 1976),
guinea pigs (Gasiewicz and Neal, 1979} and mice (Gasiewicz et al.,
1983a,b). Urinary excretion played less of a role in these species,
accounting for <1 to 28% of total excreted radioactivity while fecal
excretion accounted for 72 to >99% of the eliminated radioactivity.
Urinary excretion accounted for a more substantial proportion of body
elimination in hamsters (41% as compared with 59% by feces) (Olson,
et al., 1980a) and that strain of mice (DBA/2J) which preferentially
accumulated 2,3,7,8-TCDD in body fat (Gasiewicz et al., 1983a,b).
9 The failure to detect metabolites of 2,3,7,8-TCDD in liver and fat
(Olson et al., 19S3) indicates that elimination of the metabolites
occurs rapidly and that the rate of elimination is governed primarily
by the rare of hepatic metabolism.
IV. HEALTH EFFECTS
Humans
0 Either acute or chronic exposure to 2,3,7,8-TCDD (usually in combi-
nation with other substances) may result in chloracne, altered liver
function, hematological lesions, porphyria cutanea tarda, hyperpig-
mentation, hirsutism and neural degeneration in the extremities (U.S.
E?rv, 1985a). Stevens (1981) has estimated that the minimum cumulative
toxic dose of 2,3,7,8-TCDD in humans is 0.1 ug/kg.
6 Rowe (1968) has described experiments showing a dose-response for
chloracne in humans acutely exposed to topical applications of
2,3,7,8-TCDD.
0 The toxic effects of chloracne from exposure to 2,3,7,8-TCDD may
persist for many years, though other effects noted in various
individuals are apparently reversible after a short period. Epidemio-
logical studies have failed to demonstrate a convincing connection
between 2,3,7,8-TCDD exposure and spontaneous abortions or malfor-
mations in humans. Some evidence of cytogenetic damage has been
reported in humans exposed to chemicals contaminated with 2,3,7,8-TCDD,
but negative results have also been reported; exposures were not
guantitated and the other chemicals cannot be ruled out as causative
agents (U.S. EPA, 1985a).
0 Swedish case-control studies provide limited evidence for the carcino-
genicity of phenoxy acids or chlorophenols or both in humans. However,
with respect to the dioxin impurities contained within them, the evidence
for the human carcinogenicity for 2,3,7,8-TCDD based on epidemiologic
studies is only suggestive because of the difficulty of evaluating
the risk of 2,3,7,8-TCDD exposure in the presence of the confounding
effects of phenoxy acids and/or chlorophenol (U.S. EPA, 1985a).
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Animals
Short-term Exposure
0 There are wide variations in species sensitivity to the acute toxicity
of 2,3,7,8-TCDD. LDjqs range from 0.6 ugAg for the male guinea pig
to >5,000 ugA9 bw for the male hamster (^chwetz et al., 1973; Olson,
et al., 1980b; Henck et al., 1981). The toxic manifestations seem
to be the same whether the compound is given as a single oral dose or
as a limited number of multiple treatments, with death occurring from
5 to 45 days post-treatment. Lethal exposures result in weight loss,
often described as "wasting away" and thymic atrophy. In some species,
particularly rats and mice, extensive liver damage is observed (Gupta
et al., 1973). In general, no specific cause of death has been
identified, although extensive hemorrhaging has been implicated in
mice (Vos et al., 1974).
0 In rats, single high doses (200 ugAg) produce liver necrosis (Jones
and Butler, 1 974), while lower doses (5 and 25 ugAg) result in fatty
changes in the liver and proliferation of the endoplasmic reticulum
(Fowler et al., 1973). Other effects seen in some species include
induction of microsomal enzymes, degeneration of plasma membranes
witn loss of ATPase activity, a decreased ability to excrete some
xenobiotics in the bile, porphyria, altered gastrointestinal absorption
of some nutrients and decreased blood cellularity (U.S. EPA, 1985a).
Turner and Collins (1983) found treatment-related liver lesions in
guinea pigs given single gavage doses of 2,3,7,8-TCDD at 0.1 ugAs
and higher.
0 2,3,7,8-TCDD is an immunotoxin in laboratory animals, predominantly
affecting cell-mediated immunity. Hypersensitivity, adverse effects
on the thymus and increased sensitivity to antigens have demonstrated
the inmunotoxic potential of 2,3,7,8-TCDD. Weanling rodents sho*
greater susceptibility to immune effects compared to adults (U.S.
EPA, 1985a).
Long-term Exposure
0 In rats and mice, the liver appears to be the most sensitive organ
following chronic or subchronic exposure. Hepatotoxicity develops
following a long induction period and the changes persist for long
periods following the termination of exposure (King and Roesler,
1974; Goldstein et al., 1982).
0 Liver lesions as well as other toxic signs were observed in the
following studies in rats and mice. In the subchronic studies, the
NOAEL of 0.01 ugAg/day (Kociba et al., 1976) and 0.5 ugAg/weelt
(NTP, 1980) have been reported for rats. A NOAEL of 2 ugAg/week was
identified for female mice and a LOAEL of 1 ugAg/week for male mice
in the NTP (1980) subchronic study. A NOAEL of 0.001 ugAg bw/day, a
LOAEL of 0.01 ugAg/day, and an effect level of 0.1 ugAg/day have
been reported for rats following chronic dietary exposure (Kociba
et al., 1978a,b, 197*; NTP, 1980). Toth et al. (1978, 1979) observed
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toxic effects in mice at doses as low as 0.007 ugAg/week given for
one year by gavage. Gavage dosing for two years led to toxic hepatiti
at a NOAEL of 0.05 ugAg/week and a LOAEL of 0.5 ugAg/week in rats,
a LOAEL of 0.5 ugAg/week in male nice, and a LOAEL of 2.0 ug/kg/week
in female mice (NTP, 1980).
# DeCaprio et al. (1986) fed 2,3,7,8-TCDD in the diet for 90 days to
male and female Hartley guinea pigs, and found NOAELs of 0.12 and
0.61 (male) and 0.68 (female) mgAg/dayj decreased body weight gain,
increased relative liver weights, decreased relative thymus weights,
and hepatocellular cytoplasmic inclusion bodies at 4.90 (males) and
4.86 (females) mgAg/day; and, mortality and other mentioned effects
at 26 (males) and 31 (females) mgAg/day.
Reproductive Effects
0 Adverse effects of 2, 3,7,8-TCDD on reproduction in rats exposed
through the diet were observed by Murray et al. (1979) and are
detailed under Lifetime Health Advisory.
Developmental Effects
° 2,3,7,8-TCDD has been demonstrated to be teratogenic in mice. The mos
common malformations observed are cleft palate and kidney anomalies;
however, other malformations have been observed occasionally. With an
effect level of 1 ugAg/day, 2,3,7,8-TCDD is the most potent teratogen
known. At higher doses, 2,3,7,8-TCDD has a marked fetotoxic effect,
as measured by decreased fetal weight and increased fetal toxicity.
Hemorrhagic GI tract has been associated with 2,3,7,8-TCDD fetal
toxicity (U.S. EPA, 1985a).
® Poland and Glover (1980) produced evidence that responsiveness of
mice to cleft palate from 2, 3,7,8-TCDD treatment is related to trie
presence of Ah receptor.
° In rats, it has also been consistently observed that 2,3,7,8-TCDD
produces fetotoxic responses. In this species, the most common fetal
anomalies observed were edema, hemorrhage and malformation of the
kidney with effects observed at doses of *0.01 ugAg/day. In
addition, there is some evidence that 2,3,7,8-TCDD can induce micro-
somal enzymes in the fetus exposed in utero, and this induction is
accompanied by damage to the fine structure of the liver cell; however
other reports indicate that enzyme induction occurs only after birth
following exposure to 2,3,7,8-TCDD through the mother's milk. As in
mice, hemorrhagic GI tracts have been observed in rat fetuses exposed
in utero to 2,3,7,8-TCDD (U.S. EPA, 1985a).
° Rabbits and monkeys are also susceptible to the fetotoxic effects of
2,3,7,9-TCDD; however, the studies of these species have been too
limited to clearly demonstrate a teratogenic response or define a
threshold dose for fetotoxicity (U.S. EPA, 1985a).
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Mutagenicity
° _In vivo and i£ vitro mutagenicity tests have produced inconclusive
evidence as to the mutagenicity of TCDD (U.S. EPA, 1985a).
0 Early reports indicated that 2,3,7,8-TCDD was mutagenic in-S^. typhi-
murium strain TA1532 (Hussain et al., 1972; Seiler, 1973); however,
later attempts to confirm these results have been unsuccessful (Nebert,
et al., 1976; McCann, 1978; Gilbert et al., 1980; Geiger and Neal,
1981). 2,3,7,8-TCDD has been reported to be nutagenic to £. coli in
vitro (Hussain et al., 1972) and to S^. cerevislae in vitro, and in a
host-mediated assay (Bronzetti et al., 1983). Covalent interactions
with nucleic acids are minimal if they occur at all (Kondorosi et al.,
1973; Poland and Glover, 1979). Only marginal effects have been
observed on the incidence of chromosomal aberrations ill vivo (Green
and Moreland, 1975). A test for unscheduled DNA synthesis in cultured
male rat hepatocytes was negative (Althaus et al., 1982). Loprieno
et al. (1982) reported 2,3,7,8-TCDD as clastogenic in mice in vivo,
negative for cytogenetic effects in vivo, and negative for unscheduled
DNA synthesis in a human cell live in vitro. Hay (1983) reported
2,3,7,8-TCDD as mutagenic in the baby hamster kidney cell transfor-
mation assay.
Carcinogenicity
° Several bioassays have demonstrated this compound to be a potent
carcinogen in rats and mice (Kociba et al., 1978a; Toth et al., 1979;
NTP, I960). Adenomas or carcinomas of the thyroid, hepatocellular
carcinomas, carcinomas of the tongue and hard palate, and adenomas of
the adrenal gland have been induced in rats and mice.
0 Significant (P <0.05) neoplastic effects were evident at dietary
levels of 0.01 and 0.1 ug/kg/day but not at 0.001 ug/kg/day in the
two-year study with Sprague-Dawley rats by Kociba et al. (1978). In
Osborne-Menael rats given 2,3,7,8-TCDD in corn oil:acetone twice
weekly for total weekly doses of 0.01, 0.05 and 0.5 ug/kq/week for
two years, significant (P <0.05) tumor increases-were thyroid in mid-
and high-dose males and liver in high-dose males (NTP, 1980). In the
NTP (1980) study in which B6C3F1 mice were dosed like the rats except
that females received 0.04, 0.2 and 2.0 ug/kg/week, significant
(P <0.05) tumor increases were in liver in high-dose males and females
and thyroid in high-dose males.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-d^y, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) = mg/L ( /L)
(UF) x ( L/day)
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where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mgAg bw/day.
BW = assumed body weight of a child (10 Jcg) or
an adult (70 kg).
UF » uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines,
L/day ¦ assumed daily water consumption of a child
¦1 L/day) or an adult (2 L/day).
One-day Health Advisor/
Turner and Collins (1983) administered single oral doses of 2,3,7,8-TCDD
at 0.1, 0.5, 2.5, 12.5 or 20 ugAg in aqueous methyl cellulose to groups of
4 to 7 female guinea pigs. Survivors were killed 42 days after dosing and
examined for histopathologic changes in the liver. Four of the 7 animals in
the highest dose group and 1 of 5 in the 12.5 ug/kg group died before the end
of the observation period. Mild histopathologic changes including steatosis
(fatty change), focal necrosis and cytoplasmic degeneration were noted in
animals from all treated groups, but not in controls. Die authors indicated
that quantitative differences among the dosage groups were not detectable by
light microscopy.
A LOAEL of C.1 ug/kg can be derived from the study of Turner and Collins
(1983) for calculating a One-day HA, using an uncertainty factor (UF) of 1,000
for an animal LOAEL. This UF consists of two 10-fold factors to account for
both intra- and interspecies variability to the toxicity of this chemical in
the absence of chemical-specific data, and an additional 10-fold factor
because the HA is based on a LOAEL and not a NOAEL.
For a 10-rtg child consuming 1 L of drinking water per day, the One-day
HA is calculated as follows:
One-day HA = (0.1 ugAg/day) (10 kg) = 0.0010 ug/L
(1,000) (1 L/day)
where:
0.1 ugAg = LOAEL derived from studies by Turner and Collins (1983).
1 0 kg ¦» assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an aniaal study.
1 L/day = assumed daily water consumption of a child.
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Ten-day Health Advisory
Because of the demonstrated sensitivity of the guinea pig to acute
toxicity of 2, 3,7,8-TCDD, the Ten-day HA is derived by dividing the One-day
HA by ten. The Ten-day HA is, therefore, 0.0001 ug/L.
Longer-term Health Advisory
The three-generation reproduction study in rats by Murray et al. (1979)
has been selected because the animals in this study were administered 2,3,7,8-
TCDD by diet on a daily basis for an appropriate duration as opposed to the
gavage method of treatment used in other studies considered and because the
adverse effect was on reproduction. Comparison with the other studies in
which different treatment protocols were used suggests that the dose of
0.001 ug/kg/day, concluded by the U.S. EPA as a LOAEL for adverse effects
on the pups and dams in the Murray et al. (1979) study would be protective
against the toxic effects found in the other studies. Although DeCaprio
et al. (1986) found NOAELs of 0.61 and 0.68 ngAg/day in their 90-day guinea
pig study, this dose is slightly below the LOAEL of 0.001 ug/kg/day
(1 ng/kg/day) in another species which, in turn, is below the LOAEL of
4.86 ng/kg/day in the DeCaprio et al. (1986) study.
Using an uncertainty factor of 1,000 for an animal LOAEL (i.e., 10-fold
for intra- and 10-fold for interspecies variability to the toxicity of a
chemical in the absence of specific data, and an additional 10-fold factor
because the estimate is based on a LOAEL rather than a NOAEL), a Longer-term
HA can be calculated from the LOAEL of 0.001 ug/kg/day concluded for the
Murray et al. (1979) study.
For a 10-kg child consuming 1 L of drinking water each day, the Longer-
term HA is calculated as follows:
Lonoer-terx HA = (0.001 ug/kg/day) (10 kg) = 0.00001 ug/L
(1,000) (1 L/day)
where:
0.001 u'g/kg/day = LOAEL from study by Murray et al. (1 979).
1 0 kg = assumed weight of child
1,000 b uncertainty factor, chosen in accordance with NAS/ODa
guidelines for use with a LOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
By substituting 70-kg body weight and daily consumption of 2L of water
for the adult in the above equation, the Longer-term HA for the 70-kg adult
becomes 0.000035 ug/L.
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March 31, 19£7
12
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Oose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Hater Equivalent Level
(DWEL) can be determined (Step 2). A DUEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or £ carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The EPA has developed for comparison with cancer-based criteria, a pre-
sumed safe daily intake level based on noncarcinogenic effects as indicated
in U.S. EPA (19S4b). For consistency, the rationale used by EPA for the
calculation of this value in U.S. EPA (1984b) is used here for the DWEL
calculation. The rationale as presented in U.S. EPA (1984b) is as follows:
2,3,7,8-TCDD displays an unusually high degree of reproductive
toxicity. It is teratogenic, fetotoxic and reduces fertility. In a
3-generation reproductive study, Murray et al. (1979) reported a
reduction in fertility after daily dosing at 0.1 or 0.01 ug 2,3,7,6-
TCDD/kg in the Fi and F2 generations of Sprague-Dawley rats. Although
Murray et al. (1979) considered the lowest dose tested, 0.001 ug/kg,
to.be a no-observed-effect level (NOEL), a re-evaluation of these data
by Nisbet and Paxton (1982), using different statistical methods,
indicated that there was a reduction in the gestation index, decreased
fetal weight, increased liver to body weight ratio, and increased
incidence of dilated renal pelvis at the 0.001 ugA9 dose. The
reevaluated data would suggest that equivocal adverse effects were
seen at the lowest dose (0.001 ug/kg/day) and that this dose should,
therefore, represent a lowest-observed-adverse-effect level (LOAEL).
Schantz et al. (1979) found reductions in fertility and various other
toxic effects in rhesus monkeys fed a 50 ppt 2,3,7,8-TCDD diet for
20 months. This corresponds to a calculated daily dose of 0.0015 ug
2,3,7,6-TCDD/kg/day. These results suggest that monkeys may be
somewhat rtore sensitive than rats, since the effects in monkeys were
more severe and not equivocal. Since the data from the limited study by
Schantz et al. (1979) are supportive of the findings by Murray et al.
(1979) it seems reasonable to determine an ADI based on the LOAEL.
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From these results, a LOAEL of 0.001 ugAg was identified. Using this
LOAEL, the DWEL is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (0.00T ug/kg/day) = 1 x 10-6 ug/fcg/day
(1,000)
where:
0.001 ug/kg/day = LOAEL.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (1 X 10-6 u?/kg/day) (70 kg) = 0.000035 /L
(2 L/ day)
where:
1 x 10-5 ugAg/day = RfD.
70 kg = assumed body weight of an adult. .
2 L/ day = assumed daily water consumption of an adult.
2,3,7,8-TCDD is placed in Group B: Probable human carcinogen. The
estimated excess cancer risk associated with lifetime exposure to drinking
water containing 2,3,7,8-TCDD at 3.5 x 1 0"5 ug/L is approximately 2 x 10~4.
Tnis estimate represents the. upper 95% confidence limit from extrapolations
prepared by EPA's Carcinogen Assessment Group using the linearized, multistage
model. The actual risk is unlikely to exceed this value, but there is
considerable uncertainty as to the accuracy of risks calculated by this
methodology•
Evaluation of Carcinooenic Potential
° Cancer potency estimates were derived using the multistage model ani
the tumor data on female rats in the chronic feeding study by Kociba
et al. (1978a) (U.S. EPA, 1985a,b).
0 The 95% upper-limit carcinogenic potency factor for humans, qi*, is
1 .56 x 105 (mgAg/day)-1. For a 70 kg human drinking 2 L wate r/day,
the water concentration should be 2.2 x 10~6 ug/L in order to keep
the upper-limit individual lifetime cancer risk at 10-5. Water
concentrations corresponding to excess cancer risk of 1X3-4 and 10-6
are, therefore, 2.2 x 10-5 and 2.2 x 10"7 ug/L, respectively.
" Maximum likelihood estimates as well as 95% upper limits of cancer
risks by the multistage model have been calculated (U.S. EPA, 1985b).
For example, at 1 x 10"3 ng/kg/day or 0.035 ng/L cancer risk estimates
189
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March 31, 195"
are 1.1 x 10"4 (MLE) and 1.5 x 10-4 (ul) and at 1 x 10"2 ng/kg/day
cancer risk estimates are 1.1 x 10-3 (MLE) and 1.5~x 10""3 (UL).
0 The EPA's Carcinogen Assessment Group has estimated cancer risks with
other models besides the nultistage (U.S. EPA, 1985b). As an example,
1 x 10*3 ngAg/day lifetime exposure was associated with additional
risks (95% upper confidence limit) of 1.5 x 10""4 by the nultistage
and one-hit, 2.9 x 10~3 by the Weibull, ^nd 7.5 x 1CT® ty the log-
probit, using the Kociba analysis of the data. While recognized as
statistically alternative approaches, the range of risks described by
using any of these modeling approaches has little biological signifi-
cance unless data can be used to support the selection of one model
over another. In the interest of consistency of approach and in
providing an upper bound on the potential cancer risk, the EPA has
recommended use of the linearized nultistage approach.
° The IARC (1981) classified TCDD as a 2B chemical (sufficient animal
evidence; inadequate human evidence) for carcinogenicity.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), 2,3,7,8-TCDD may be classified in
Group 32: Probable human carcinogen. This category is for agents for
which there is inadequate evidence from human studies and sufficient
evidence from animal studies.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 For 2,3,7,8-TCDD, the U.S. EPA has established criteria of 1.3 x 10~7,
1.3 x 10~® or 1.3 x 10~9 ug/L in ambient waters, based on an assume:!
daily consumption of 6.5 g of contaminated fish and shellfish and 2 L
of drinking water (U.S. EPA, 1984b). Under these conditions, 94.2%
of the total exposure would result from the consumption of aquatic
organisms. The recommended levels correspond to estimated hum-,
lifetime excess cancer risks of 10~5, io~® or 10-7, respectively.
These values are considerably lower than the HAs for drinking water,
reflecting the high bioaccumulation potential of this conpound in
aquatic species.-
° The FDA advises that fish containing >50 ppt of 2,3,7,8-TCDD should
not be consumed and those containing >25 ppt, but <50 ppt, should not
be consumed more than twice a month (FDA, 1983). This is reflected
in a Canadian limit of 20 ppt in the Lake Ontario commercial fish
inported into-the United States (NFOC, 1981).
0 An ADI of 10-4 ug/kg bw/day has been proposed previously for 2,3,7,8-
TCDD fcy the National Academy of Sciences Safe Drinking Water Committee
(MAS, 1977). This ADI was based on a 13-week rat feeding study by
Kociba et al. (1976) and wa
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Karen 31, 1 9C
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VII. ANALYTICAL METHODS
0 Determination of dioxin is by a gas chromatographic/mass spectrometer
(GC-MS) method (Method 613. U.S. EPA, 1984c). In this method, a one
liter sample is spiked with an internal standard of a labeled dioxin
and extracted with methylene chloride using a separatory funnel. The
methylene chloride extract is exchanged to hexane during concentration
to a volume of approximately 1 mL. The extract is then analyzed by
capillary column GC/MS to separate and measure dioxin. The method
detection limit is dependent upon the nature of interferences, but it
is estimated to be about 0.02 ug/L.
VIII. TREATMENT TECHNOLOGIES
° Because of its high toxicity and low potential for occurrence in
drinking water, very little information is available on the removal
of dioxins from drinking water. Granular activated carbon adsorption
is likely to be the most reasonable treatment approach and the small
amount of empirical evidence available bears this out.
0 While looking for a method to concentrate polychlorinated dibenzo-p-
dioxins and dibenzofurans, scientists from the U.S. Fish and Wildlife
Service's fish-pesticide research laboratory in Columbia, Missouri,
found that TCDD is extremely difficult to recover from GAC once it
has been adsorbed (Chemical Engineering and News, 1977). Subsequent
pilot-scale tests of carbon adsorption of Agent Orange [50-50 mixture
of the acid esters of 2,4,5-T and 2,4-dichlorophenoxyacetic acid
(2,4-D)] reduced an initial concentration of 10 mg/L dioxin in the
herbicide to a final concentration of less than 0.1 mg/L. Details of
the adsorption test were not reported by the authors. Based on these
data and the reported low water solubility of 0.2 ug/L dioxin in
water (Bollen and Norris, 1979), it appears that GAC adsorption of
dioxin fron water is potentially feasible.
191
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2, 3,7,8-Tetrachlorodibenzo-p-Dioxin
March 31, 19S ~
-16-
IX. REFERENCES
Adams, W.J., and K.M. Blaine. A ter solubilxty of 2,3,7,B*TCDD. Monssnto
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Allen, J.R., J.P. Van Miller and D.H. Norback. 1975. Tissue distribution,
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Bollen, w.B., and L.A. Norris. 1979. Influence of 2,3,7,8-tetrachlorodibenzo-
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Bronzetti, G., E. Zeiger, I. Lee, K. Suzuki and H.V. Mailing. 1983. Muta-
genicity study of TCDD and ashes from urban incinerator "in vitro" and
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Chemical Engineering and News. 1977. Method rids Agent Orange of TCDD con-
tamination. 55(11):25.
Cheng, S.C., F.E. Hileman and J.M. Schroy. Nov., 1983-March, 1984. Monsanto
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p-dioxin i.-. the guinea pig. Comparisons with a PCB-containing trans-
former fluid pyrolysate. Fund. Appl. Toxicol. 6:454-463.
Diamond Shamrock. 1985. Letter to U.S. EPA, Office of Drinking Water, with
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FDA. 1983. Food and Drug Administration. Statement by S.A. Miller, Director,
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2,3,7,6-Tetrachlorocioenzo-p-Dioxin
March ji, la?"1
-1 7
Gasiewicz, T.A., and R.A. Neal. 1979. 2,3,7,8-Tetrachlorodibenzo-p-dioxin
tissue distribution, excretion, and effects on clinical chemical parameters
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Gasiewicz, T.A., J.R. Olson, L.E. Geiger and R.A. Neal. 1983a. Absorption,
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p-dioxin. Biochem. Pharmacol. 31 (.8): 1 607—1 613.
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dioxin. American Chemical Society National Meeting. Abst. 23(2) :1-i.
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Huetter, R., and M. Philippi. 1982. Studies on microbial metabolism of TCDD
under laboratory conditions. Pergamon Ser. Environ. Sci. 5:87-93.
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effects of TCDD on bacterial systems. Ambio. 1:32-33.
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Jones, G,, and W.H. Butler. 1974. A morphological study of the liver lesion
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112:93-97.
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King, M.E., and A.R. Roesler. 1974. Subacute intubation study on rats with
the compound 2,3,7,8-tetrachloridioxin. U.S. EPA. NTIS PB 257 677, p. 2
Kociba, R.J., P.A. Keeler, C.N. Park and P.J. Gehring. 1976. 2,3,7,8-Tetra-
chlorodibenzo-p-dioxin results of a 13-week oral toxicity study in rats.
Toxicol. Appl. Pharmacol. 35:553-574.
Kociba, R.J., D.G. Keyes, J.E. Beyer et al. 1978a. Results of a two-year
chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-
dioxin in rats. Toxicol. Appl. Pharmacol. 46(2):279-303.
Kociba, R.J., D.G. Keyes.x J.E.Beyer and R.M. Carreon. 1978b. Toxicologic
studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Toxicol.
Occup. Med. 4:281-287.
Kociba, R.J., D.G. Keyes, J.E. Beyer, R.M. Carreon and P.J. Gehring. 1979.
Long-term toxicologic studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) in laboratory animals. Ann. NY Acad. Sci. 320:397-404.
Kondorosi, A., I. Fedorcsak, F. Solymosy, L. Ehrenberg and S. Osterman-Golkar.
1973. Inactivation of QBRNA by electrophiles. Mutat. Res. 17:149-161.
Loprieno, N., I. Skrana, D. Rusciano, D. Lascialfari and T. Lari. 1982.
_In vivo cytogenetic studies on mice and rats exposed to tetrachlorodi-
benzo-p-dioxin (TCDD). Chlorinated Dioxins and Related Compounds, Impact
on the Environment. Book 5. pp. 419-428.
Manara, L., P. Coccia and T. Croci. 1982. Persistent tissue levels of TCDD
in the mouse and their reduction as related to prevention of toxicity.
Drug Metab. Rev. 13(3):423-446.
McCann, J. 1978. Unpublished study. (Cited in Wassom et al., 1978)
McNultv, W.P., K.A. Nielsen-Smith, J.O. Lay, Jr. et al. 1982. Persistence
of TCDD in monkey adipose tissue. Food Cosmet. Toxic. 20:985-987.
Moore, J.A., M.w. Harris and P.W. Albrp. 1976. Tissue distribution of
C4c) tetrachlorodibenzo-p-dioxin in pregnant and neonatal rats. Toxicol
Appl. Pharmacol. 37(1):146-147.
Murray, F.J., F.A. Smith, K.D. Nitschke, C.G. Humiston, R.J. Kociba and
B.A. Schwetz. 1979. Three-generation reproduction study of rats given
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol. Appl.
Pharmacol. 50:241-251.
NAS. 1977. National Academy of Sciences. Drinking Water and Health: Part I
NAS, Washington, D.C. pp. 500-513.
Nau, H., and R. Bass. 1981. Transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) to the mouse embryo an>i fetus. Toxicology. 20(4):299-306.
-------
2,3,7, 8-Tetracr.lorodioenzo-p-Dioxin
March 31, 19S
19
Nau, H., R. Bass and D. Neubert. 1982. Transfer of 2,3,7,8-tetrachlordibenzo-
p-dioxin (TCDD) to the mouse embryo, fetus and neonate. In_: Chlorinated
Dioxins and Related Compounds. Impact on the Environment. 0. Huntzinger,
R.w. Frei, E. Merian, and F. Pocchiari, Eds. Pergamon Press, NY.
pp. 325-337.
Neal, R.A., J.R. Olsen, T.A. Gasiewicz and L.E. G^iger. 1982. The toxico-
kinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mammalian systems.
Drug Metab. Rev, 13:355-385.
Nebert, D., S. Thorgiersson and J. Felton. 1976. Genetic differences in
mutagenesis, carcinogenesis, and drug toxicity. In: In vitro Metabolic
Activation in Mutagenesis Testing, F. de Serros, J. Folets, J. Bend, and
R. Philpot, Eds. Elsevier/North Holland Biomedical Press, Amsterdam,
pp. 105-124.
Nisbet, I.C.T., and M.B. Paxton. 1982. Statistical aspects of three-genera-
tion studies of the reproductive toxicity of TCDD and 2,4,5-T. Am. Stat.
Vol. 36(3):290-298.
Nolan, R.J., F.A. Smith and J.G. Hefner. 1979. Elimination and tissue dis-
tribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female guinea
pigs following a single oral dose. Toxicol. Appl. Pharmacol. 48(1):A162.
NRCC. 1931. National Research Council of Canada. Polychlorinated Dibenzo-
p-Dixons: Criteria for Their Effects on Man and His Environment.
NRCC/CNRC Associate Committee on Scientific Criteria for Environmental
Quality, Ottawa, Canada. Publ. No. NRCC 18574, ISSN 0316-0114. 251 pp.
NTF. 1980. National Toxicology Program. Bioassay of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin for possible carcinogenicity (gavage study). Carcino-
genesis Testing Program, NCI, NIH, Bethesda, MD; NTP, Research Triangle
Par.K, N3. DHHS Publ. No. (NIH) 82-1 765.
Olson, J.R., and W.Z. Bittner. 1983. Comparative metabolism and elixinataor.
of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicologist. 3:103.
Olson, J.R., T.A. Gasiewicz and R.A. Neal. 1980a. Tissue distribution,
excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
in the Golden Syrian Hamster. Toxicol. Appl. Pharmacol. 56:78-85.
Olson, J.R., M.A. Holscher and R.A. Neal. 1980b. Toxicity of 2,3,7,8-tetra-
chlorodibenzo-p-dioxin in the Golden Syrian hamster. Toxicol. Appl.
Pharmacol. 55:67-78.
Olson, J.R., T.A. Gasiewicz, L.E. Geiger and R.A. Neal. 1983. The metabolisr.
of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mammalian systems. In: Acci-
dental Exposure to Dioxins: Human Health Aspects, R. Coulston, and
F. Pocchiari, Eds. Academic Press, NY. pp. 81-100.
Piper, W.N., R.Q. Rose and P.J. Ger.ring. 1973. Excretion and tissue distri-
bution of 2,3,7,8-tetrachlordibenzo-p-dioxin in the rat. Environ. Health
Perspect. 5:241-244,
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2,3,7,8-Tetrachlorodioenzo-p-Dioxin
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Poiger, H., and C. Schlatter. 1979. Biological degradation of TCDD in rats.
Nature. 281 (5733):706-707.
Poiger, H., and C. Schlatter. 1980. Influence of solvents and adsorbents
on dermal and intestinal absorption of TCDO. Food Cosmet. Toxicol.
18(5):477-481.
Poiger, H., and C. Schlatter. 1986. Pharmacokinetics of 2,3,7,8-TCDD in
man. Chemosphere. In press. Presented at the Fifth International
Symposium on Chlorinated Dioxins and Related Compounds. Final Programme.
September 16-21, 1985. Bayreuth, F.R.G.
Poiger, H., H. Weber and Ch. Schlatter. 1982. Special aspects of metabolism
and kinetics of TCDD in dogs and rats. Assessment of toxicity of TCDD-
metabolite(s) in guinea pigs. In: Chlorinated Dioxins and Related
Compounds. Impact on the Environment. 0. Hutzinger, R.W. Frei, E. Meriar.
and F. Pocchiari, Eds. Pergamon Press, NY. pp. 317-325.
Poland, A., and E. Glover. 1979. An estimate of the maximum in vivo covalent
binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rat liver protein,
ribosomal RNA and DNA. Cancer Res. 39(9):3341-3344.
Poland, A., and E. Glover. 1980. 2,3,7,8-Tetrachlorodibenzo-p-dioxin:
Segregation of toxicity with the Ah locus. Molec. Pharmacol. 17:86-94.
Rose, J.Q.,_ J.C. Ramsey, T.H. Wentzler, R.A. Hummel and P.J. Gehring. 1976.
The fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin following single and
repeated oral doses to the rat. Toxicol. Appl. Pharmacol. 36(2):209-226.
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the Environmental Protection Agency of the United States of America.
RICA.
Ryan, J.J., R. Lizotte and B.P-Y. Lau. 1985. Chlorinated dibenzo-p-dioxins
and chlorinated dibenzofurans in Canadian human adipose tissue. Cheno-
sphere. 14:697-706.
Sawahata, T., J.R. Olson and R.A. Neal. 1982. Identification of metabolites
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) formed on incubation with
isolated rat hepatocytes. Biochem. Biophys. Res. Commun. 105(1):341-346.
Schantz, S.L., D.A. Barsotti and J.R. Allen. 1979. Toxicological effects
produced in nonhuman primates chronically exposed to 50 parts per trillion
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chlorinated dibenzo-p-dioxins. Environ. Health Perspect. 5:87-99.
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Biochem. Pharmacol. 14:82-93.
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testing of herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and
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67:417-429.
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synthetic organic chemicals, occurrence in drinking water, food, and
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197
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March 31, 19?"
EPICHLOROHYDRIN
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking -ater. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or 2 carcinogens are correlated with carcinogenic risk estimates oy
employing a cancer potency (unit risk) value together with assumptions far
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually, derived from the linear multistage model with 95% upper
confidence limits. This .provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculatei
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that ars
derived can differ by several orders of magnitude.
198
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Lpichlorohycr
Karen 31, 19r ~
2-
This Health Advisory (HA) is based on information presented in the Offic
of Drinking Water's Health Effects Criteria Document (CD) for Epichlorohydnr.
(U.S. EPA, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is availab
for review at each EPA Regional Office of Drinking Water counterpart (e.g.,
Water Supply Branch or Drinking Water, Branch), or for a fee from the National
Technical Information Service, U.S. Department of/Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB #86-118023/AS. The toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
GENERAL INFORMATION AND PROPERTIES
CAS No. 106-89-8
Structural Formula
° l-Chloro-2,3-epoxypropane, 3-chloro1-1,2-epoxypropane, (chloromethyl)
oxirane, 2-(cnloromethyl) oxirane and chloropropylene oxide.
0 Used in the manufacture of: epoxide resins, surface active agents,
pharmaceuticals, and agricultural chemicals (Verschueren, 19S3).
Properties (U.S. EPA, 1985a)
Synonyms •
Uses
Molecular Formula
Molecular Weigr.t
P.iysical Sta.i
Boiling Point
Meltinc Point
Densi ty
Vapor Pressure
Specific Gravity
Water Solubility
Log Octanol/Water Partition
C3H5CIO
92.53
Colorless liquid
116.1°C
-57.2°C
66 g/L at 20#C
0.26
12 mm at 20°C
1.18 at 20°C
Coefficient
Taste Threshold
Odor Threshold
0.5 - 1.0 mg/L; 3 mg/L (Amoore and
Conversion Factor
Irritation Inresnold
Hautala, 1983)
1 mg/m3 = 0.265 ppm
1 ppm = 3.78 mg/m3
0.1 mg/L
L 99
-------
E.-cr. 1 o r or. yd ri r.
Mar:h 31, 19c"
-3-
Occurrenca
0 Total epichlorohydrin production in 1982 was approximately 350 mil-
lion pounds. Though epichlorohydrin reportedly hydrolyzes readily in
aqueous solution (hydrolysis half-life of 8.2 days at 20°C and pH 7)
to water soluble alcohols, its use in water treatment resins and
coatings make exposure possible (Mabey and Mill, 1978).
0 No information has been located in either State or Federal surveys to
indicate the presence or absence of epichlorohydrin in drinking water.
III. PHARMACOKINETICS
Absorption
0 Epichlorohydrin is absorbed readily following either oral, inhalation
or dermal exposures (U.S. EPA, 1985a).
0 Gingell et al. (1985) assessed the pharmacokinetics and metabolism
of epichlorohydrin in male Fischer 344 rats treated (6 mg/kg once by
gavage) with [2—14C] epichlorohydrin (98% pure) in water and sacrificed
after 3 days. Ready absorption was shown by an initial elimination
half-life of 2 hours and total excreta recovery of 91.61% of the
radiolabel.
0 Smith et al. ( 1 979) have reported the extensive absorption of epichloro-
hydrin in water by male Fischer 344 rats (190 to 220 g) following a
single gavage exposure. Based on excretion data, the extent of
absorption, approximately 100% within 72 hours after administration,
appeared to be similar following doses of' either 1 or 100 mg/kc b« .
° Stfith et al. (1979) indicated that epichlorohydrin was absorbed
readily oy .nale Fischer 344 rats (190 to 220 g) following a 6-ho-r
exposure to atmospheres containing 1 or 100 ppm epichloronydrin
(approximately 3.78 or 378 mg/m3). Uptake rates of 15.48 and 1394
ug./hr were calculated for exposures to 1 and 100 ppm, respectively.
The investigators stated that these exposures correspond to doses or
0.37 and 33 mg/kg bw.
0 Tne toxicity study of Kremneva and Tolgskaya (1961) indicates that
epichlorohydrin also is absorbed following dermal exposure. When the
tails of mice were immersed in epichlorohydrin either for a single
exposure of 1 hour or for repeated exposures of 20 to 30 minutes/day
on 2 to 3 successive days, toxic signs and death were observed within
3 days.
Distribution
0 In the study by Gingell et :1. (1985), 8-9% of 14C was in tissues,
with the highest levels (sp---ific activity, dpm x 10~3/g tissue wet
weight) in liver (177.5; 2.82% of dose), kidney (127.1; 0.41% of dose),
and forestorcach (81.6; 0.03% of dose).
200
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Epichlorohyjr:"
March 31, 191"
-4-
0 Smith et al. (1979) compared the distribution of [1,3-14c]-epichloro-
hydrin in male Fischer 344 rats following oral (100mg/kg bw) or
inhalation (100 ppm for 6 hours) exposure. At 3 hours post-exposure
in the oral study and at the termination of inhalation exposure, the
plasma levels of radioactivity were 36.1 and 18.3 mg/g, respectively.
Concentrations in tissues were expressed as ug equivalents of epi-
chlorohydrin per g of tissue. After oral treatment, the greatest
concentrations were in stomach, followed by intestine, kidney, liver,
pancreas and lung. Following inhalation exposure, the highest
levels were in nasal turbinates, followed by intestine, liver and
kidney.
Metabolism
° Gingell et al. (1985) concluded that the initial elimination half-
life of 2 hours indicated rapid metabolism in their study. Main
urinary metabolites were N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-
cysteine and K -chlorohydrin, representing 36 and 4% of the delivered
dose, respectively. One major metabolite' and 4 minor metabolites
were identified in urine. Ihese investigators stated that the presen
of the two dominant urinary metabolites is consistent with initial
metabolic reactions being conjugation of the epoxide with glutathione
and hydration of the epoxide.
0 Smith et al. (1979) administered [1,3-1^CJ-epichlorohydrin to male
Fischer 344 rats as single oral doses of 1 or 100 mg/kg bw or as
6-hour inhalation exposures to 1 or 100 ppm (approximately 3.78 or
378 mg/m3). Urinary metabolites were separated by ion-exclusion
chromatography. Seven radioactive peaks were found in the urine
following oral dosing and six radioactive peaks following inhalation
exposure, but none corresponded to epichlorohydrin. The authors
noted that the patterns of urinary metabolite excretion were similar
following oral or inhalational dosing; metabolites were not identifie
° Epichlorohydrin has two electrophilic centers and may bind to cellula
nucleopriles. It is also a substrate for epoxide hydratase resulting
in the formation of a'-chlorohydrin which may be oxidized to oxalic
acid, converted to glycidol or phosphorylated to 3-chloroglycero-
phosphate (U.S. EPA, 1985a). However, Gingell et al. (1985) did not
find oxalic acid as a metabolite in their study.
0 Rossi et al. (1983) found that epichlorohydrin rapidly disappeared
from the blood of CD1 mice, with a half-life of approximately five
minutes, with -chlorohydrin appearing as epichlorohydrin levels
dropped. &• -Chlorohydrin, however, had a much longer half-life for
disappearance (50-60 minutes).
Excretion
° In the study by Gingell et al. (1985), the half-life of initial
elimination of ^C in both urine and exhaled air was about 2 hours.
Approximately 38% of the radioactive dose was exhaled as CO2, 50% was
excreted as urinary metabolites, and 39% was eliminated in feces.
201
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° Smith et al. (1979) administered [1,3-14c]-epichlorohydrin by
single gavage doses of 1 or 100 mg/kg to groups of four male Fischer
344 rats. In parallel experiments, four rats were exposed (hea.i
only) to atmospheres containing 100 ppm (378 mg/m^) epichlorohydrin
for six hours. An additional three rats were exposed to atmospheres
containing 1 ppm (3.78 mg/m^) for six hours. The rates or routes of
excretion essentially were unaffected by either the route of exposure
or the dose administered. Urine was the major route of excretion,
accounting for 46% to 54% of the dose. Ai{ additional 25% to 42% was
recovered as ^C02 in the expired air. Only 3% to 6% of the dose was
recovered in the feces. Excretion^ was biphasic, with an initial
rapid phase that dominated the first^24 hours post-exposure and a
slower second phas^ that was dominant after 24 hours. The calculated
half-lives for elimination from the plasma were 1 to 2 hours and 26
to 27 hours for the fast and slow phases, respectively.
IV. HEALTH EFFECT;
Humans
0 In humans, acute effects have been reported following both dermal and
inhalation exposures (U.S. EPA, 1985a). Dermal exposure produces
predominantly local irritation effects, but inhalation produces
significant systemic effects, including hepatic and renal toxicity.
In one case report of a worker exposed to epichlorohydrin vapor,
systemic effects were evident for at least-2 years after the exposure.
(U.S. EPA, 1985a) Chronic exposure to epichlorohydrin has beers
associated with chromosome and chromatid breaks, decreased hemoglobir.
concentration, decreased erythrocyte counts and decreased leukocyte
counts. Increases (not statistically significant) in the mortality
du
-------
Lono-term Exdosuts
0 Epichlorohydrin given in drinking water at levels of 375, 750 ani
1,500 ppm (18, 39 and 89 mg/kg/day) to male Wistar rats for 81 wee>-.s
induced forestomach hyperplasia and decreased body weights at all
doses (Konishi et al., 1980).
0 With gavage administration of epichlorohydrin in water at doses of 2
and 10 mg/kg, 5 days/week for 104 weeks, stomach hyperplasia and a
dose-related decrease in white blood cells were observed in male and
female Wistar rats (Van Each. 1982).
N
8 Inhalation exposure of Fischer 344 rats, Sprague-Dawley rats,
B6C3F1 mice and New Zealand rabbits to epichlorohydrin at 19 mg/m3
for 90 days was without observable effect. Higher exposure levels
induced nasal irritation, eye irritation, kidney lesions and respirato
tract lesions (Quast et al., 1979; John et al., 1983).
0 Lifetime inhalation exposure of male Sprague-Dawley rats to 38 and
114 mg/m3 epichlorohydrin elicited kidney lesions (Laskin et al., 1980
Reproductive Effects
° Male and female Wistar rats were given epichlorohydrin in water start-
ing 10 days before mating and continuing for three months (Van Esch,
1981). A dose of 2 mg/kg was ineffective. A 10 mgAg dose reduced
fertility and crossmating with untreated rats attributed the antifsr-
tilitv effect to males. Sterility of male rats given epichlorohydrin
orally also was observed by Hahn (1970) and Cooper et al. (1974)
with gavage doses of 15 mgAg and higher for 1.5 and 5 days, respective
however, these investigators showed the effect to be reversible.
0 Exposure of male rats to epichlorohydrin by inhalation at levels above
19 mc/r-3 for 10 weeks resulted in reversible sterility, and the
fertility of male rabbits was unaffected by inhalation exposure
leveiu of epichlorohydrin as high as 189 mg/m3 (John et al., 19S3).
Developmental Effects
0 Epichlorohydrin was not teratogenic when given by gavage in cotton-
seed oil to pregnant CD rats and CD-1 mice on days 6 through 15 of
gestation (Marks et al., 1982). Doses above 40 mg/kg were maternally
toxic (reduced body weight, increased liver weight, death) in rats.
Doses above 80 mg/kg were maternally toxic (increased liver weight,
death) and fetotoxic (reduced body weight) to mice.
° Inhalation exposures of pregnant Sprague-Dawley rats and New Zealani
rabbits to 9.5 and 95 mg/m3 of epichlorohydrin during gestation days
6 through 15 (rats) and 6 through 18 (rabbits) were neither teratogeni
nor fetotoxic. Pregnant lats exposed to 95 mg/m3 weighed less than
controls (Pilny et al., 1979).
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Kutagemci ty
0 Epichlorohydrin is a mutagen in several systems (U.S. EPA, 1985a).
It is a potent inducer of base-pair substitution-type mutations m
prokaryotic systems. Incubation with mammalian liver homogenates
results in a marked reduction in mutation frequency. Epichlorohydrin
also induces gene mutations and very likely chromosomal aberrations
in mouse lymphoma cell cultures (Moore-Brown and Clive, 1979) and
clastogenesis in human lymphocytes in vitro (Norppa et al., 1981)
but not in rat liver cell cultures (Dean and Hodson-Walker, 1979).
Epichlorohydrin was found to induce sister chromatid exchange in
•cultured human lymphocytes (Norppa et al., 1981; Carbone et al.,
1981; White, 1980). Examination of occupationally exposed workers
indicates that chromosomal aberrations also occur in vivo (Picciano,
1979a,b; Kucerova et al., 1977; Sram et al., 1976).
° In in vivo studies, epichlorohydrin treatment results in an increase-
incidence of sex-linked recessive lethals in Drosophila when admini-
stered by injection, but not when incorporated in the food (Knap?
et al., 1982; Wurgler and Graf, 1981). In other in vivo studies,
epichlorohydrin has produced negative results in the mouse dominant
lethal assay (Epstein et al., 1972; Sram et al., 1976) and the mouse
micronucleus assay (Kirkhart, 1981; Tsuchimoto and Matter, 1981).
Ciastogenic effects of epichlorohydrin in bone marrow cells _in vivo
were found in mice (Sram et al., 1976) but not in rats (Dabney
et al., 1979).
Carcinogenicity
6 Epichlorohydrin is carcinogenic at the site of administration.
0 Administration of 375, 750 and 1,500 ppm epichlorohydrin in drinkin?
water [equivalent to 18, 39 and 89 mg/kg/day based on data by the
authors (total doses of 5.0, 8.9 and 15.1 g/rat during 81 weeks of
treatment divided by body weight)] to male Wistar rats for 81 wee'-.s
resulted in forestomach hyperplasia at all doses and papillomas and
carcinomas of the forestomach at the two highest doses (Konishi
e: al., 1931).
0 Lifetime gavage treatment of male and female Wistar rats with aqueous
epichlorohydrin solution at doses of 2 and 10 mg/kg induced papillomas
and carcinomas of the forestomach (Wester et al., 1985; Van Esch,
1982).
0 Laskin et al. (1980) found nasal carcinomas in male Sprague-Dawley
rats exposed to 378 mg/m^ of epichlorohydrin by inhalation 6 hours/da.-
5 days/week for six weeks followed by lifetime observation.
0 Subcutaneous injection of epichlorohydrin in ICR/Ha Swiss mice induced
local sarcomas; epic'nlorohy- in was effective as an initiator but not.
as a complete carcinogen on •_ne skin of ICR/Ha Swiss mice (Van Duuren
et. al., 1572; 1974).
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Epichloronydr:r
Karen 31, 19i
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicit;
The HAs for noncarcinogenic toxicants are derived using the following formal
HA = (NOAEL or LOAEL) x (BW) 0 mg/L { ug/L)
(OF) x ( L/day)
where:
NOAEL or LOAEL ¦ No- or Lowest-Observed-Adverse-Effect-Level
in mgAg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
v1 L/day) or an adult (2 L/day).
Organoleptic Properties
A reported tnreshold for odor perception of epichlorohydrin is 0.5 to
1.0 mg/L, and 0.1 mc/L was cited as the threshold for its irritant action by
the NAS (1980). Anoore and Hautala (1983) reported an odor threshold of 3
mg/L.
One-day Health Advisory
Because appropriate data for calculation of a One-day HA are not avail-
able, tne Ten-day HA (0.1 •*. mg/L) is recommended for use as the One-day Hi.
Ten-day Health Advisory
The reproductive toxicity study by Van Esch (1981) can be used to deriv
the Ten-day HA. In this study, male and female rats were given epichloro-
hydrin by gavage 5 days/week at doses of 0, 2 or 10 mgAg« Exposure was
started 10 days prior to mating and continued until the generation was
produced. The fertility index at the first mating was reduced in the high-
dose group but not in the low-dose group. The study of Hahn (1970) which
reported infertility in male rats exposed by gavage to epichlorohydrin at
15 mg/kg/day for 12 days supports an assumption that at least a portion of
the reduced fertility index observed by Van Esch (1981) was the result of
infertility in the males associated with the ten-day exposure prior to matim
In this study, 2 mg/Kc was a NOAEL for reproductive effects and is appropria
for use in derivi ng the Ten-day H. .
Using the NOAEL of 2 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as fellows:
205
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Eoic'".Lcro".
March 31, 19="
-9-
Ten-day HA = 2 ^ppf'ffi^/day)^ (7) = °'14 ^ (14° U9/U
where:
2 n»g/kg/day = NQAEL based on absence of reproductive toxicity in rats.
10 kg = assumed body weight of a child.
5/7 = conversion of dose to represent continuous exposure
(7 days per week).
1 L/day = assumed daily water consumption of a child.
Although the antifertility effect in male rats in the Van Esch (1981)
study relates to men as a specific sensitive sufcpcpulation for this effect,
this study is preferred for the calculation of a Ten-day HA for the general
population because of its design with oral short-term exposure and its
demonstration of no-effect and effect levels. Additionally, the 2 mg/kg
NOEL in the Van Esch (1981) study appears consistent with the dose responses
in the overall Van Esch (1931) work where both systemic and reproductive
effects were found with 10-day oral exposures to 10 mg/kg of epichlorohydrin.
Longer-term Health Advisory
There are insufficient data for calculation of a Longer-term HA. Tne
D.EL (0.07 r.g/L), is recommended as a conservative estimate of the Longer-terrr.
HA.
Lifetime Health Advisors--
The Lifetime H-. represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. Tne Lifetime H-.
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived fror-.
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consunption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. Tf the contaminant is classified as a
Group A or 3 carcinogen, according t. the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
206
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¦.z 1 <
-icro.v:: n:
Marcn 31, l=r;
-1 0-
Of the reviewed studies in which the effects of long-terra exposure to
epichloronydrin were investigated (Laskin et al., 1980; Konishi et al., 198".,
also reported by Kawabata, 1981; Wester et al.', 1985, also reported by Van Esc..,
1982), the Laskin et al. (1980) study was selected as the most appropriate
from which to derive the DWEL. Forestomach hyperplasia in all three treatment
groups and papillomas and carcinomas of the forestomach in the two highest
dose groups were found in the study by Konishi et al. (1980). Since the
hyperplasia could be considered a pre-neoplastic effect and the progression
of forestomach lesions beyond the 81-week duration of this study is uncertain,
it would be questionable to use this effect in the low-dose group (18 mgAg/day )
for calculating a DWEL for drinking water exposure. Dose-response for
toxicity/carcinogenicity in the Konishi et al. (1980) drinking water study
is given preference over that in the bolus gavage dosing study "By Wester, et
al. (1985), and use of the estimated 2.16 mg/kg/day dose in the Laskin, et
al. (1980) study is concluded to be consistent with the dose-response indicated
by the Konishi et al. (1980) study. The LOAEL based on renal damage of 2.16
mg/kg/day estimated from the data in the Laskin et ale (1980) study was,
therefore, used to derive a DWEL. Additionally, carcinogenic effects were
not apparent at the LOAEL in the Laskin et al. (1980) study. Using this
LOAEL, the OWEL is derived as follows:
Step 1s Conversion of Inhalation Exposure to.Oral Exposure
Applying the 38 mg/m3 inhalation LOAEL in the Laskin et al. (1980)
study and the assumptions in U.S. EPA (1985a) for converting inhalation
exposure to oral exposure for the rat, the estimated oral dose would be:
(38 nig/ir.3 ) (0.0093 m3/hr)(6 hr/day) (5 ) (0.5 )
(0.35 kg) (7)
2.16 mg/kg/day
where:
38 nig/:: 3 = LOAEL based on kidney toxicity in rats.
0.0092 r3 = amount of air breathed by a rat/hour.
6 nr/da/ = a 6-hour exposure each day.
5/7 = adjust from a 5 days/week exposure -to 7 days/week,
0.5 = the assumed inhalation absorption factor.
0.35 kg = the assumed weight of a rat.
Step 2: Determination of the Reference Dose (RfD)
RfD = (2-16 mg/kg/day) =» 0.002 mg/kg/day (2 ugAg/day)
(1,000)
where:
2.16 mg/kg/day = LOAEL based on kidney toxicity in rats.
1,000 = uncertainty factor, chosen in accordance with NAS/0DW
guidelines for use with a LOAEL from an animal stud;.
207
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Marcr. 2'., 1 i-
-1 1-
Step 3: Decermi nation of the Drinking Water Equivalent Level (DWr.~)
DWEL = (0-002 mg/kg/day) (70 kg) = 0#07 mg/L (70 ug/L)
(2 L/day)
0.002 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
f
2 L/day = assumed daily water consumption of an adult.
Epichlorohydrin may be classified in Group B: Probable human carcinogen.
Hie estimated excess cancer risk associated with lifetime exposure to drinking
water containing epichlorohydrin at 70 ug/L is approximately 2 x 10-5. This
estimate represents the upper 95% confidence limit from extrapolations prepares
by EPA's Carcinogen Assessment Group using the linearized, multistage model.
The actual risk is unlikely to exceed this value, but there is considerable
uncertainty as to the accuracy of risks calculated by this methodology.
Evaluation of Carcinogenic Potential
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), epichlorohydrin may be classified
in Croup E2: Probable human carcinogen. This category is for agents
for which there is inadequate evidence from human studies and
sufficient evidence from animal studies.
0 The study of Konishi et al. (1980) provides appropriate data for a
quantitative risk assessment based on the relevant route of exposure
and the observed dose-response pattern. Using the calculated of
9.5 x 10~2 (mg/kg/day)"1, the 95% upper-limit lifetime dose associate;:
witri a 10-5 risk level may be calculated to equal 70.7 ug/day.
Assuring an average water consumption of 2 L/day, this risk level
corresponds to a water concentration of 35.4 ug/L. Corresponding
levels for 10"° and 10"4 are 3.54 and 354 ug/L, respectively.
° Maximun likelihood estimates as well as 95% upper limits of car.ce:
risks by the multistage model have been calculated (U.S. EPA, 195-4).
For example, at 10 ug/L cancer risk estimates are 1.4 x 10"17 (MLHli
and 2.8 x 10-6 (UL) and at 100 ug/L cancer risk estimates are 2.6 >:
10-14 (MLE) and 2.8 x 10-5 (UL).
0 The EPA's Carcinogen Assessment Group has estimated cancer risks wit.
other models besides the multistage (U.S. EPA, 1984). As an example,
10 uc/L lifetime exposure was associated with additional risks (95%
upper confidence limit) of 2.8 x 10-5 by the multistage, 3.4 x 10--
by the one-hit, 0 by the Weibull, and 0 by the log-probit. While
recognized as statistically alternative approaches, the range of
risks described by using any of these modeling approaches has little
biological significance unless data can be used to support the seler-
tion of one model over anot r. In the interest of consistency of
approach and in providing ar. upper bound on the potential cancer ris'-:,
tne E?A has recommended use of the linearized multistage approach.
208
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-1 2-
0 Epichloronydrin is classified as a 2B carcinogen by IARC (1982) w:;r.
sufficient animal evidence and inadequate human evidence.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The NAS (1980) SNARLs (Suggested-No-Adverse-Response-Levels) for
1- or 7-day exposures to epichlorohydrin are 0.84 and 0.53 mg/L,
respectively. An ADI (Acceptable Daily Intake) or a cancer risk was
not calculated by the NAS (1980).
0 The ACGIH has recommended a TLV (Threshold Limit Value) of 2 ppm
(10 mg/m^) (ACGIH, 1982). Current OSHA standards allow a TWA occupa-
tional exposure of 19 mg/m3 (29 CFR 1910.1000); however, they are
currently considering lowering this value to 0.5 ppm (2 mg/ir>3) with
a ceiling value of 15 ppm (60 mg/m3) for 15 minutes. Occupational
standards in other countries range from 0.26 ppm in Russia and
Czechoslovakia to 3.6 ppm in the Federal Republic of Germany (Sran,
et ai., 1980).
0 Epichlorohydrin has not been regulated under the Safe Drinking Water
Act; however, discharge of >1,000 pounds (454 kg) into navigable
waters is prohibited under the Clean Water Act (40 CFR 116).
0 Epichloronydrin is also classified as a "hazardous waste" by the U.S.
EPA and quantities exceeding 100 kg must be disposed of in a special
landfill (40 CFR 261; 40 CFR 122).
0 The proposed RMCL by the U.S. EPA Office of Drinking Water is zero
(U.S. EPA, 1985b).
ai. ANALYTICAL METHODS
0 Tnere is no standardized method for the determination of epichloro-
hydrin in drinking water samples. However, epichlorohydrin may be
determined by a purge-and~trap gas chromatographic/mass spectrometry
procedure used for the determination of volatile organic compounds
in water (U.S. EPA, 1985c). This method calls for the bubbling of
an inert gas through the sample and trapping epichlorohydrin on an
adsorbent material. The adsorbant material is heated to drive off
epichlorohydrin onto a gas chromatographic column. The gas chromatc-
graph is temperature programmed to separate the method analytes which
are then detected by the mass spectrometer.
CII. TREATMENT TECHNOLOGIES
0 No data are available on the removal of epichlorohydrin from potable
water by any treatment te nique (ESE, 1984; U.S. EPA, 1985d).
0 Tne amenability of epichlorohydrin to removal by conventional treat-
ment cr by adsorption is not known. The Henry's Law Constant for
209
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epichlorohydrin has been estimated to be 2.44 x 1 G~5 atm x m^/tr.oie
(ESE, 1984). This -value suggests that aeration is unlikely to be a
successful removal technique for epichlorohydrin. It also has been
concluded that epichlorohydrin would not be removed from water by
ozone oxidation (U.S. EPA, 1985d).
210
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£.o.cnioronvanr:
March
1 9i
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XX. REFERENCES
ACGIH, 1982. American .Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical agents in
the workroom environment. Cincinnati, Ohio.
Amoore, J.E., and £. Hautala. 1983. Odor as an aid to chemical safety:
Odor threshold compounds with threshold unit,values and volatilities for
214 industrial chemicals in air and water dilution. J. Appl. Toxicol.
3:272-290.
Carbone, P., G. Barbata, G. Margiotta, A. Tomasino and G. Granata. 1981.
Low epichlorohydrin concentrations induce sister chromatid exchanges in
• human lymphocytes in vitro. Caryologia. 34(3):261-266.
40 CFR 116. Code of Federal Regulations.
40 CFR 122. Code of Federal Regulations.
40 CFR 261. Code of Federal Regulations.
Cooper, E.R., A.R. Jones and H. Jackson. 1974. Effects of alpha-chlorohydrir.
and related compounds on the reproductive organs and fertility of the
male rat. J. Reprod. Fert. 39(2)s379-386.
Dabney, B.J., R.v. Johnston, J.F. Quast and C.N. Park. 1979. Epichlorohydri r.
— Subchronic studies. III. Cytogenetic evaluation of bone marrow
cells fros rats exposed by inhalation to epichlorohydrin for four weeris.
ICPEM (International Commission for Protection Against Environmental
Mutagens and Carcinogens) Document No. 128. 15 pp.
Dean, B.J., and G. Hoason-Walker. 1979. An in vitro chromosome assay usinc
cultjred rat-liver cells. Mutat. Res. 64:329-337.
E3S. 1 SS-,. E.-.v-ronnencal Science and Engineering. Review of treatabi.li t.
data for removal of twenty-five synthetic organic chemicals frorr. dnr.ur.:
water. U.S. EPA. Office of Drinking Water.
Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop. 1972. Detection
of chemical mutagens by the dominant lethal assay in the mouse. Toxicol.
Appl. Pharmacol. 23:288-325.
Gingell, R., H.R. Mitschke, I. Dzidic, P.W. Beatty, V.L. Sarvin and A.C. Pace.
1985. Disposition and metabolism of [2-14C] epichlorohydrin after oral
administration to rats. Drug Metab. Dispos. 13:333-341.
Hahn, J.D. 1970. Post-testicular antifertility effects of epichlorohydrin
and 2,3-epoxypropar.ol. Nature (London). 226:87.
IARC 1982. International Agency f r Research on Cancer. IARC monographs
on the evaluation of the carcinogenic rice of chemicals to humans.
Chemical Industrial Processes and Industries Associated with Cancer in
Humans. Suppl . 4, pp. 1 22-1 23.
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l 9='
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John, J.A., J.F. Quast, F.J. Murray, L.S. Calhoun and R.E. Staples. 1 963.
Inhalation toxicity of epichlorohydrin: Effects on fertility in rats
and rabbits. Toxicol. Appl. Pharmacol. 68:415-423.
Kawabata, A. 1981. Studies on the carcinogenic activity of epichlorohydrin
by oral administration in male Wistar rats. J. Nara Med. Assoc.
32:270-280.
Kirkhart, B. 1981. Micronucleus test on 21 compounds. _lE: Evaluation of
Short-Term Tests for Carcinogens, F.J. deSerres and J. Ashby, eds.
Elsevier/North Holland, Amsterdam, pp. 698-704.
Knapp, A.G.A.C., C.E. Vood? and P.G.N. Kramers. 1982. Comparison of the
mutagenic potency of 2-chloroethanol, 2-bromoethanol, 1,2-epoxybutane
epichlorohydrin and glycidaldehyde in Klebsiella pneumoniae, Prosophilia
melanoaaster and L5178Y mouse lymphoma cells. Mutat. Res. 101:199-208.
Konishi, T., A. Kawabata, A. Denda et al. 1980. Forestomach tumors induced
by orally administered epichlorohydrin in male Wistar rats. Gann.
71:922-923.
Kremneva, S.N., and M.S. Tolgskaya. 1961. Toxicology of epichlorohydrin.
Toksikol. Nov. Prom. Khim. Veschestv. 2:28-41.
Kucerova, M., v.s. Zhurkov, Z. Polwkova and J.E. Ivanova. 1977. Mutagenic
effect of epichlorohydrin. II. Analysis of chromosomal aberrations in
lymphocytes of persons occupationally exposed to epichlorohydrin.
Mutat. Res. 43:355-360,
Laskin, S., A.R. Sellakumar, M. Kuschner et al. 1980. Inhalation carcino-
genicity of epicr.lorohydrin in non-inbred Sprague-Dawley rats. J. Natl.
Cancer Inst. 65(4):751-758.
Mabey, w., and T. Mill. 1 978. Critical review of hydrolysis of organic com-
pounds in water under environmental conditions. J. Phys. Che.-. Ref. Oat;.
7:365-4"5.
Marks, T.a., F.S. Gerling and R.E. Staples. 1982. Teratogenic evaluation
of epichlorohydrin in the mouse and rat and glycidol'in the mouse.
J. Toxicol. Environ. Health. 9:87-96.
Moore-Brown, U.K., and D. Clive. 1979. The L5178Y/TK+/- mutagen assay
system: In situ results. Banbury Report. 2:71-88.
NAS. 1980. National Academy of Sciences. Drinking Water and Health.
Volume 3. National Academy Press. Washington, D.c. pp. 111-124.
Norppa, H., K. Hem-iinki, M. Sorsa and H. Vainio. 1981. Effect of mono-
substituted epoxides on chromosome aberrations and SCE in cultured human
lympnocytea. Mutat. Res. 91:<33-250.
Picciano, D. 1979a. Cytogenic investigation of occupational exposure to
epichlorohydrin. Mutat. Res. 66:169-173.
212
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£.3lc.'.j.oro".
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Picciano, D. 1979b. Faulty experimental design and underutilization of
cytogenetic data. Benzene and epichlorohydrin. Ann. NY Acad. Sci.
329:321-327.
Pilny, M.K., T.S. Lederer, J.S. Murray, et al. 1979. Epichlorohydrin sub-
chronic studies. IV. The effects of maternally inhaled epichlorohydrin
on rat and rabbit embryonal and fetal development. Unpublished report.
Toxicol. Res. Lab., Health Environ. Sci., Dow Chemical U.S.A., Midland, Ml•
Quast, J.F., J.W. Henck, B.J. Pastma, O.J. Scheutz and M.J. McKenna. 1979.
Epichlorohydrin subchronic studies. I. A 90-day inhalation, study in
laboratory rodents (Fischer 344 rats, Sprague-Dawley rats, and B6C3Fi
mice). Dow Chemica] U.S.A., Midland, MI. 166 pp.
Rossi, A.M., D. Migliore, D. Lascialfari, I. Sbrana and N. Loprieno. 1983.
Genotoxicity, metabolism, and blood kinetics of epichlorohydrin in mice.
Mutat. Res. 118:213-226.
Smith, F.A., P.w. Langvardt and J.D. Young. 1979. Pharmacokinetics of
epichlorohydrin (EPI) administered to rats by gavage or inhalation.
Dow Chemical U.S.A., Toxicology Research Laboratory, Midland, MI. 52 pp.
Sram, R.J., M. Cerna and M. Kucerova. 1976. Uie genetic risk of epichloro-
hydrin as related to the occupational exposure. Biol. Zbl. 95:451-462.
Sram, R.J., 2. Zudova and N.P. Kuleshovo 1980. Cytogenic analysis of peri-
pheral lymphocytes in workers occupationally exposed to epichlorohydrin.
Mut. Res. 70:1 1 5-1 20.
Tsuchimoto, T., and B.E. Matter. 1981. Activity of coded compounds in the
micronucleus test. _In: Evaluation of Short-Term Tests for Carcinogens,
F.J. Seeres and J. Ashby, eds. Elsevier/North Holland, Amsterdam.
pp . 705-71 1.
U.S. EPA. 1954. U.S. Environmental Protection Agency. Health assess^e--,
document for epichlorohydrin. Final report. Office of Health and
Environments! Assessment. Washington, D.C. EPA-600/8-83-032F.
U.S. EFA. 1985a. U.S. Environmental Protection Agency. Drinking water
criteria document for epichlorohydrin. Final Draft. Office of Drinking
Water. Washington, D.C. ECAD^FN-413.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. National primary-
drinking water regulations; Synthetic organic chemicals, inorganic
chemicals and microorganisms; Proposed rule. Federal Register.
50(219):4693-47002. November 13.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography.'
mass spectrometry. Environme-.tal Monitoring and Support Laboratory,
Cincinnati, Ohio 45263.
213
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U.S. EPA. 1 985d. U.S. Environmental Protection Agency. Technologies a.-.;
costs for removal of organic chemicals from potable water supplies.
Draft. Science and Technology Branch, CSD, ODW, Washington, D.C.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register 51(185):33992-34003.
September 24.
•Van Duuren, B.L., C. Katz and B.M. Goldschmidt. 1/972. Direct-acting alkyl-
ating carcinogens ~ Chloro ethers and related compounds. Toxicol.
Appl. Pharmacol. 22:279-280.
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Carcinogenic activity of alkylating agents. J. Natl. Cancer Inst.
53:695-700.
Van Esch, G.J. 1981. Induction of preneoplastic lesions in the forestomach
of rats after oral administration of 1-chloro-2,3-epoxypropane. I.
Range finding studies. Prepared by Ryksinstitute Voor De Volksgezondhelri
Bilthoven Rapport nr. 627805 005.
Van Esch, G.J. 1982. Induction of preneoplastic lesions in the forestomach
of rats dfter oral administration of 1-chloro-2,3-epoxypropane. II.
Carcinogenicity study. Prepared by Ryksinstitute Voor De Volksgezondheld
Bilthoven Rapport nr. 627805 005.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals.
2nd ed. Van Nostrand Reinhold Co., NY. pp. 611-613.
Wester, P.W., C.A. Van Der Heiden, A. Bisschop, and G.J. Van Esch. 19S5.
Carcinogenicity study with epichlorohydrin (CEP) by gavage in rats.
Toxicol. 36:325-329.
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Mutat. Res. 78:171-176.
Wurgler, F.E., and U. Graf. 1981. Mutagenic activity of ten coded compound®
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Holland, Amsterdam, pp. 666-672.
214
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ETHYLBENZENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible' for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as nev information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Kealtn Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probaole
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates b:'
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer, unit
ns-: is usual!;- derived from the linear multistage model with 95% upper
confidence li-.its. Tnis provides a low-dose estimate of cancer risk to
.humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculate.:
using the One-hit, Weibull, Logit or Probit models. There is no current,
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
215
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Etnvloenzer.e
1ar:ii 3", 1
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This Health Advisory is based on information presented in the Office of
Drinking Water's Health Effects Criteria Document (CD) for Ethylbenzene (U.S.
EPA, 1985a). The HA and CD formats are similar for easy reference. Individua
desiring further information on the toxicological data base or rationale for
risk characterization should consult the CD. The CD is available for review
at each EPA Regional Office of Drinking Water counterpart (e.g«, Water Supply
Branch or Drinking Water Branch), or for a fee from the National Technical
Information Service, U.S. Department of Commerce, 5285 Port Royal Rd.,
Springfield, VA 22161, PB # 86-117835/AS. The toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
GENERAL INFORMATION AND PROPERTIES (Verschueren, 1983; Amoore and Hautala, 19S
Chemical Name Ethylbenzene
Cas No. 100-41-4
Chemical Structure
Styrene manufacture
Acetophenone manufacture
Solvent
Aspnalt constituent
Napt'na constituent
Synonyms
Phenyl ethane, ethvlbenzol, EB
Uses
Properties
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Log Octanol/Water Partition
106.1 8
Colorless liquid
136.2°C
-94.97°C
7 mm at 20°C
152 mg/L (at 20°C)
3.15
Coefficient
Taste Threshold (water)
Odor Thresnold (water)
Odor Tnreshold (air)
Conversion Factor
0.029 mg/L
0.029 mg/L
0.062 mg/L
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Ma re p.
J1 , iv.
-3-
Occurrence
0 Ethylbenzene, a clear, flammable liquid found in gasoline, -is produced
commercially by the alkylation of benzene with ethylene. In 1982,
the U.S. production of ethylbenzene totaled 3.3 million tons.
0 Very little information is available on the occurrence of ethylbenzene
in 12,000 drinking water supplies in the U.S. drawing water from
surface rivers and streams. However, the testing of 945 ground water
supplies has revealed that approximately 0.6 % contain ethylbenzene.
lhe median concentration detected in "non random" segment of the
study was 0.87 ug/L (Westrick et al., 1983).
II. PHARMACOKINETICS
Absorption
° Data regarding the absorption of ethylbenzene from the gastrointestinal
tract of humans following oral ingestion could not be located.
° Since approximately 90% of an oral dose of ethylbenzene (1.78 g/rabbit)
is excreted as metabolites (El Masry et al., 1956), the chemical is
readily absorbed in rabbits.
° For human volunteers exposed by inhalation to ethylbenzene for 8 hours
at 100, 187, 200 or 370 mg/m3, the average percent of vapor absorbed
(measured spectrophotometrically) through the respiratory tract was
64% (Bardoce] and Bardodejova, 1970).
0 Absorption of an aqueous solution of ethylbenzene through human hand s'.i
(10s.3 to 113.9 mg/L for 1 to 2 hours) was equivalent to 118 ug/cm^/ho-r
(Dutkiewi-z and Tyras, 1967).
Distribution
0 Following a 6-hour inhalation exposure at 1 mg/m3, absorbed ethylbenzene
is distribjted throughout the body in rats. However, the highest
levels were detected in the kidney, lung, adipose tissue, digestive
tract and liver (Chin et al., 1980).
Metabolism
° After inhalation exposure, ethylbenzene undergoes rapid metabolism
in humans, primarily to form mandelic acid and phenylglyoxylic acid.
These two metabolites accounted for 64% and 25%, respectively, of the
absorbed dose in humans (Bardodej and Bardodejova, 1970). Formation
of minor metabolites including methylphenyl carbinol and 2-ethylphencL
accounted for approximately 5% and 1%, respectively, in'humans (Baraode;
and Bardoaeiova, 1370; Angerer and Lehnert, 1979).
0 The major metabolites formed in humans and rats are not the same.
Mandelic acid and phenylglyoxylic acid constitute 64 and 25% of tne
metabolites in humans (Bardodej and Bardodejova, 1970), while in
217
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r-tnyioenzens.
March 31} 19:~
-4-
rats, 1-phenylethanol (25%), benzoic acid (27%) and mandelic acxc
(25%) are the main metabolites (Engstrom, 1985).
Excretion
0 Urinary excretion of metabolites by rabbits was reported to be
complete within 24 hours after oral dosing with 1.78 grams/rabbit
(El Masry et al., 1956).
0 In humans, most of the inhaled dose was eliminated in the urine
within 24 hours after exposure was terminated (Engstrom and BjurstroT
1978; Hagemann and Angerer, 1979).
HEALTH EFFECTS
Humans
0 In experiments with human volunteers, an 8-hour inhalation exposure
to ethylbenzene at a concentration of 100 ppm (435 mg/m^) did not
result in adverse health effects (Bardodej and Bardodejova, 1970).
Increasing this level (increase not specified) resulted in sleepiness
fatigue, headache and mild eye and respiratory irritation.
Animals
Short-term Exposure
6 Estimated acute LD5Q values of 3.5 g/kg to 5<>46 g/kg were reported in
rats (Wolf et al., 1956; Smyth et al., 1962).
0 An acute dermal LD50 value of 17.8 ml/kg (approximately 15,400 mg/kg)
was reported in rabbits (Smyth et al., 1962).
0 Ar. i.-inald .ior. exposure of 4,000 ppn (approximately 17,400 mg/.T.3) f :v
four hours was lethal to 3 of 6 rats (Smyth et al., 1962).
0 During ld^q studies systemic toxic effects were observed predominant!
in the liver and kidney (Wolf et al., 1956) and central nervous systs
(Faustov, 1958).
0 Other acute effects include irritation of the conjunctiva (Wolf et al
1956) and slight necrosis of the cornea (Smyth et al., 1962).
Long-term Exposure
0 Liver and kidney effects were observed in rats (10 females/dose)
exposed orally to ethylbenzene in olive oil for six months (Wolf
et al., 19bb). uoses of 408 and 680 mgAg/day caused increases in
liver and Kidney weights, and cloudiness and swelling of hepatocytes
and renal tubular epithelium. No effects were observed in rats
exposed to 13.6 and 136 mg/kg/day.
0 No cnronic exposure studies were identified in the available literata
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March 31, is
-5-
Resroauctive Effects
0 No studies on the effects of ethylbenzene on reproduction were located
in the available literature.
Developmental Effects
0 Ethylbenzene did not elicit embryotoxicity, fototoxicity or terato-
genicity in inhalation studies at concentrations up to 1,000 ppm
(4,348 mg/m3) in rats and rabbits for 6 to 7 hours/day on days 1 to
19 and 1 to 24 of gestation, respectively (Hardin et al., 1981).
0 Femal^ rats exposed at 1,000 ppm had increased liver, kidney and
spleen weights suggestive of maternal toxicity. Biere was no maternal
toxicity observed when the rats were exposed to 100 ppm of ethylbenzene.
(Hardin et al., 1981).
Mutagenicity
0 No mutagenic activity was detected in S_. typhimurium strains TA98,
TA100, TA1535, TA1537 following ethylbenzene exposure both with and
without metabolic activation in plate assays at concentrations up to
3 mg/plate (Florin et al., 1980; Nestmann et al., 1980).
0 Dean et al. (1985) reported that ethylbenzene (0.2 to 2,000 ug/plate)
did not induce mutations in bacteria, gene conversion in yeast or
chromosome damage in rat liver (RL4) epithelial cells.
0 In the Drosophila recessive lethal test, ethylbenzene did not increase
the frequency of recessive lethals (Donner et al., 1979).
Carcinogenici ty
0 Pertinent data on the carcinogenic potential of ethylbenzene were not
identified in the available literature. An NCI bioassay is in the
planning stage.
V. QUANTIFICATION' OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = '(NOAEL or LOAEL) x (BW) = /L ( /L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mgAg bw/day.
219
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Etnylbenzene
.'¦larch 3'
1 9:
-6-
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day - assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
Ho adequate dose-response data exist using the oral route of exposure
from which to calculate a One-day Health Advisory. Therefore, the derivation
of the one-day level is bas$d upon a 100 ppm (435 mg/m3) NOAEL identified in
18 human male volunteers following a single 8-hour inhalation exposure as
conducted by Bardodej and Bardodejova (1970). An inhalation absorption
efficiency of 64% is used, based on data from that study (Bardodej and
Bardodejova, 1970).
The total absorbed dose and the One-day HA for a 10 kg child are
calculated as follows:
Step 1: Determination of Total Absorbed Dose (TAD)
TAD = (435 mg/m3) (8 m3/day) (0.64) , 31,8 mgAg/day
(70 kg) * y
Step 2: Determination of One-day HA
One-dav HA = (31.8 mg/kq/day) (10 kg) = 32 mg/L (32000 ug/L)
(10) (1 L/day)
where:
435 mg/m3 = NOAEL based on absence of effects in humans following
inhalation exposure.
8 m3/day ¦= assumed volume of air inhaled per daily 8-hour exposure.
0.64 a absorption efficiency reported by Bardodej and Bardodejova
(1970).
70 kg = assumed body weight of an adult.
10 kg = assumed body weight of a child.
2 L/day = assumed daily water consumption of an adults
1 L/day = assumed daily water consumption of a child.
10 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from a human study•
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itnyloenzeTe
-7-
Ten-day Healtn Advisory
Because of the lack of appropriate exposure duration data, the ten-day
HA will be calculated from the One-day HA. The One-day HA will be divided by
10 to give estimated Ten-day HA values. The resulting Ten-day HA for a child
is as follows:
Ten-day HA = 32^mg/L - 3.2 mg/L f3,200 ug/L)
Longer-term Health Advisory
There are insufficient data to calculate a Longer-term HA. It is
recommended that the DWEL, adjusted for 10 kg, be used as a conservative
estimate for a longer-term exposure.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step processc Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the noael (or loael), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (io.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. Tne Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 13==
is assuned for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised it.
assessing the risks associated with lifetime exposure to this chemical.
The study by Wolf et al. (1956) has been determined to be the most
appropriate for derivation of the Lifetime Health Advisory. Rats were
administered oral gavage doses of 13.6, 136, 408 or 680 mg/kg/day ethylbenzene
in olive oil for 130 days of the 182-day test period. A vehicle control of
olive oil (2.5 ml) was run concurrently. No effects were noted in groups of
rats exposed at 13.6 and 136 mg/kg/day. Increases in liver and kidney weights
were reported following oral administration of 408 or 680 mgAg/day. There
were also slight histopathological changes at these dose levels. These
included cloudiness and swelling of hepatocytes and renal tubular epitheliur.
From these results, a NOAEL of 136 mg/kg/day was identified.
A Drinking Water Equivalent Level (DWEL) and Lifetime Health Advisory
are calculated as follows:
221
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Ethylbenzene
March 31, "19
Step 1: Determination of the Reference Dose (RfD)
RfD = (136 mq/kq/day) (5) = 0<097 mgAg/day
(1,000) (7)
where:
136 mgAg/day » NOAEL for absence of renal and hepatic effects _in
rats exposed for 130 days.
5/7 - conversion of 5 days/week dosing regimen to continuous
7 days/week exposure pattern.
1,000 » uncertainty factor, chosen in accordance with NAS/ODn
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 2: Determination of the Drinking Hater Equivalent Level (DWEL)
DWEL - (0.097 mg/kq/day)(70 kg) - 3,4 mg/L (3|400 ug/L)
(2 L/day)
where:
0.097 mg/kg/day ¦ RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the' Lifetime Health Advisory
Lifetime HA = (3.4 mg/L) (20%) = 0.68 mg/L
where:
3.4 mg/L = DWEL.
20% 3 assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 Because of the lack of data, an assessment of the carcinogenic risk
of ethylbenzene is not possible at this time.
0 The International Agency for Research on Cancer has not classified
ethylbenzene in any of its categories of carcinogenic potentials
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogen risk (U.S. EPA, 1986), ethylbenzene is classified in
Group L: not classified. This category is for agents with inadequate
animal evidence of carcinogenicity.
9 9 9
At **
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Etnylbenzene
March ji, ia:
-9-
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 Tne American Conference of Government Industrial Hygienists has
recommended an occupational standard (TWA) in air and TLV of 100 pp-
(435 mg/m3; ACGIH, 1980).
0 EPA/ODW has proposed a RMCL of 0.68 mg/L (CJ.S. EPA, 1985e).
VII. ANALYTICAL METHODS
0 Analysis of ethylbenzene is Jiy-«-purge-and-trap gas chromatographic
procedure used for the determination of volatile aromatic organic
compounds in water (U.S. EPA, 1985b). This method calls for the
bubbling of an inert gas through the sample and trapping ethylbenzene
on an adsorbant material. The adsorbant material is heated to drive
off ethylbenzene onto a gas chromatographic column. The gas chroma to
graph is temperature programmed to separate the method analytes which
are then detected by the photoionization detector. This method is
applicable to the measurement of ethylbenzene over a concentration
range of 0.02 to 1500 ug/L. Confirmatory analysis for benzene is by
mas-s spectrometry (U.S. EPA, 1985c). The detection limit for
confirmation by mass spectrometry is 0.2 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Aeration appears to offer the best potential for removing ethylbenzene
from contaminated water. Ethylbenzene has a high Henry's Law Constant
of 35 atm (U.S.- EPA, 1985d). •
° In ao actual packed aeration column (PAC) pilot testing program,
ethylbenzene removal efficiencies ranged from 71.8 to >99.8% (U.S.
EPA, l9S5d). The column used had a one foot diameter and was packed
with Tripack packing material (#2). Influent concentrations of
ethylbenzene ranged from <1 to 200 ug/L. Air-to-water ratios varied
from 10:1 to 126:1. Liquid loading rates varied from 12.7"to 50.9
gpm/ft2. Ambient water temperature was 70°F. Removal efficiencies
were >90% for all test runs but one. In this single exception, an
efficiency of 71 „8% was obtained. In this test run the ethylbenzene
concentration was high (200 ppb) and the air-to-water ratio low -
10:1 (U.S. EPA, 1985d).
0 A field test of PAC also was conducted on water contaminated by a
gasoline spill (Cummins, 1985). Several benzene derivatives including
ethylbenzene were found in this water. The aeration column was
7,3 x 0.6 m and was packed to 5.5 m with 1 inch plastic saddles.
Air-to-water ratios of from 8:1 to 88:1 were used. Ethylbenzene
was decreased to below detection (<0.5 ug/L) whenever the air-to-water
ratio;- vore 20:1 or greater. Ethylbenzene was detected if lower
air-to-water ratios were used. A total of 75 samples were tested.
223
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Ethyibenzene
March 31, 19.
-1 0-
0 Decarbonators, which can be considered as modified aerators, were us-;;
to remove synthetic organic contaminants including ethyibenzene at Water
Factory 21 (U.S. EPA, 1985d). The air-to-water ratio was 22:1. Level-
of influent ethyibenzene contamination were 0.067 and 0.23 ug/I^. The
decarbonators removed 39.8 and 56.51% of the ethyibenzene, respective l:1.
0 Granular activated carbon (GAC) also is at least partially effective
in the removal of ethyibenzene from solution by adsorption. Over two
separate trial periods, GAC was found to remove some of the ethyibenzene
from contaminated drinking water. At an influent concentration of
0c06 ug/L, 45% of the ethyibenzene was removed* When the influent
was 0.07 ug/L, 17% was removed (McCarty et al., 1979).
0 Application of for ethyibenzene removal was tested at the Sunny
Isles Water Treatment Plant (Florida) (U.S. EPA, 1985d). For a
14-month period, 7.1 mg/L PAC was added to the water at the wellfield.
For 3 of 5 samples analyzed, >99% of the ethyibenzene was removed;
for 2 samples, the removal rate was only 33%.
0 In one study, conventional treatment was found to reduce the ethyl-
benzene in water containing 0.7 ug/L by 43% (U.S. EPA, 1985d).
224
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E* nvl oer.z an:
March 31
--1 1-
IX. REFERENCES
ACGIH. 1980. American Conference of Industrial Government Hygienists.
Ethylbenzene. Documentation of the Threshold Limit Values. 4th ed.,
p. 176.
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety; odor-
threshold compared with Threshold Limit Values and volatilities for 214
industrial chemicals in air and water dilution. J. Appl. Toxicol.
3:272-290.
Angerer, J., and G. Lehnert. 1979. Occupational chronic exposure to solvents.
VIII. Phenolic compounds: Metabolites of alkylbenzenes in man: Simultaneous
exposure to ethylbenzene and xylenes. Int. Arch. Occup. Environ. Health.
43:145-150.
Bardodej, Z., and E. Bardodejova. 1970. Biotransformation of ethylbenzene,
styrene and alpha-methylstyrene in man. Am. Ind. Hyg. Assoc. J.
31:206-209.
Chin, B.K.,' J.A. McKelvey, T.R. Tyler, L.J. Calisti, S.J. Kozbelt and L.J.
Sullivan. 1980. Absorption, distribution and excretion of ethylbenzene,
ethylcyclohexsne and methylethylbenzene isomers in rats. Bull. Environ.
Contam. Toxicol. 24:477-483.
Cummins, M.D. 1985. Field evaluation of packed column stripping, Pastrap,
LA. U.S. Environmental Protection Agency, Office of'Drinking Water.
Dean, B.J., T.M. Brooks, G. Hodson-Walker and D.H. Hutson. 1985. Genetic
toxicology testing of 41 industrial chemicals. Mutat. Res. 153:57-77.
Donner, M., J. Maki-Paakkanen, N. Norppa, M. Sorsa and H. Vaino. 1979.
Genetic toxicology of xylenes. Mutat. Res. 74:171-172.
Dutkiewic*:, T., and H. Tyras. 1967. Study of the skin absorption of ethyl-
benzene in man. Br. J. Ind. Med. 24:330-332.
El Masry, A.X., J.N. Smith and R.T. Williams. 1956.- The metabolism of
alkylbenzenes: n-Propylbenzene and n-butylbenzene with further obser-
vations on ethylbenzene. Biochem. J. 64:50-56.
Engstrom, J., and R. Bjurstrom. 1978. Exposure to xylene and ethylbenzene.
II. . Concentration in subcutaneous adipose tissue. Scand. J. Work Environ.
Healih. 4:195-203.
Engstrom, K.L. 1984. Metabolism of inhaled ethylbenzene in rats. Scand. J.
Work Environ. Hlth. 10:83-87.
Faustov, A.S. 1S58. Toxicity of aromatic hydrocarbons. I. Comparative
toxicity of some aromatic hydrocarbons. II. Some problems of the toxic-
hygiene properties of aromatic hydrocarbons. Tr. Voronezh. Gos. Med.
Inst. 35:247-255; 257-262. (Chem. Abstr. 54:25279d)
225
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1 - :
-12-
nutin, i., u. Kutoerg, m. uurvail and C.R. Enzell. 1980. Screening of
tobacco smoke constituents for mutagenicity using the Ames test. Toxi-
cology. 18:219-232.
Hagemann, J.f and J. Angerer. 1979. Biological monitoring in occupational
ethylbenzene loading. Kolloq., Ber. Jahrestag. Dtsch. Ges. Arbeitsmec.,
19th. pp. 421-425. (Chem. Abstr. 94:196880)
Hardin, B.D., G»P. Bond, H.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier.
1981. Testing of selected workplace chemicals for teratogenic potential.
Scand. J. Work Environ. Health. 7(Suppl. 4):66-75.
Kiese, M., and W. Lenk. 1973. w- and (w-1)-Hydroxylation of 4-chloropro-
pionanilide by rabbits and rabbit liver microsomes. Biochem. Pharmacol.
22:2565-2574.
McCarty, P„L., D. Argo and M. Reinhard. 1979. Operational experiences with
activated carbon adsorbers at Water Factory 21. JAWWA. 11:683-689.
Mihail, G., A.Zlavog, V, Anghelache and J. Bodnar. 1972. Serum ornithine
carbamoyltransferase, test for evaluating hepatic alterations caused by
some industrial toxic substances. Igiena. 21:267-276. (Chem. Abstr.
79:1036)
NCI. 1983. National Cancer Institute. National Toxicology Program —
Toxicology Testing Program. Chemicals on Standard Protocol: Management
Statuso June 15, 1983.
Nestmann, E.R., E.G-H. Lee, TJ. Ma tula, G.R., Douglas and J.Co Mueller.
1980. Mutagenicity of constituents identified in pulp and paper mill
effluents using the Salmonella/mammalian-microsome assay. Mutat. Res.
79:203-212.
Smyth, H.F., C.P. Carpenter, C.S. Weil, U.C. Pozzani and J.A. Stregel.
1962. Range-finding toxicity data. List VI. Am. Ind. Hyg. Assoc. J.
23:95-107.
U.S. EPA. 1985a. U.S.•Environmental Protection Agency. Draft. Drinking
water criteria document for ethylbenzene. Office of Drinking. Water.
U.S. EPA. 1985b. UoS. Environmental Protection Agency. Method 503.1. Volatile
aromatic organic compounds in water by purge and trap gas chromatography.
Environmental Monitoring and Support Laboratory, Cincinnati, Ohio 45268.
U.S«-EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1. Volatile
organic compounds in water by purge and trap gas chromatography/mass
spectrometry. Environmental Monitoring and Support Laboratory, Cincinnati,
Ohio 45268.
U.S. EPA. 19G5d. U.S. Environmental Protection Agency. (Draft) Technologies
and costs for the removal of synthetic organic chemicals from potable
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D.C.
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-1 3-
U.S. EPA. 1985e. U.S. Environmental Protection Agency. Proposed RMCL for
SOCs, IOCs and Microbials. Federal Register. 50(219):46936-47023.
November 13.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assesment. Federal Register. 51(185):33992-34003.
September 24.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals.
2nd ed. Van Nostrand Reinhold Company, NY. pp. 628-630.
Vinokurova, M.I. 1970. Combined effect of styrene, butadiene and ethylbenzene
on the functional indexes of the cardiovascular system. Tr. Azerb.
Nauchno.-Issled. Inst. Gig. Tr. Prof. Zabol. 4:21-26. (Chem. Abstr.
81:140347)
Westrick, J.J., J.W. Mello and R.F. Thomas. 1983. The ground water supply
survey: Summary of volatile organic contaminant occurrence data.
EPA-0DW/T3D, Cincinnati, Ohio.
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1956. Toxicological studies of certain alkylated benzenes and benzene.
Arch. InJ. Health. 14:387-398.
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March 31, iy«/
ETHYLENE GLYCOL
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinkino water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills cr contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HA? are not recommended. TUe che.mical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upp-?r
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptionsthe estimates that are
derived can differ by several orders of magnitude.
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This Health Advisory is based upon information presented in the Office
of Drinking Water's Health Advisory Document for Ethylene Glycol (U.S. EF.-.,
1981). The 19S1 Health Advisory is available for review at each EPA Region
Office of Drinking Water counterpart (e.g., Water Supply Branch or Drinking
Water Branch).
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 107-21-1
Structural Formula
CH2-OH
I
ch2-oh
Synonyms
1,2-ethanediol
Uses
Antifreeze in cooling and heating systems, industrial humectant,
ingredient of electrolytic condensers, solvent in paint and plastic
industries and in the formulation of ink.
Properties (Verschueren, 1977; Windholz, 1983)
Chemical Formula
Molecular Weight
Physical State
Boilinc Point
Melting Feint
Density
Vapor Pressure
Specific Gravity
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C2H602
62.1
colorless liquid
197.6°C
-12.60C
0.05 mm (20°C)
1.113 (20°C)
completely miscible
Occurrence
In 1933, 4.5 billion pounds of ethylene glycol were produced (U.S.
ITC, 1SP4). The majority of ethylene glycol is used consumptively
(CZ'.i,
Releases of ethylene glycol to the environment can occur during pro
uction, use and release. The major source of release is from the
disposal of used antifreeze. Releases of ethylene glycol occur
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March 31, 19S7
-3-
largely to water and land during disposal; releases to the atmosphere
are limited by ethlyene glycol's low vapor pressure. Releases of
ethylene glycol to the environment are dispersed widely.
0 Ethylene glycol in the environment rapidly partitions to water due to
its solubility and low vapor pressure. Releases to surface water are
biodegraded rapidly. Releases of ethylene glycol to land have
resulted in the contamination of ground water (U.S. EPA, 1980).
Based upon its physical properties, ethylene glycol is not expected to
bioaccumulate.
° There is little information on the presence of ethylene glycol in
water, food and air. Because of its rapid degradation in the environ-
ment, ethylene glycol is not expected to be a common contaminant in
air, food or surface water; however, contamination of ground water is
possible. A more likely source of ethylene glycol exposure is the
inadvertant contamination of drinking water from the misuse of
antifreeze.
III. PHARMACOKINETICS
Absorption
° Ethylene glycol is absorbed rapidly after ingestion. Reif (1950),
on three separate occasions, drank pure ethylene glycol in 100 ml of
water. Amounts consumed were 5.5, 11.0 and 13.2 g, which would corre-
spond to 73.5, 157 and 188.6 mg/kg, respectively, assuming a body
weight of 70 kg for an adult. Ethylene glycol was recovered in the
urine at 24 to 31% of the administered dose within 24 to 48 hours.
Oxalic acid concentrations in the urine were higher than normal with
a peak or. the fourth day.
Metabolis*-
° Gessner et al. (1961) studied the fate of ethylene glycol in Chinchilla
rabbits, albino rats, guinea pigs and cats. Doses up to 10.0 g/kg of
ethylene glycol (14C2) were given orally or subcutaneously, but most
of the data were derived from animals receiving 0.1 to 2.0 g/kg (100
to 2000 mg/kg). At low doses (0.124 g/kg), rabbits exhaled about 601
of the dose as CO2 and excreted 20% of it in the urine in a time
period of 80 to 100 hours; 50% of the dose was exhaled as CO2 in the
first 18 hours after dosing. In one set of experiments with rabbits,
urine contained ethylene glycol (10.3%), oxalic acid (0.01%) and urea
(0.65%), Nearly one-half of the radioactivity was eliminated in the
urine when the dose was increased to 2.5 to 5.0 g/kg. The increase
in the radioactivity in the urine was attributed by the. authors to
unmetabolized ethylene glycol.
0 In an in vitro experiment utilizing rat liver slices, Gessner et al.
(1561) identified the intermediate metabolites of ethylene glycol
(1 ^C) as glycoaldehyde am? glyoxylic acid.
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"'arch 31, 1?CT
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IV. HEALTH EFFECTS
Humans
0 A controlled study of human exposure to ethylene glycol was reported
by Reif (1950). The investigator drank 5.5, 11.0 and 13.2 g of
ethylene glycol with 100 ml of water on separate occasions and
collected his urine for about 14 days after each trial to quantify
ethylene glycol and oxalic acid levels. Assuming a body weight of 70
kg, doses consumed would be 78.5, 157.0 and 188.6 mg/kg. Reif found
that 24 to 31% of the ethylene glycol was excreted in the urine in an
unchanged form within 24 to 36 hours, while urinary oxalic acid
levels were elevated for 8 to 12 days. No oxalate crystals were
found in the urine, and he reported no impairment of health from
these doses.
° Ethylene glycol ingestion by humans results in a variety of CNS/
behavioral effects including numbness, visual disturbances, light-
headedness, headache and lethargy (Berman et al., 1957), with doses
estimated at 1,000 mg/kg0 After ingesting a dose of approximately
3,000 ntg/kg, patients exhibited ataxia, somnolence and slurred speech,
followed by disorientation with a mental status alternating between
stupor and agitation (Parry and Wallach, 1974). At doses which were
eventually fatal, coma developed after a period of restlessness,
delerium, convulsive seizures and a loss of reflexes (Pons and Custer,
1946). These same symptoms of ataxia, incoordination, somnolence,
coma and eventual death have been reported in dogs (Nunamaker et al.,
1971 ).
Animals
Short-term Exposure
0 An extensive series of dose-mortality trials were conducted by Laug
et al. (1939) for several species of laboratory animals. Mice, rats
and guinea pigs were tested by administering single doses of ethylene
glycol by stomach tubes. Calculated LD50 values were: mice, 13.1
ml/kg (14,253 mg/kg); rats, 5.5 ml/kg (5,984 mg/kg); guinea pigs,
7.35 ml/kg (7,997 mg/kg). It was noted that the animals showed signs
of weakness, and lack of motor coordination shortly after receiving
doses of ethylene glycol. Prostration and coma were later symptoms,
followed by death in 18 hours to 6 days. Congestion of the lungs,
bladders filled with protein rich urine, hydropic degeneration of the
cells lining the cortical convoluted tubules, and focal necrosis of
the liver were nearly always found.
0 NIOSH M983-84) lists the following oral LD50 data for ethylene glycol:
rat (4, 7CC nr'*:r). mouse (7,500 mg/kg), guinea pig (6,610 mg/kg).
Long-terir Expos'ir*7-
0 In a study by Elood et al. (1962) ethylene glycol was fed to two rncle
rhesus monkeys and one female Rhesus monkey for three years. Ethylene
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March 31, 1987
-5-
glycol was incorporated in the monkey chow and made available to the
animals on an ad lib basis. The animals consumed 200 to 250 g of
chow/day. From the given body weights of 15.45 and 7.25 kg for the
males and 7.4 kg for the female, the amount of ethylene glycol consume:
would range from approximately 25 to 69 mg/kg/day for males and 135
to 170 mg/kg/day for females. Prior to the start of the experiment,
and at quarterly intervals, the animals were x-rayed to detect the
possible appearance of calcification of the urinary tract. At the
time of sacrifice all abdominal and endocrine organs, as well as a
bone marrow sample, were examined histb'pathologically. No abnormal
calcium deposits were demonstrated by x-ray; microscopic examinations
of tissues were unremarkable. The authors concluded that this species
was capable of handling the administered ethylene glycol without any
discernible toxic effects.
In a study by Blood (1965), ethylene glycol was fed to groups of 16
male and 16 female Sprague-Dawley rats for 2 years at concentrations
of 0.0, 0.1, 0.2, 0.5, 1 or 4% by weight in the diet (corresponds to
approximately 0, 50, 100, 250, 500 or 2,000 mg/kg/day (Lehman, 1959)).
Increased mortality appeared in males receiving the 1 and 4% diets.
Calcification of the kidneys and oxalate-containing calculi were
observed in males at doses of 0.5% and greater. Females were similarly
affected at the 1% level and greater for calcification and at the 4%
level for calculi. Increased water consumption and protein in the
urine was evident in males at both 1 and 4% and in females at 4% diet
levels. A probable NOAEL of 0.2% was determined (approximately 100
mg/kg/day) and a LOAEL of 0.5% (approximately 250 mg/kg/day).
A recently completed toxicity study in groups of 130 Fischer 344 rats
per sex per level fed ethylene glycol at dosages of approximately
1.0, Q.2, 0.04 or 0.0 g/kg/day for up to 2 years (DePass et al.,
1986a) identified a NOAEL of 0.04 g/kg/day (40 mg/kg/day). The
mortality rate was increased in the high-dosed males with all deai by
475 days i.-.to the study. Oxalate nephrosis was the primary cause of
death. Othe.r effects noted in the high-dosed males only included:
reduced body weight g^in, increased water intake, increased B'Jt." and
creatinine, reduced RBCs, hematocrit and hemoglobin, increased
neutrophil count, increased urine volume and reduced urinary specific
gravity and pH. Additionally, all high-dosed rats had increased
kidney weights and urinary calcium oxalate crystals. High-dosed
females also showed the presence of uric acid crystals in the urine.
Histopathological changes in the high-dosed males included tubular
cell hyperplasia, tubular dilation and peritubular nephritis. At the
next lower dose, 0.2 g/kg/day, an increase in incidence and amount of
calcium oxalate crystals was evident in both sexes. It is apparent
in this study that the male rat is more sensitive to the effects of
ethylene glycol.
These sane authors treated 80 CD-I mice per sex per leOel to the
same concentrations of ethylene glycol in the diet and found no
clinical or histopathological evidence of toxicity attributable to
its intake.
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Etr.vler,
i-;arc
-6-
Reproductive Effects
0 Timed-pregnant CD rats were dosed by gavage on days 6 through 15 of
gestation with ethylene glycol at 0, 1,250, 2,500 or 5,000 mg/kg/da.-
(Price et al., 1985). No maternal deaths or distinctive clinical
signs were noted. Significant decreases in maternal weight were dose-
related in rats at all levels. Other significant changes included
reduced gravid uterus weight, corrected gestational weight gain
and reduced fetal body weight per litter at the mid and high doses
and increases in post-implantation>losses per litter, significant
only at the high dose. This study established a LOAEL of 1,250
mg/kg/day for maternal effects and a NOAEL of 1,250 mg/kg/day for
fetal effects.
0 Timed-pregnant CD-1 mice were dosed by gavage on days 6 through 15 of
gestation with ethylene glycol at 0, 750, 1f500 or 3,000 mg/kg/day
(Price et al., 1985). No maternal deaths or distinctive clinical
signs were noted. Significant decreases in maternal weight, gravid
uterus weight and corrected gestational weight gain were evident at
the mi£ and high doses<> Fetal body weight per litter was also signifi-
cantly reduced at ail doses. This study established a NOAEL of 750
mg/kg/day for maternal effects and a LOAEL of 750 mg/kg/day for fetal
effects.
° In a continuous breeding study, Lamb et al. (1985) dosed CD-1 mice
with ethylene glycol by continuous administration in drinking water
at 0.0, 0.25, 0.5 or 1%. Slight but statistically significant
decreases were found in the numbers of litters per fertile pair
(p <0.01), live pups per litter (p <0»05) and mean live pup weight
(p <0.01) at the 1% level when compared to Fg controls. No clinical
signs of toxicity or significant adverse effects on body weight or
water consumption were seen in this study but two deaths at the 0.5%
level may have been related to oxalate crystal deposition. This
study established a NOAEL for reproductive effects of 0.5% (w/v) in
drinking water. (Between days 98 and 105 on the study, this level
corresponded to an average daily intake of 0.84 g/kg.)
° In a three-generation reproduction study, DePass et al. (1986b) fee
ethylene glycol to Fischer 344 rats at levels of approximately 1.0,
0.2, 0.04 or 0.0 g/kg/day. No evidence of reduced fertility or
increased fetal death was observed in any groups receiving the test
diet. This study established a NOAEL for maternal and fetal effects
at 1,000 mg/kg/day (highest dose tested).
Developmental Effects
0 Lamb et ,al. (1985), in a continuous breeding study using CD-1 mice,
administered ethylene glycol on a continuous basis for 126 days at
levelr, r.f 0.0, C.25, 0.5 or 1% in drinking water. The final offspring
of these continuously bred mice were examined and the authors noted
facial anomalies in a number of the offspring of the high-dosed mice.
Examination for skeletal - fects demonstrated a pattern including
reduction in size of the bones in the skull, fused ribs and abnormally
233
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March 31, 1987
-7-
shaped sternabrae and vertebrae. No similar findings were noted at
the two lower dose levels. This study established a NOAEL of 0.5%
(w/v) in drinking water Cor developmental effects in mice. (Between
days 98 and 105, the average daily intake corresponded to approxi-
mately 840 mg/kg for the parental generation.)
° Administration of ethylene glycol by gavajge on days 6 through 15 of
gestation at levels of 0, 1,250, 2,500 or 5,000 mg/kg/day in rats and
0, 750, 1,500 or 3,000 ing/kg/day in mice resulted in significant
increases in the percentage of malformed live fetuses per litter
and/or the percent of litters with malformed fetuses at all dose
levels with >95% of the litters affected at the high dose for both
species. The most common malformations included craniofacial and
neural tube closure defects and axial skeletal hyperplasia in both
specie1; (Price et al., 1985). This study established a LOAEL of
approximately 1 ,250 mg/kg/day in rats and 750 mgAg/day in mice (the
lowest levels fed).
Mutagenicity
0 I:v a dominant lethal mutagenesis study in rats, DePass et al. (1986b)
bred at weekly intervals the F2 males (fed ethylene glycol in the
diet at 1.0, 0.2, 0.4 or 0.0 g/kg/day) from a three-generation
reproduction study to 3 consecutive lots of untreated females. Ho
evidence of reduced fertility or increased fetal death was observed
in any of the groups receiving ethylene glycol. This study established
a NOAEL for mutagenic effects at 1,000 mgA9/day (highest dose tested).
0 Ethylene glycol demonstrated no significant mutagenic activity in the
Salmonella mutagenicity (Ames) test with or without microsomal acti-
vation (Clark et al., 1979).
Carcinogenici ty
0 No evidence of an oncogenic effect of ethylene glycol in 80 CD-I mice
p=r sex p^r level or 130 Fischer 344 rats per sex per level was seen
when fed in the diet at approximately 1.0, 0.2, 0.04 or 0.0 g/kg/day
for 24 months. Mortality of the high-dosed male rats in this study
was 100% after 475 days of feeding. Death was attributed to oxalate
nephrosis (DePass et al., 1986a).
0 In studies designed to determine the toxic and carcinogenic potential
of several biological preservatives, ethylene glycol was administered
subcutaneously at 5 dose levels to groups of 20 weanling Fischer 344
rats (Mason et al., 1971). The LD50 for a single injection was
5,300 mg/kg. When given subcutaneously, twice weekly for four weeks,
the maximum tolerated daily dose was found to be lower than 1,700
irc/kj (total dose of 13,600 mg/kg). In a long-term study, 4 groups
cf 80, 60, 4C rnd 20 rats were injected subcutaneously twice weekly
for S2 w^eks with 1,000, 300, 100 and 30 mg/kg, respectively. Animals
were observed for an additional six months following treatment. It
these animals, there was n-> evidence of ethylene glycol toxicity
based on survival tine, we.ght gain and drug related organ pathology.
234
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Ethylene Glycol
March 31, 1987
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) 3 mg/L ( ug/L)
(OF) x ( L/day)
where:
NOAEL or LOAEL « No- or Lowest-Observed-Adverse-Effeet-Leve1
in mgAg bw/day0
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF * uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
__ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
Data from the study of Reif (1950) were used to identify an oral NOAEI
in humans. This investigator drank a 188.6 mg/kg dose of ethylene glycol
with no discernable effects. Thus, a One-day HA for children exposed to
ethylene glycol in drinking water may be calculated as follows:
For a child:
One-day H.-. = (188.6 mg/kg/day)(10 kg) = 18.86 mg/L (id, 000 ug/L)
(100) (1 L/day)
where:
188.6 mg/kg/day = NOAEL in humans consuming up to this dose in water.
10 kg ° assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from a human study.
An additional factor of 10 has been added for a study
with only one subject.
1 L/day = assumed daily water consumption of a child.
Ten-dav F^alt.1-. Vi vis cry
There are not sufficient dat* to calculate a Ten-day Health Advisory.
The Longer-term HA of 5.5 mg/L for the 10 kg child can serve as a conservative
235
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March 31, 1957
-9-
estimate of an exposure which would be considered adequately protective over
a ten-day exposure period.
Longer-term Health Advisory
Exposure of male and female Rhesus monkeys to 55 to 170 mg/kg/day ethylene
glycol in the diet for three years caused no adverse respohse (Blood et al.,
1962). A Longer-term HA based on these data is calculated as fallows:
For a 10-kg child:
Longer-term HA = j_55 mg/kg/day) (10 kg) = /L (5'500 ug/L)
* (100) (1 L/day) ^
where:
55 mg/kg/day = NOAEL, based on absence of toxic signs in the monkey.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
For a 70-ka adult:
Longer-term HA = (55 mg/kg/day) (70 kg) = 19.25 mg/L (19,250 un/L)
(100)' (2 L/day)
where:
55 mg/kg/day = NOAEL, based on absence of toxic signs in the monkey.
70 kc = assumed body weight of an adult.
100 = uncertainty factor, chosefl in accordance with NAS/OD".,'
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime H<\
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADD. The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived fro-
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) car; be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
236
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Ethylene Glycol March 31, 1 98"7
-1 0-
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986) ,__then caution should be exercised in
assessing the risks associated with lifeti-q^e exposure to this chemical.
The study of Blood (1965) is considered most appropriate for calculating
a Lifetime Health Advisory. In this study rats were fed ethylene glycol in
the diet at concentrations of 0.0, 0o1, 0.2, 0.5, 1, or 4% (approximately 0,
50, 100, 250, 500 or 2,000 mg/kg/day according to Lehman, 1959) for up to two
years. This study identified a NOAEL of 0.2% (100 mg/kg/day) primarily for
kidney effects in rats. Using this NOAEL, the Lifetime HA is calculated as
follows:
Step Is Determination of the Reference Dose (RfD)
RfD - (100 mg/kg/day) „ , mg/kg/day
(100)
where:
100 mg/kg/day = NOAEL for kidney effects in rats.
100 o uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (1 mg/kg/day) (70 kg) = 35 mg/L (35,000 ug/L)
(2 L/day)
where:
1 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA - (35 mg/L) (20%) « 7 mg/L (7,000 ug/L)
where:
3d mc/L = DWEL.
20% = assumed relative source contribution from water.
237
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Etryle-c- Glyccl
March 31, 1987
-1 1 -
Evaluation of Carcinogenic Potential
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), ethylene glycol may be classified
in Group D: Not classified. This category is for agents with inade-
quate animal evidence of carcinogenicity. The study by DePass et al.
(1986a) was not a definitive indicator for carcinogenicity. The
study indicated a difference in time to-detection of lymphocarcinomas
in the female rat. The incidence of this tumor type was not signifi-
cantly different.
VI. OTHER CRITERIA, GUIDANCE AV.'D STANDARDS
° ACGIH (1984* has proposed a ceiling limit of 50 ppm ( 125 mg/m^)
for vapor and mist to minimize irritation of respiratory passages.
VII. ANALYTICAL METHODS
0 There is no standardized method for the determination of ethylene
glycol in drinking water samples. A procedure has been developed
(Hartman and Bowman, 1977) to determine the presence of ethylene
glycol in drugs and pharmaceutical formulations at concentration
levels of 5-200 mg/L. This procedure is based on direct aqueous
injection-gas chromatography of samples. It is probable that'this
procedure also applies to drinking water samples at concentration
levels"of at least 5 mg/L.
VIII. TREATMENT TECHNOLOGIES
0 Ethylene glycol is completely miscible with water (Windholz, 1963)
and has a low vapor pressure of 1 mmHg at 53°C (CRC Handbook o:
Chenistry and Physics, 1982). These two factors make it impractical
to consider aeration as a form of removal. Treatment with activate.?,
carbon does not ramove much of this compound from solution either.
The adsortability of ethylene glycol is only 0.0136 mg/g carbon with
only 6.3% ethylene glycol retention (Veschueren, 1977). No infornatu
was found on the removal of this compound from drinking water using
other techniques.
0 Ethylene glycol may contaminate drinking water due to misapplication
of the chemical as an antifreeze in potable water systems or through
crossconnections with non-potable fire protection or heating/cooling
systems. In these cases vigorous flushing of the contaminated compo-
nents of the distribution system should be sufficient.
2 3 8
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Ethv lene
March 31, 153'
-1 2-
IX. REFERENCES
ACGIH. 1984. American Conference of Governmental Industrial Hygienists.
Documentation of the threshold limit values. 4th ed. 1980-1984 Supplen-:-'-1.
pp. 182-183.
Berman, L.B., G.E. Schreiner and J. Feys. 1957. The nephrotoxic lesion of
ethylene glycol. Ann. Int. Med. 46:611-619.
Blood, F„R., G.A. Elliott and M.S. Wright. 1962. Chronic toxicity of
ethylene glycol in the monkey. Toxicol. Appl. Pharmacol. 4:489-491.
Blood", F.R. 1965. Chronic toxicity of ethylene, glycol in the rat.
Fd. Cosmet. Toxicol. 3:229-234.
CEH. 1983. Chemical Economics Handbook. Ethylene Glycol. 652.5030. Stanford
Research Institute, Menlo Park, California.
Clark, C.R., T.C. Marshall, B.S. Merickel, A. Sanches, D.G. Brownstein and
C.He Hobbs.- 1979. Toxicological assessment of heat transfer fluids
proposed for use in solar energy applications. Toxicol. Appl. Pharmacol.
51:529-535.
CRC Handbook of Chemistry and Physics. 1982. A Ready-Reference Book of
Chemical and Physical Data. 62nd Ed. Boca Raton, Florida-, p. D-175.
DePass, L.R., R.H. Garman, M.D. Woodside, H.E. Giddens-, R.R. Maronpot and
C.S. Weil. ".986a. Chronic toxicity and oncogenicity studies of ethylene
glycol in rats and mice. Fund. Appl. Toxicol. 7:547-565.
DePass, L.R., M.D. Woodside, R.R. Maronpot and C.S. Weil. 1986b. Three-
generation reproduction and dominant lethal mutagenesis studies of
ethylene glycol in the rat. Fund. Appl. Toxicol. 7:566-572.
Gessnsr, P.JC., D.V. Parke and R.T. Williams. 1961. Studies in detoxication Sf.
The metabolism of 14C labelled ethylene glycol. Biochem. J. 79:482-489.
Hartman, P.A., and P.B. Bowman. 1977. Simple GLC determination of ethylene
oxide and its reaction products in drugs and formulation. J. Pharm. Sci.
66:789-792.
Lamb, J.C., IV, R.R. Maronpot, D.K. Gulati, V.S. Russell, L. Homme1-Barnes
and P.S. Sabharwal. 1985. Reproductive and developmental toxicity of
ethylene glycol in the mouse. Toxicol. Appl. Pharmacol. 81:100-112.
Laug, E.P., H.O. Calvery, H.J. Morris and G. Woodward. 1939. The toxicology
of some glycols and derivatives. J. Ind. Hyg. Toxicol. 21:173-201.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and
cosmetics. Association of Food and Drug Officials of the United States.
239
-------
March 31, 19S7
-13-
Mason, M.M., C.C. Cate and J. Baker. 1971. Toxicology and carcinogenesis
of various chemicals used in the preparation of vaccines. Clin. Toxicol.
4:185-204.
NIOSH. 1983-84. National Institute of Occupational Safety and Health.
Registry of toxic effects of chemical substances. U.S. Dept. of Health,
Education and Welfare, Supplement, p. 904. /
Nunamaker, D.M., W, Medway and P. Berg. 1971. Treatment of ethylene glycol
poisoning in the dog. J. Am. Vet. Med. Assoc. 159:310-314.
Parry, M.F., and R. Wallach. 1974. Ethylene glycol poisoning. Am. J. Med^-
57:143-150.
Pons, C.A., and R.P. Custer. 1946. Acute ethylene glycol poisoning. A
clinico-pathological report of eighteen fatal cases. Am. J. Med. Sci.
211:544-552.
Price, C.J., C.A. Kimmel, R.W. Tyl and M.C. Marr. 1985. The developmental
toxicity of ethylene glycol in rats and mice.. Toxicol. Appl. Pharmacol.
81:113-127.
Reif, G. 1950. Self-experiments with ethylene glycol. Pharmazie. 5:276-278.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Damages and Threats
Caused.by Hazardous Material Sites. Oil and Special Materials Control
Division. Draft, p. 43.
U.S. EPA. 1931. U.S. Environmental Protection Agency. Health Advisory
Document for Ethylene Glycol. Draft. Office of Drinking Water.
U.S. EP*-.. 195c. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk. Federal Register. 51(185):33992-34003. September 24.
U.S. ITC. 1994. U.S. International Trade Commission. Synthetic Organic
Chemicals, United States Production and Sales, 1983. Washington, D.C.
USITC PuDlication 1588.
Verschueren, K. 1977. Handbook of environmental data on organic chemicals.
New York, NY: Von Nostrand Reinhold Company, p. 322.
Windholz, r;., ed. 1983. The Merck Index, 10th ed. Merck and Company, Inc.,
Rahway, KJ.
240
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March 31, 1 9? 7
HEXACHLOROBENZENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office 'of Drinking
Hater (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. Biey are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogeni
risk from such exposure. For those substances that are known, or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure ana the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
-------
Hexachlorobenzene
March 31, 19S^
-2-
This Health Advisory (HA) is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for hexachlorobenzer.e
(U.S. EPA, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further-information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for review at each EPA Regional Office of Drinking Hater counterpart (e.g.,
Water Supply Branch or Drinking Water Branch), or for a fee from the National
Technical Information Service, UcS. Department of Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB # 86-117777/AS. The toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 118-74-1
Structural formula
CI
Cl-^^Cl
Cl~Xf^Cl
CI
Synonyms
Uses
HCB, HEXA C.B., Perchlorobenzene
Hexachlorobenzene is not manufactured as a commercial product in the
United States, but an estimated 2-5 million pounds were produced each
year during the synthesis of several chlorinated chemicals as of 1975
(Mumma and Lawless, 1975). Hexachlorobenzene also is an ingredient of
a fungicide of which 200,000 pounds were imported each year as of 19"7?
(IARC, 1979).
Properties (U.S. EPA, 1985a)
Chemical Formula
Molecular Weight
Boiling Point
Melting Point
Density
Vapor Pressure (mm Hg)
Water Solubility
Henry's Law Constant
Odor Threshoic
Taste Threshold
Conversion Factor
C6C16
284.79
322.9°C
2308C
1.57 g/mL at 23°C
1 at 144.4°C
1.68 x 10-5 at 25°C
1.089 x 10-5 at 20#C
0.005 mg/L at 25°C
0.12 atm m3 mol-1
Not available
Not available
2 42
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March 31, 193"
-3-
Occurrence
0 Hexachlorobenzene (HCB) is a synthetic organic compound with no
natural sources. HCB is no longer directly produced but occurs as a
byproduct during the manufacture of other chlorinated compounds. KCa
has been used as a fungicide, but this use has been discontinued.
HCB can.occur as a contaminant in a number of chemically similar
compounds, which are used as pesticides
-------
Hexachlorobenzene
Marcn 31, 19c
-4-
HCB at concentrations approaching those of fat. Other tissues (e.g.,
liver, kidneys, lungs, heart, spleen and blood) generally contain
lower amounts of HCB.
0 Intravenous injection of HCB results in a tissue distribution similar
to the following oral administration (U.S. EPA, 1985a).
• Hexachlorobenzene is transported via the placenta and is distributed
in fetal tissue (O.S. EPA, 1985a).
Metabolism
° The metabolism of HCB has been studied in male and female rats following
oral administration, in Rhesus monkeys and beagles following intravenous
injection and in rabbits following intraperitoneal injection (Renner,
1981).
° Hexachlorobenzene is metabolized slowly into other lower chlorinated
benzenes, chlorinated phenols and other minor metabolites, and forms
glucuronide and glutathione conjugates (Renner„ 1981)o
•" Tissues were found to contain mainly unchanged HCB together with
small amounts of metabolites (Renner, 1981).
0 Only small amounts of HCB metabolites were detected in feces. Most
of the HCB metabolites were excreted in the urine together with small
amounts of unchanged HCB (U.S. EPA, 1985a).
Excretion
° The excretion of HCB from treated animals is slow and occurs mainly
as the parent compound through the feces, with relatively little
being excreted in the urine. It is characterized by an initial rapii
phase followed by a very slow phase. This slow phase of excretion
can be enhanced by the administration of mineral oil, paraffin and
n-hexadecane (U.S. EPA, 1985a).
° Both biliary and intestinal excretion contribute to fecal excretion («.S.
EPA, 1985a).
0 A three-compartment mammalian model has been reported for the behavior
of HCB in beagles and Rhesus monkeys following intravenous injection
of a single dose. Radioactivity was not detected in exhaled air
following intraperitoneal injection of 14c-HCB. Hexachlorobenzene ha =
been detected in the milk of nursing mammals (U.S. EPA, 1985a).
IV. HEALTH EFFECTS
Humans
° The exposure of humans to seed wheat contaminated with HCB. in Turkey
from 1955-1959 caused an epidemic of HCB—induced PCT, also known as
244
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hexacr.ioroocri;e,'ic
¦larch 31, 195
-5-
porphyria turcica, which is manifested by disturbed porphyrin metabolism,
cutaneous lesions and hyperpigmentation. Two investigators (Cair. and
Nigogosyan, 1963) estimated that 0.05 to 0.2 g/day were ingested. In
children under 1 year of age, pink sores were observed as well as 95%
mortality (U.S. EPA, 1985a).
0 Follow-up studies conducted with patients 20 to 25 years after the
onset of porphyria showed that a few patients (10%) still had active
porphyria, whereas >50% exhibited hyperpigmentation (78%) and scarring
(83%) as well as other dermatologic, neurologic and skeletal features
of HCB toxicity. Enlarged thyroids were diagnosed in 60% of the
female patients. Hexachlorobenzene residues also were found in the
blood, fat or breast milk of some patients (U.S. EPA, 1985a).
Animals
Short-terni Exposure
° Information on the acute toxicity of HCB is limited to oral LD50
values determined with a few mammalian species. The following ld50
values were reported in the available literature: rats, 3,500-10,000
mgAg; rabbits, 2,600 mg/kg; cats, 1,700 mg/kg; and mice, 4,000 mg/kg
(MAS, 1977; IARC, 1979; Sax, 1979).
Lonq»term Exposure
0 Subchronic oral toxicity studies with a number of mammalian species
indicated statistically significant increases in liver and kidney
(rats only) weights in hexachlorobenzene-treated animals. Some
studies have shewn increases in the weights of other organs as well.
Chronic oral toxicity studies revealed similar effects to those seen
in the subchronic studies plus HCB-associated mortality and variojs
hepatic and renal lesions. These subchronic and chronic effects were
usually dose-related with effect levels as low as 2 mg/kg/day in
subchronic studies and 0.29 to 0.4 mg/kg/day in chronic studies.
Other effects included multiple alopecia and scabbing, together with
neurologic effects in rats, mice and dogs (U.S. EPA, 1985a).
0 Dose-related histopathologic changes in the ovaries of monkeys given
8 to 128 mg/kg/day by gavage for 60 days also have been reported
(U.S. EPA, 1985a).
0 The livers of HCB-exposed animals have shown histologic changes such
as irregular shaped and moderately enlarged liver mitochondria and
increases in the size of the centrilobular hepatocytes (U.S. EPA,
1985a).
0 Increased porphyrin levels in the liver and in urine have been reported
for all species studied except the dog. Hexachlorobenzene was found
to cause the accumulation of ^-H-steroids which induce porphyrin bio-
synthesis ar.a to inhibit uroporphyrinogen decarboxylases (U.S. EPA,
1985a).
245
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H e x a c r. i o r o D e n z e r. e
March 3'., 1S~.
-6-
0 The inhibition of uroporphyrinogen decarboxylases appears'to be due
to pentachlorophenol, a HCB metabolite (U.S. EPA, 1985a).
0 Indications are that females are more susceptible to HCB-induced
porphyria than are males, which may be related to higher estrogen
levels and greater HCB metabolism in females (U.S. EPA, 1985a).
° Hexachlorobenzene was reported to produce a mixed-type induction of
cytochromes resembling that produced by a combination of phenobarbital
(P-450) and 3,4-benzpyrene (P-448). In addition the activities of
several hepatic microsomal enzymes were found to be induced by HCB
(U.S. EPA, 1985a).
Reproductive Effects
0 Hexachlorobenzene has been shown to cross the placenta into fetal
tissues and to be present in the milk of nursing dams (U.S. EPA, 1985a).
° The NOAEL in a four-generation reproduction study with rats was
reported to be 20.ppm of HCB in the diet (Grant et ale, 1977). Pups
from treated dams receiving diets containing 80 ppm HCB recovered
from elevated liver weights when nursed by untested foster dams
(Mendoza et al., 1378).
0 Hepatomegaly and reduced survival were reported in kittens from cats
receiving 263 ppm of HCB in their diets (8.7 mg/day/cat (Hansen
et al., "979).
° Three infant Rhesus monkeys nursed by mothers given HCB by gavage at
64 mg/kg/day for 60 days developed clinical signs of toxicity, and
2 infants which died while nursing had severely congested lungs or
bilateral hemorrhagic pneumonia (Bailey et al., 1980).
0 Feeding female minks with dietary HCB at doses as low as 1 ppm during
gestation ani lactation resulted in increased mortality of kits (Rush
et al., 1983).
Developmental Effects
° Fetal mice from dams treated with 100 mg HCB/kg/day by gavage during
days 7 through 16 of gestation exhibited teratogenic responses, e.g.,
cleft palate, and decreased fetal weight. Maternal liver:body weights
were also increased (Courtney et al., 1976).
0 Hexachlorobenzene was not teratogenic in Wistar rats with gavage
doses of 10, 20, 40, 60, 80 or 120 mg HCB/kg/day in corn oil or 0.25%
aqueous gum tragacanth given during gestation days 6-21. Maternal
toxicity (bod> weight loss, central nervous system effects) and reduced
fetal body wei^..c occurred at the two highest doses (Khera, 1974).
246
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Mutagenicity
° Hexachlorobenzene was not found to be mutagenic in 5 strains of
S. typhimurium, with or without metabolic activation (Lawlor et al.,
T979K
° Hexachlorobenzene was mutagenic in the yeast, £. cerevisiae, at a
minimum concentration of 100 ppm (Guerzoni et al.» 1976).
° Hexachlorobenzene was negative in dominant lethal nutation studies
with rats (Khera, 1974; Simon et al., 1979).-
# In a lifetime study with HCB administration to hamsters, hepatoma was
induced in both males and females (Cabral et alo, 1977). The response
at a dose of 4 to 5 mgA9/day dissolved in corn oil and mixed in the
feed was 47% for both sexes; controls had no hepatomas. In addition
to hepatomas, hamsters responded to HCB treatment with malignant
liver haemangioendotheliomas and thyroid adenomas. The incidence of
haemangioendotheliomas was 20% in males (versus 0% in controls) at
8 nig/kg/day and 12% in. females (versus 0% in controls) at 16 mgAg/day
Thyroid adenomas occurred at 14% incidence in males treated with
16 mgAg- HCB (versus 0% in controls).
0 • Liver cell tumors, described as hepatomas, also were produced in both
sexes of Sv.-Us mice (Cabral et al., 1979). At 24 mg/kg/day, the
incidence was 34% for females and 16% for males, and the response
showed a dose-dependency not only in the number of tumor-bearing
animals but also in the latent period, and multiplicity and size of
tumors. In ICR mice, HCB administered concurrently with polychlorinat<
terphenyl induced hepatocellular carcinomas (Shirai et al., 1976).
0 In rats, the target organs for HCB-induced tumors in various studies
included the liver, kidney, adrenal gland and parathyroid gland.
Liver tumors ware found in three studies which included three differed
strains of rat: Agus, Wistar and Sprague-Dawley. These tumors were
induced with doses between 1.5 and 8 mg/kg/day. The incidence was as
high as 100% in Agus rats but lower for the other strains. Renal
cell tumors were found in one study on Sprague-Dawley rats. In two
studies with Sprague-Dawley rats, significant increases in adrenal
pheochromocytoma in females were found. In one of these studies the
incidence of parathyroid tumors in males was increased significantly
as well (Smith and Cabral, 1980; Lambrecht, et al., 1983a, 1983b;
Arnold, 1983, 1984; Arnold et al., 1985).
0 Lambrecht .et al. (1983a, 1983b) fed male and female Sprague-Dawley
rats HCB ir, the diet for up to two years at estimated doses of
4-5 incj/yg/day ar.d 8-9.5 mg/kg/day. By 48 weeks, females had gross
liver tumors. Significant" increases in tumor incidence included
hepatorr.a' in ooth sexes at both doses, hepatocellular carcinomas in
females at both doses, renal cell adenomas in females at both doses,
and adrenal pheochromocytoma in females at both doses. Hepatocellular
carcinoma was slightly higher in males at both doses.
247
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Kexacfilorooenzene
March 3"i, 19i"
-8-
0 The data on HCB provide sufficient evidence of the carcinogenicity of
HCB since there were increased incidences of malignant tumors of the
liver in two species (haemangioendothelioma in hamsters and hepato-
cellular carcinoma in rats) as well as reports of hepatoma in mice,
rats and hamsters•
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identity a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA - (NOAEL or LOAEL) x (BW) „ « (
(UF) x ( L/day)
where:
NOAEL or LOAEL « No- or Lowest-Observed-Adverse-Effeet-Level
in mgAg bw/day.
BW = assumed body weight of a-child (10 kg) or
an adult (70 kg).
UF » uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
_____ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
The following Health Advisories, which are based on toxicological effects,
are above.the solubility of hexachlorobenzene in water (0.005 mg/L at 25°C).
One-day and Ten-day Health Advisories
Available evidence for the acute toxicity of hexachlorobenzene is con-
sidered to be insufficient for calculation of One-day and Ten-day Health
Advisory (HAs). Ifterefore, the Longer-term HA (0.05 mg/L) for a 10-kg child
is proposed as a conservative estimate for One-day and Ten-day HAs for the
10-kg childo
Longer-term Health Advisory
In the Kuiper-Goodman et al. (1977) study, groups of 70 male and 70
female Charles River (COBS) rats were fed diets with hexachlorobenzene at
0.5, 2.0, 8.0 or 32.0 mg/kg bw/day dissolved in corn oil for as long as 15
weeks. Female rats were found to be more susceptible to hexachlorobenzene,
as indicated by all parameters studied, and an "apparent" NOAEL of 0.5 mg/kg/
day was concluded by the authors. Increased liver porphyrin levels in females
and increases in the size of centrilobular hepatocytes along with the depletion
of hepatocellular marker enzymes were noted with higher doses.
248
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c X i C j. Z I* O 0 6
-Ch 21, 19T
-9--
Using the NOAEL of 0.5 mg/kg bw/day reported by Kuiper-Goodman et al.
(1977), the Longer-term HA for a 10-kg child is calculated as follows:
Lonaer-term HA = CO-5 mgAq/day) (10 kg) = 0.050 mg/L (50 ug/L)
(100) (1 L/day)
where:
0.5 mg/kg/day = NOAEL based on absence of liver effects.
10 kg » assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with nas/odw
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
For a 70 kg-adult:
Lonaer-term HA " <0-5 mgAq/day) (70 kg) - 0.175 mg/L (175 ug/L)
(100) (2 L/day)
where:
0.5 mg/kg/day = NOAEL based on absence of liver effects.
70 kg =» assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODX
guidelines for use with a NOAEL from an animal study.
2 L/day =¦¦ assumed daily water consumption of an adult.
Lifetime Health Advisor'/
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived fror.
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinkin7
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived frcn the multiplication of the RfD by the assumed body
weight of an adult ana divided by the assumed daily water consumption of ar.
adult. Tne Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, ths relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
249
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Hexachlorobenzene
March 31, 19i
-1 0
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The derivation of the DWEL is based on a 130-week study by Arnold et al.
(1985). This study involved feeding sale and female Sprague-Dawley rats (the
Fq generation) diets containing 0, 0.32, 1.6, 8,0 or 40 ppm of hexachlorobenzene
(analytical grade) for 90 days before nating and until 32 days after parturition
(at weaning).
The number of offspring (F<| generation) from these matings was reduced
to 50 males and 50 females per dose group at 28 days of age and fed their
respective parents' diets. Thus, the Fi animals were exposed to hexachloro-
benzene and metabolites jLn utero, from maternal nursing and from their diets
for the remainder of their lifetime (130 weeks). No hexachlorobenzene-induced
effects were reported in the 0.32 ppm hexachlorobenzene Fj group, indicating
this level is a NOAEL. Although a significant (p<0.05) increase in the inci-
dence of periportal glycogen depletion was found in Pf male rats fed 1.6 ppm
hexachlorobenzene, the 1.6 ppm level of hexachlorobenzene also is concluded
to be a NOAEL in that this result was not evident In other treated groups of
male rats. The 8.0 ppm hexachlorobenzene Fi groups were reported to have
an increase (p<0.05) in the incidence of hepatic centrilobular basophilic
chromogenesis. The 40 ppm hexachlorobenzene F^ groups were reported to have
increases (p<0.05) in pup mortality, hepatic centrilobular basophilic chromo-
genesis, peribiliary lymphocytosis and fibrosis, severe chronic nephrosis in
males, adrenal pheochromocytomas in females and parathyroid tumors in males.
It is difficult to estimate lifetime doses on a mgAg bw basis in this study
because of the initial exposure of the animals to hexachlorobenzene and its
metabolites _in utero and during lactation. However, in an attempt to estimate
the lifetime hexachlorobenzene doses on a mgAg bw basis, the 1.6 mgAg
hexachlorobenzene dietary level, interpreted from this study as the highest
NOAEL level, was converted to a daily intake dose of 0.08 mgAg bw/day by
averaging the dosage.data provided by Arnold (1984).
Using this NOAEL, the DWEL is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - (0.08 mgAg/day) (1,000 ug/mg) _ 0.8 ugAg/day
(100) *
where:
0.08 mgAg/day = NOAEL.
1,000 ug/mg ¦ Conversion of NOAEL in mg to ug.
100 = uncertainty factor, chosen in accordance with NAS/0DW
guidelines for use with a NOAEL from an animal study.
50
-------
ncxacr. ioroaar.
V?I
-1 1-
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL » (0-8 ug/kg/day) (70 kg) „ 28 Ug/L
(2 L/day)
where:
0.8 ug/kg/day = RfD.
70 kg a assumed body weight of an adult.
2 L/day «* assumed daily water consumption of an adult.
Hexachlorobenzene may be classified as Group B« probable human carcinogen.
The estimated excess cancer risk associated with lifetime exposure to drinking
water containing hexachlorobenzene at 28 ug/L is approximately 1 x 10~3.
This estimate represents the upper 95% confidence limit from extrapolations
prepared by EPA's Carcinogen Assessment Group using the linearized, multistage
model. The actual risk is unlikely to exceed this value, but there is considerable
uncertainty as to the accuracy of risks calculated by this methodology.
Evaluation of Carcinogenic Potential
0 Data on hepatocellular carcinomas in female rats after oral ingestion
from tne study by Lambrecht et al. (1983) have been used by the U.S.
EPA Carcinogenic Assessment Group to estimate the carcinogenic potency
of hexachlorobenzene and the risks associated with one unit of the
compound in drinking water (U.S. EPA, 1984b). This particular data
set was selected because it is a malignant tumor in the primary target
organ and results in the highest potency estimate. The 95% upper bound
cancer risks associated with 1 ug/L of hexachlorobenzene in drinking
water is estimated to be 4.9 x 10-5. Accordingly, upper bound cancar
risks of I0~6t i o~5 an
-------
Hexachlorobenz e:ie
March 31, 19i
-1 2-
0 In the absence of evidence of human carcinogenicity, hexachlorobenzene
would be classed in 1ARC category 2B, meaning that it has been demon-
strated to be carcinogenic in animals and is probably carcinogenic in
humans.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), hexachlorobenzene may be classified
in Group B2: Probable human carcinogen. This category is for agents for
which there is inadequate evidence from human studies and sufficient
evidence from animal studies.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
® The U.S. EPA (1980) has set ambient water quality criteria for hexa-
chlorobenzene of 7.2, 0.72, and 0.072 ug/L corresponding to cancer
risks of 10-5, 10-6, and 10-7, respectively, assuming 70 kg humans
daily consume 2 L of water and 60S g of fish and shellfish.
8 The National Academy of Sciences (1.983) estimated a cancer risk of
1.85 x 10"6, with lifetime consumption of 1 L of water containing
1 ug of hexachlorobenzene, based on the carcinogenicity study in mice
by Cabral et al. (1979). In 1980, the NAS also calculated a 7-day
SNARL (suggested-no-adverse-response-level) of 0.03 mg/L.
0 The WHO (1984) guideline value for hexachlorobenzene is 0.01 ug/L.
VII. ANALYTICAL METHODS
0 Determination of hexachlorobenzene is by a liquid-liquid extraction
gas chromatographic procedure (U.S. EPA, 1978; Standard Methods, 19S5).
Specifically, the procedure involves the use of 15% methylene chloride
in hexane for sample extraction, followed by drying with anhydrous
sodium sulfate, concentration of the extract and identification by gas
chromatography. Detection and measurement is accomplished by electron
capture, microcoulometric or electrolytic conductivity gas chromato-
graphy. Identification may be corroborated through the use of two
unlike columns or by gas chromatography-mass spectroscopy (GC-MS).
The method sensitivity is 0.001 to 0.010 ug/L for single component
pesticides and 0.050 to 1.0 ug/L for multiple component pesticides
when analyzing a 1-liter sample with the electron capture detector.
VIII. TREATMENT TECHNOLOGIES
0 Treatment technologies for the removal of hexachlorobenzene (HCB)
from water have not been evaluated extensively. An evaluation of
sorce of tne pny&ical and/or chemical properties of hexachlorobenzene
indicates that carbon adsorption is a candidate for further investi-
gation. Individual or combinations of technologies selected to
attempt hexachlorobenzene removal must be based on a case-by-case
technical evaluation, and an assessment of the economics involved.
252
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Kexac.'.lorojer.zsne y.arcr. 31, 19£"
-1 3-
0 -Based on its Freundlich constants (K = 450; 1/n = 0.6) hexachloro-
benzene is a viable candidate for removal from water by activated
"carbon adsorption (U.S. EPA, 1985b). There are, however, limited
available data to substantiate this. Home water treatment units of
the line bypass faucet and pour-through type were tested by Gulf
South Research Institute to determine their effectiveness in removing
hexachlorobenzene from water. Six of ten units tested had initial
efficiencies of 99%; however, by the end of the test the effectiveness
of some units had fallen to as low as 45% (U.S. EPA, 1985b).
0 Hexacnioroo^nzene has a Henry's Law Constant of 2.06 atm at 20°C (U.S.
EPA, 1985b). This indicates that air stripping would not be effective
in removing HCB from solution.
253
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nexacrilorobenzene
Maren 31, IS:*"
-14-
IX. REFERENCES
Arnold, D.L. 1983. Personal communication to Murial M. Lippman, ERNACO, Inc.
Silver Spring, MD.
Arnold; D.L. 1984. Personal communication to Murial He Lippman, ERNACO, inc.
Silver Spring, MD.
Arnold, D.L., CoA. Moodie, S.M. Charbonneau, H.R. Grice, P.P. McGuire, F.R.
Bryce» B.T. Collins, ZoZ. Zavidzka, D.R. Krevski, E.A. Nera and I.C. Munrc.
1985. Long-term toxicity of hexachlorobenzene in the rat and the effect
of dietary vitamin A. Food Chem. Toxicol. 23:779-793.
Bailey, J., V. Knauf, W. Mueller and W. Hobson. 1980. Transfer of hexachloro-
benzene and polychlorinated biphenyls to nursing infant Rhesus monkeys:
Enhanced toxicity. Environ. Res. 21(1)s190-196.
Cabral, J«R.P., P„ Shubik, T. Mollner and F. Raitano. 1977. Carcinogenic
activity of hexachlorobenzene in hamsters. Nature (London). 269:510-511.
Cabral, J.R.P., T. Mollner, F. Raitano and P. Shubik. 1979. Carcinogenesis
of hexachlorobenzene in mice. Int. J. Cancer. 23(1):47-52.
Cam, C. and G. Nigogosyan. 1963. Acquired toxic porphyria cutanea tarda
due to hexachlorobenzene. J. Am. Med. Assoc. 183(2)s88-91.
Courtney, K.D., M.F. Copeland and A. Robbins. 1976. The effects of penta-
chloronitrobenzene, hexachlorobenzene and related compounds on fetal
development. Toxicol. Appl. Pharmacol. 35:239-256.
Guerzoni, M.E., L. Del Cupolo and I. Ponti. 1976. Mutagenic activity of
pesticides (Attivita mutagenica degli antiporrositari). Rev. Sci.
Tecnnol. Alementi Nutri. Um. 6:161-165,,
Grant, D.L., W.E.J. Phillips and G.V. Hatina. 1977. Effect of hexachloro-
benzene on reproduction in the rat. Arch. Environ. Contam. Toxicol.
5(2):207-216.
Hansen, L.G., R.H. Teske, S.M. Sundlof and J. Simon. 1979. Hexachlorobenzene
and feline reproduction: Effects of ground pork contaminated by dietary
exposure or spiked with purified hexachlorobenzene. Vet. Hum. Toxicol.
21(4):248-253.
IARC. 1979. International Agency for Research on Cancer. IARC monographs
on the evaluation of the carcinogenic risk of chemical to humans.
Hexachlorobenzene. IARC, Lyon, France. 20:155-178.
Khera, K.S. 1974. Teratogenicity and dominant lethal studies on hexachloro-
benzene in rats, t'ooa Cosmet. Toxicol. 12:471=477.
Kuiper-Goodman, T., D.L. Grant, C.A. Moodie, G.O. Korsrud and I.C. Munro.
1977. Subacute toxicity of hexachlorobenzene in the rat. Toxicol. Appl.
Pharmacol. 4 0(3):529-549.
254
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Hexachlorobenzene
March 31, 1st
-1 5-
Lambrecht, R.W., E. Ertruk, E.E. Grunden, H.A. Peters, C.R. Morris and G.T.
Bryan. 1983a-. Renal tumors in rats (R) chronically exposed to hexa-
chlorobenzene (HCB). Proc. Am. Assoc, Cancer Res. 24:59. (Abstr.)
Lambrecht, R.W., E. Ertruk, E.E. Grunden, H.A. Peters, C.R. Morris and G.T.
Bryan. 1983b. Hepatocarcinogenicity of chronically administered hexa-
chlorobenzene in rata. Fed. Prod. 42(4)j78^. (Abstr.)
Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic
activity of nine chlorinated phenols, seven chlorinated benzenes, and
three chlorinated hexanes. Environ. Mutagen. 1<143. (Abstr.)
Lu, P.Y., and R.L. Metcalf. 1975. Environmental fate and biodegradability of
benzene derivatives as studied in a model aquatic ecosystem. Environ.
Health Perspec. 20:269-284.
Mendoza, C.E., B.T. Collins, J.B. Shields and G.W. Laver. 1978. Effects of
hexacnlorobenzene or hexabromobenzene on body and organ weights of
preweaning rata after a reciprocal transfer between the treated and
control dams. J. Agric. Pood Chera. ¦ 26(4)s941-945.
Mumma, C.E., and E.W. Lawless. 1975. Survey of industrial processing data.
Task I - Hexachlorobenzene and hexachlorobutadiene pollution from chloro-
earbon process. Prepared by Midvest Res. Inst, under Contract No.
68-01-2105, EPA 560/3-75-003. NT1S PB 243 641.
NAS. 1980. National Academy of Sciences. Drinking Water and Health. Volume 3.
Safe Drinking Water Committee, NAS, Washington, D.C. pp. 210-215.
NAS. 1983. National Academy of Sciences. Drinking Water and Health. Volume 5.
Safe Drinking Water Committee, NAS, Washington, D.C. pp. 49-56.
Senner, G. 1981, Biotransformation of the fungicides hexachlorobenzene ani
pentachloronitrobenzene. Xenobiotica 11(7):435-446.
Rush, G.F., J.H. Smith, K, Malta, et al. 1983. Perinatal hexachlorobenzene
toxicity in the mink. Environ. Res. 31:116-124.
Sax, N.I, 1979, Dangerous Properties of Industrial Materials, 5th ed.
Van Nostrand Reinhold Col, NY. p. 716.
Shirai, T., Y. Miyata, K. Nakanishi, G. Murasaki and N. Ito. 1978. Hepato-
carcinogenicity of polychlorinated terphenyl (PCX) in ICR mice and its
enhancement by hexachlorobenzene (HCB). Cancer Lett. 4(53:271-275.
Simon, G.S., R.G. Tardiff and J.F, Bor2elleca. 1979, Failure of hexachloro-
benzene to induce dominant lethal mutations in the rat. Toxicol. Appl.
Pharmacol. 47(2):4*5-419.
Smith, A.f?., J, Cabral. 1980. Liver-cell tumors in rats fed hexachloro-
benzene. Cancer Lett. 11(2):169-112,
255
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Hexacnlorobenzene
March 31, 19 3
-1 6-
Standard Methods. 1985. Method 509A. Organochlorine Pesticides. Standard
Methods for the Examination of Water and Wastewater, 16th Edition, APKA,
AWWA, WPCF, 1985.
U.S. EPA. 1978. U.S. Environmental Protection Agency. Method for organo-
chlorine pesticides in drinking water. In: Methods for Organochlorine
Pesticides and Chlorphenoxy Acid Herbicides in Drinking Water and Raw
Source Water, Interim, July 1978.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water quality
criteria for chlorinated benzenes. Environmental Criteria and Assessment
Office, Cincinnati, OH. EPA 440/ 5-80-028. NTIS PB 81-117392.
U.S." EPA. 1984a. U„S Environmental Protection Agency. Miscellaneous synthetic
organic chemicals, occurrence in drinking water, food and air. Office
of Drinking Water.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. Health assessment
document for chlorinated benzenes. Office of Health and Environmental
Assessment, EPA-600/8«84~015„
U.S. EPA. 1985a» U.S. Environmental Protection Agency. Drinking water
criteria document for hexachlorobenzene. Environmental Criteria and
Assessment Office, Cincinnati, OH. ECAO-CIN»424. (Final Draft)
U.S. EPA. 1985b. U.S. Environmental Protection Agency* Technologies and
costs for the reiroval of synthetic organic chemicals from potable water
supplies. Science and Technology Branch, Criteria and Standards
Division, Office of Drinking Water. Washington, DC.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register 51(185):33992-340G3.
September 24.
WHO. 1984. World Health Organization. Guidelines for drinking water quality.
Volume I. Recommendations. WHO, Geneva, p. 83.
256
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larch 31 , 1 9S~
n-HEXANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effect*/ analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models- is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
257
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n-Hexane
March 31, 19 S~
-2-
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 110-54-3
Structural Formula
H H H H H H
I I I II I
H=C-C-C-C-C-C-H
I N M I
I11IHB
Synonyms
° Esani, Heksan, Hexahen (NIOSH, 1978)
Uses
° Hexane is used commercially as a solvent in gxues, vsnusnes, cements
and inks (NIOSH, 1977).
9 Hexane also is used in the seed oil industry to extract the natural
oils from various seeds, including soybeans and cotton seeds.
Properties (Windholz, 1983)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Specific Gravity
Vapor Pressure
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence
0 Hexane has not been included in Federal and State surveys of drinking
water and no other information on the occurrence of hexane has been
located.
III. PHARMACOKINETICS
Absorption
0 Bus et al. (1983) studied the absorption of n-hexane in rats following
a single 6-hour inhalational exposure to 1,000 (2,780 mg/m3), 3,000
(8,340 mg/m3) or 10,000 (27,800 mg/m3) ppm c14-n-hexane. Total
CH'3(CH2) 4CH3
86.18
Liquid
68.7°C
0.655 at 25°C.
150 nm at 25°C
23 mg/liter
1 ppm m 2o78 mg/m3
258
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n-Hexane
March 31, 1967
-3-
radioactivity collected in the various excreta fractions was approxi-
mately 98% of the total administered dose levels.
Distribution
* No information was found in the available literature on distribution
of n-Hexane.
Metabolism
* DiVincenzo et al. (1976) studied the metabolism of n-hexane in
guinea pigs. The chemical was dissolved in corn oil and injected
intraperitoneally in a single dose of 450 agA? body weight in male
guinea pigs. Blood samples were collected 1, 2, 4, 6, 8, 12 and 16
hours after the dose was administered. The two major metabolites of
n-hexane in the serum were identified as 2,5-hexanedione and 5-hydroxy-
2-hexanone; however, they were not quantified.
° Studies in shoe factory workers show that n-hexane is metabolized to
2-hexanol, 2,5-hexanedione, 2,5-dimethylfuran and 0-valerolactone
(Perbillini et al., 1980).
° Baker and Rickert (1981) studied metabolism of n-hexane in the
Fischer-344 rat following inhalation of n-hexane. Male' F-344 rats
were exposed to 5.00 (1,390 mg/m3), 1,000 (2,780 mg/m3), 3,000 (8,340
mg/m3) cr 10,000 (27,800 mg/m3) ppm n-hexane in the air. n-Hexane and
its metabolites, methyl-n-butyl ketone (MBK), 2,5-dimethylfuran (DMFU),
2,5-hexanedione (2,5-HD), 2-hexanol and 1-hexanol, were quantified by
GC/KS in several tissues at time intervals during and following a
single 6-hr exposure to n-hexane. Urinary metabolites were quantified
following a single n-hexane exposure. n-Hexane concentrations achieved
an apparent steady state within two hours in all tissues. Peak blood
concentrations of n-hexane were 1, 2, 8 and 12 ug/ml and peak sciatic
nerve concentrations were. 12, 48, 130 and 430 ug/g at 500 (1,390 mg/m3),
1,000 (2,780 mg/m3), 3,000 (8,340 mg/m3) and 10,000 (27,800 mg/m3) ppn,
respectively. The halflives of n-hexane and MBK were on the order of
1 to 2 hours in all tissues except the kidneys (K1/2 ¦ 5 to 6 hrs).
The data showed a complex relationship between n-hexane exposure and
peak concentrations of the remaining metabolites. Tissue concentrations
of 2,5-HD were not proportional to dose. Highest 2,5-HD concentrations
were-found following exposure to 1,000 ppm n-hexane in the blood,
kidneys and sciatic nerve (6.1, 55 and 25 ug/g, respectively). The
data indicated that the metabolism and elimination of n-hexane were
dependent upon exposure concentration. Consequently, n-hexane exposure
concentration cannot be directly correlated with tissue 2,5-HD concen-
trations .
Excretion
0 The metabolites -sf n-hexane in urine and their concentrations following
n-hexane (commercial) exposure of shoe factory workers were: 2-hexanol
(0.5 mg/liter), 2,5-hexanedione (10.1 mg/liter), O-valerolactone (2.4
mg/liter) and 2,5-dimethylfuran (5.2 mg/liter) (Perbillini et al.,
1980) .
259
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n-Hexane
March 31, 1967
-4-
IV. HEALTH EFFECTS
Humans
0 Hershkowits et al. (1971 ) reported the effects of inhalation of
»°>hexane vapor on three female employees who worked in a furniture
factory. n-Hexane concentrations in the room averaged 650 (1,807
ag/m3) ppm with peaks up to 1,300 (3,614 mg/m3) ppm. The first
synptoms appeared 2 to 4 awnths after the beginning of exposure and
the three enployees were hospitalized 6 to 10 Months later when they
complained of one or more of the following symptoms: headache,
burning sensation of the face, abdominal cramps, auabsiess and weakness
of the distal extremities° Physical examination revealed bilateral
foot-drop gait, bilateral wrist drop and absence of Achilles tendon
reflexes. Electromyographic examination of these patients indicated
fibrillation potentials in the small muscles of the hands and feet.
Biopsies of the anterior tibial muscle and sural nerves of two of the
patients revealed that the muscles contained small engulated fibers
and other fibers with clear central zones (denervation type injury).
Small bundles of axons from the Basel® sections were studied by
electron microscopy and found to contain dense bodies and fibrous
formations, increased numbers of neurofilaments and abnormal membranous
structures with clumped and degenerated mitochondrial. Motor-end
plates also were damaged, with swollen terminal axoplasmic expansions,
an increased number of degenerated mitochondria and an increased
number of glycogen granules, dense bodies, large osmophilic membranes,
synaptic folds and vesicles» The investigators reported that the
health of these employees improved after leaving their employment.
Animals
Short-term Exposure
° Kimura et al. (1971 ) studied the oral toxicity of a single dose of
n-hexane in different age groups of rats: newborn (1 to 2 days old,
5 to 8 a), 14 days old (16 to 50 g), young adult (80 to 160 g) and
older adult (300 to 470 g). The undiluted solvents were administered
orally to non-fasted rats. A precise LD50 value for n-hexane could not
be determined for the newborn rats because of measurement limitations,
but doses of less than 1 mlA? body weight were lethal. The acute
oral LD50 was 24.0 mlA9 (15.7 gAg) for 14-day old rats, 49.0 ml/kg
(12.1 g/kg) for young adults and 43.5 ml/kg (28.9 g/kg) for older
adult rats.
Hewett et al. (1980) carried out experiments in which groups of
male adult Sprague-Dawley rats were given a single oral dose of
1,290 mgAg of n-hexane solubilized in corn oil (control animals
received corn oil alone). This segment of the experiment was to
provide eviaence of potentiation of chloroform toxicity in rats
pretreated with n-hexane, methyl n-butyl ketone or 2,5-hexanedione.
n-Hexane-induced hepatotoxicity was estimated 42 hours later by
measuring enzyme activity of glutamic-pyruvic transferase (GPT) and
ornithine carbamyl transferase (OCT) in the plasma of animals.
e
260
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n-Hexane
March 31, 1 9£"
-5-
The extent of cell damage was assessed by observing histological
changes in the liver and nephrotoxicity was evaluated by monitoring
the ability of renal cortical slices to accumulate an .organic anion
(p-aminohippurate) and cation (tetraethylammonium) and by deter-
mining the blood urea nitrogen content. The investigators reported
that the 1,290 mgAg dose of n-hexane produced no measurable effects
either on organ weight (liver, kidney) or on any parameters described
earlier. However, a single oral dose of n-hexane in rats produced
minimal changes in renal histology as indicated by the presence of
degenerated tubules in sections from these animals.
° Howd et al. (1982) studied the relation between schedules of exposure
to n-hexane and plasma levels o£ 2,5-hexanedione. Male Fischer rats
were exposed repeatedly to high concentrations of n-hexane: 4,000 ppm
for 8 hours/day for 5 days/week; 48,000 ppm for 10 ninutes every half
hour for 8 hours/day, 5 days/week; 40,000 ppm for 10 minutes every
half hour, on a background of 4,000 ppm continuous, for 8 hours/day,
5 days/week. Concentrations of n-hexane in blood and brain were
linearly related to the concentrations of n-hexane in the chamber
after a 10-ninute exposure, and declined thereafter, with half-lives
of about 2-1/2 and 4 minutes in blood and brain, respectively. Despite
the rapid elimination of n-hexane, neurotoxic levels of 2,5-hexanedione
(2,5-HD) were formed from repeated 10-minute exposures to a high con-
centration of n-hexane when the"inter-exposure interval was 20 minutes.
Neurotoxic levels of 2,5-HD also resulted from continuous exposure to
much lower concentrations of n-hexane. Both exposure schedules (4,000
ppm for 8 hours/day and 10 minutes every half hour exposure) caused
an incrsase in 2,5-HD concentrations in blood after repeated daily
treatments. The 'authors suggested that the minimal sustained plasma
2,5-HD concentration that will result in neurotoxicity appears to be
less than 50 ug/ml in the rat.
0 In vitro toxicity of n-hexane and 2,5-hexanedione using isolated
perfused rabbit hearts is reported (Raye, 1983). The hearts were
perfused using Langendorf's procedure and modified Anderson's coronary
perfusion apparatus. The force of cardiac contraction was significantly
reduced following one hour perfusion with 9.6 mg/L concentration of
n-hexane and with 0.35% v/v concentration of 2,5-hexanedione.
Dermal/Ocular Effects
0 Jakobson et al. (1982) reported results of uptake via the blood and
elimination of n-hexane (one of 10 organic solvents) following
epicutaneous exposure of anesthetized guinea pigs. The concentration
of n-hexane in the blood was monitored over a 6-hour period of n-hexane
exposure of anesthetized guinea pigs. A glass ring chamber (area:
3.1 cm2) 4 nn in thickness and 10 mm in height was glued to a clipped
area cf skin or. the back of the guinea pigs. This glass ring chamber
contained 1,0 nl of n-hexane solvent for the study. With n-hexane,
the concentrations in the blood at 0.5 and 6 hrs were 0.58 and 0.23
ug/ir.l cf n-hexane, respectively.
561
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n-Hexane
March 31, 19E"
-6-
0 Nomiyama and Nomiyama (1975) investigated the absorption rates of
n-hexane and toluene through the skin of humans. An unspecified
number of subjects immersed their hands up to the vrists in a dish
containing analytically pure n-hexane (95% n-hexane) for 1 minute.
At intervals following skin exposure, breath, blood and urine samples
were analyzed for n-hexane by gas chromatographs. The authors were
unable to detect hexane in either the breath or the blood of any of
the subjects following exposure to n-hexane. The detection limit for
n-hexane was 1 ppm in the breath and 3.5 ppm in blood. The authors
did not describe any physiological effects.
Long-term Exposure
0 Krasavage et alo (1980) studied the relative neurotoxicities of
n-hexane by the appearance of hind-limb weakness. Charles River male
rats were given oral doses of n-hexane at 570 ng/kg (6.6 mmel/kg)
5 days/week for 90 days or 1,140 or 4P000 mg/kg doses for 120 days.
As soon as hind~limb weakness clinical signs occurred, the animals
were killed and the tissues w®re examined f©£ histopathological
changes. No clinical or histological signs of neuropathy were observed
in the animals at dose levels of 570 or 1,140 ag/kg n-hexane (although
body weights were depressed at all three dose levels compared to
controls). At a dose level of 4,000 mg/kg n-hexane, the clinical and
histological signs of neuropathy occurred at approximately 101 days.
The histological changes included multi-focal axonal swellings,
adaxonal myelin infolding and paranodal myelin retraction. Jn addition
to neuropathy, histological examination of testicular tissue revealed
varying stages of atrophy of the germinal epithelium following the
administration of 4,000 mg/kg n-hexane.
0 Takeuchi et al. (1980) studied the neurotoxicity of n-hexane in
wistar strain male rats following inhalation exposure to 3,000 ppm
(8,340 mg/m3) of n-hexane for 12 hours a day for 16 weeks. The nerve
conduction velocity and the distal latency measured before the
beginning of the exposure and after the experiment showed that
(1) n-hexane disturbed the conduction velocity of the motor nerve and .
the mixed nerve and prolonged the distal latency in the rat's tail
and (2) the neuromuscular junction and the'muscle fiber of the rats
exposed to n-hexane were impaired severely as seen by light and
electron microscopy.
0 Cavender et al. (1984) reported the results Qf a 13-week vapor
inhalation study of n-hexane in rats with emphasis on neurotoxic
effects. Male and female Fischer-344 rats were exposed to 0, 3,000
(8,340 mg/m3), 6,500 (18,070 mg/m3) or 10,000 (27,800 mg/m3) ppm
n-hexane vapors 6 hours per day, 5 days per week, for 13 weeks. The
13-week exposures had no adverse effect on the growth of'female rats.
However, the mean body weight gain of male rats in the 10,000 (27,800
mg/m3) ppm was significantly lower than for controls at 4 weeks of
exposure and thereafter. In addition to the depression in body weight
gain, the males exposed to 10,000 (27,800 mg/m3) ppm had slightly but
significantly lower brain weights at necropsy. No adverse testicular
effects were noted. Axonopathy was observed in the tibial nerve in
262
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n-Hexane
March 3", 1957
-7-
four of five male rats from the 10,000 ppm group and one of five male
rats in the 6,500 (18,070 mg/m3) ppm group and in the medulla from
one male rat in the 10,000 (27,800 mg/m^) ppm group. These axonal
changes were detectable only in teased nerve fiber preparations or in
Epon embedded specimens. Histopathologic studies on Formalin fixed
tissues did not reveal any lesions that were attributed to n-hexane
exposure.
Reproductive Effects
0 Bus et al. (1979) studied the effects of aaternal inhalation ex-
posure to n-hexane on the size and survival of newborn Fischer 344
rats. Pregnant rats were exposed for 6 hours per day to 1,000 (2,780
mg/m3) ppm (3„5 g/m3) n-hexane on days 8 to 12, 12 to 16, or 8 to 16
of gestation. No significant changes in fetal resorption, body
weights, visible anomalies or the incidence of soft tissue and skeletal
anomalies were noted in any of the treatment groups. The post-natal
growth of pups born to dams exposed to n-hexane at 1,000 (2,780 mg/m3)
ppm (3.5 g/oi3) 6 hours/day on days 8 through 16 of gestation, was
depressed significantly (P < 0.05) compared to controls for up to 3
weeks after birth. However, litter weights of treated pups had
returned to control values by 7 weeks after birth. Mo anatomic
defects or neuropathic symptoms were noted in treated pups.
Developmental Effects
0 Marks et al. (1980) stated that n-hexane was not teratogenic in mice
up to a dose level of 9.90 g/kg/day. In this experiment, pregnant
outbred albino mice (CD-1) received n-hexane once daily by gavage at
doses up to 2.20 g/kg/day on days 6-15 of gestation. Other pregnant
mice received higher hexane doses (up to 9.90 g/kg/day), employing a
three times a day injection schedule. At the lower, once-daily doses
only one dam died and no teratogenic effects occurred. Higher hexane
doses were toxic: 2 of 25 dams treated with 2.83 g/kg/day, 3 of 34
treated with 7.92 g/kg/day and 5 of 33 treated with 9.90 g/kg/day
died. At the 7.92 and 9.90 g/kg/day doses, the average fetal weight
was significantly (P <0.05) reduced, but the incidence of malformations
in treated and vehicle (cottonseed oil) control groups did not differ
significantly. Thus, n-hexane was not teratogenic eVen at doses
toxic to the dam.
Mutagenicity
# No information was found in the available literature on the mutagenic
effects of n-hexane.
Carcinogenicity
0 No information was found in the available literature on the carcinogeni
effects of n-hexane.
2
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n-Hexane
March 31, 1967
-8-
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive nonc&rcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicaats are derived using the following formula:
HA ¦ (NOAEL or LOAEL) x (BW) _ mg/L (_ ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL » No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW
assumed body weight of a child (10 leg) or
an adult (70 kg).
OF • uncertainty factor (10, 100 or 1,000),. in
accordance with NAS/ODW guidelines.
___ L/day ¦ assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The results of the Hewlett et al» (1980) study in which a group of
Sprague-Dawley male rats were given a single oral dose of 1,290 mg/kg n-hexane
can be used for the derivation of a One-day HA, even though these studies (in
which other chemicals also were screened) were not designed specifically to
examine the toxicity of n-hexane. This dose produced no measurable effects
on the following parameters after 42 hours: relative liver weight, relative
kidney weight, plasma glutamic-pyruvic transaminase, plasma ornithine earbamyl
transferase, hepatic and renal histological changes, uptake of p-aminohippurate
and tetraethylammonium ion by kidney slices, and blood urea nitrogen. These
negative findings (except for body weight at the single data point are con-
sistent with the results reported by Krasavage et al° (1980) in a 90-day
study. However, a single oral dose of n-hexane in rats produced minimal
changes in renal histology as indicated by the presence "of degenerated tubules
in sections from these animals.
The One-day HA for the 10-kg child is calculated as follows:
One-day HA - (1.290 mgAg/day) (10 kg) „ 12.g Bg/L (13,000 ug/L)
(1 L/day) (1,000)
where:
1,290 mg/kg/day = LOAEL based on minimal adverse effect in male rats.
10 leg = assumed body weight of a child.
264
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n-Hexane
March 31 , 195"
-9-
1,000 ¦ uncertainty factor, chosen in accordance with nas/odw
guidelines for use with a LOAEL from an animal study.
1 L/day ¦ assumed daily water consumption of a child.
Ten-day Health Advisory
Appropriate studies for the derivation of a Ten-day HA are not available.
Use of the Longer-term HA for the 10-kg child of 4 mg/L is recommended.
Longer-term Health Advisory
The inhalation study by Takeuchi et al. (1980) was not considered because
the parameters were not examined in details However, a Longer-term HA can be
derived from a study (Krasavage et al«, 1980) in which Charles River rats
were given oral doses of 570 mgAg n-hexane 5 days/week for 90 days, 1,140
mg/kg or 4,000 mgAg for 120 days. Clinical and histological signs of neuro-
pathy were absent in the animals at dose levels of 570 and 1,140 mg/kg n-hexane
(although body weights were depressed at all three dose levels compared to
control). The lowest dose administered (570 mgAg) can be considered a
LOAEL. A safety factor of 1,000 will be used since only one species was
considered in the study and the data obtained were part of a broader study
dealing with relative neurotoxicity of n-hexane, methyl n-butyl ketone and
their metabolites.
The Longer-tart: HA for a 10-kg child is calculated as follows:
Longer-term HA = (_570 mgAg/day) (10 kg) (5) .4.07 mg/L (4,000 ug/L)
(1.000) (1 L/day) (7) * y/
where:
570 mgAg/day » LOAEL based on depressed body weight in animals.
10 kg = assumed body weight of a child.
5/7 « conversion of 5 day/week dosing schedule to 7 day/week.
1,000 « uncertainty factor, chosen in accordance with NAS/ODW
for use with a LOAEL from an animal study.
1 L/day * assumed daily water consumption of a child.
The Longer-tern HA for a 70 kg adult is:
Longer-term HA = .(>70 mg/kg/day) (70 kg) (5) .14.3 mg/L (14,000 ug/L)
(1,000) (2 L/day) (7)
where:
570 mgAg/day = LOAEL based on depressed body weight in rats.
70 kg = assumed body weight of an adult.
265
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n-Hexane
March 31, 196"
-1 0-
1,000 » uncertainty factor, chosen in accordance with NAS/ODV
guidelines for use with a LOAEL from an animal study.
2 L/day ® assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADD. The RfD is an esti-
mate of a daily exposure to the huaa» population that is likely to be without
appreciable risk o£ deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (UoSc EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Appropriate studies for the derivation of a Lifetime HA are not avail-
able at this time. The Krasavage et al. (1980) study was not considered
because the data obtained were part of a broader study dealing with other
chemicals.
Evaluation of Carcinogenic Potential
° No information was found in the available literature on the carcino-
genic effects of n-hexane.
° According to the EPA classification scheme (U.S. EPA, 1986), n-hexane
may be classified as Group D.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
° An occupational threshold limit value (TLV) of 100 ppm was set by
ACGIH (1976).
VII. ANALYTICAL METHODS
c There is no standardized method for the determination of hexane in
drinking water samples. However, hexane may be determined by a
266
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n-Hexane
March 31, 198"
-11-
purge-and-trap gas chromatographic/mass spectrometric procedure used
for the determination of volatile organic compounds in water (U.S. EFA,
1985). This method calls for the bubbling of an inert gas through
the sample and trapping hexane on an adsorbant material. The adsorbant
material is heated to drive off n-hexane onto a gas chromatographic
column. The gas chromatograph is temperature programmed to separate
the method analytes which are then detected by the mass spectrometer.
nil. TREATMENT TECHNOLOGIES
° No data are available on the removal of n-hexane by conventional or
other treatment technologies. However, the physical properties and
structure of the compound, as well as its similarity to other straight
chain aliphatic hydrocarbons, suggest that several treatment methods
may be effective in removing n-hexane.
0 ESE (1982) considered adsorption a potential treatment technique for
hexane on the basis of its structure and low solubility. According
to KcGuire and Suffet (1980), non-polar saturated hydrocarbons such
as hexane should be adsorbed on granulated activated carbon (GAC).
However, only limited data demonstrating hexane removal by GAC is
available. In a full-scale study, average hexane concentrations in
water were reduced from 0.2 ppb to 0.1 ppb on passage through each of
two 5 ft diameter (1.6 m), 11 ft (3.4 m) GAC contactors containing
Westvaco 12 x 40 GAC. The hydraulic loading for each contactor was
7.4 gpm/ft2 and the Empty Bed Contact Time was 15.2 min. .
• Packed column aeration also may remove n-hexane from drinking water.
McCarty et al. (1979) found that the Henry's Law Constant for a
chemical is a good indicator of the relative amenability of that
chemical to aeration. Accordingly, the Henry's Law Constant for
n-hexane (1 x 1C"1 atm-m^/mole) suggests that this substance will be
amenable to removal from solution by air stripping. For example, this
value is significantly higher than-that for chloroform (3.4 x 10-3
atm-m3/mole), a substance known to be amenable to air stripping
(Singley and Bilello, 1981). Air stripping is an effective, simple
and relatively inexpensive process for removing many organics from
water. However, this process transfers the contaminant directly to
the air stream. When considering use of air stripping as a treatment
process, it is suggested that careful consideration be given to the
overall environmental occurrence* fate, route of exposure and potential
health hazards associated with the chemical.
° The bciling poi.'it of- n-hexane (69#C) and of its azeotropic mixture
with water [94.41 n-hexane, 61.6°C CCRC, 1979)] suggest that boiling
would be an effective means of removing n-hexane from aqueous systems.
However, the potential health hazard from hexane inhalation would
have to be considered.
° A study reported by fcuentin et al. (1977) removed n-hexane in water
from 7.3 mg/L to 0.3 mg/L after treatment with alum and a polymeric
flocculant. This suggests that a conventional treatment process such
as coagulation/sedimentation may be effective in reducing n-hexane.
267
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n-Hexane
March 31, 1987
-1 2-
REFEREMCES
ACGIH. 1976. American Conference of Governmental Industrial Hygienists:
TLVs—threshold limit values for chemical substances in workroom air
adopted by ACGIH for 1976. Cincinnati, 011c pp. 1-54«
Baker, T„S., and D.E. Rickert. 1981. Dose-dependent uptake, distribution,
and elimination of inhaled n-hexane in the Fischer-344 rat. Toxicol.
Apple Pharmacol. 61:414-422.
Bellar, T.A., and J.J. LichLanberg. 1974. Determining volatile organics
at microgram-per-liter levels by gas chromatography. Journal AWWA.
66:739-744.
Bus, JoS., E.L. White, R.H. Tyl and CoS. Barron. 1979. Prenatal toxicity
and metabolism of n-hexane in Fischer 344 rats after inhalation exposure
during gestation. Toxicol. Appl. Pharmacol. 51:295-302.
Bus, J.S., D. Deyo and M. Cox. 1983. Disposition of radioactivity in rats
after acute inhalation exposure to c1^n-hexane. The Toxicologist. 3:135.
Cavender, F.L., H.Wo Casey, H. Salem, D.G. Graham, J.A. Swenberg and E.G. Gralla.
1984. A 13-week vapor inhalation study of n-hexane in rats with emphasis
on neurotoxic effects. Fundam. Appl. Toxicol. 4:191-201.
CRC Handbook of Chemistry and Physics. 1979. R.C. Weast and M.G. Astle, eds.
CRC Press. Nest Palm Beach, Florida.
DiVincenzo, G.D;, C.J. Kaplan and J. Dedinas. 1976. Characterization of
the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone and
methyl ethyl ketone in guinea pig serum and their clearance. Toxicol.
Appl. Pharmacol. 36:511-522.
ESE. 1982. Environmental Science and Engineering. Treatment techniques
available for removal of n-hexane. In support of Office of Drinking
Water Health Advisory prepared for Science and Technology Branch, CSD,
ODW, U.S. EPA.
Herskowitz, A., N. Ishii and H. Schaumburg. 1971. N-hexane neuropathy—
A syndrome occurring as a result of industrial exposure. N. Engl. J. Med.
285:82-85.
Hewett, W.R., H. Miyajima, M.G. Cote and G.L. Plaa. 1980. Acute alteration
of chlorofonr-induced hepato- and nephrotoxicity by n-hexane, methyl-n-
butyl ketone and 2,5-hexanedione. Toxicol. Appl. Pharmacol. 53:230-245.
Howd, R.A., L.R. Bingha-, T.M. Steeger, C.S. Rebert and G.T. Pryor. 1982.
Relation ketv;een »c.ieduie& of exposure to hexane and plasma levels of
2,5-hexaneaione. Neurobehav. Toxicol. Teratol. 4:87-91.
Jakobson, I., J.E. Wahlberg, B. Holmberg and G. Johansson. 1982. Uptake via the
blood and elimination of 10 organic solvents following epicutaneous expo-
sure of anesthetized guinea pigs. Toxicol. Appl. Pharmacol. 63:181-187.
268
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n-Hexane
March 31, 19S7
¦1 3-
Kimura, E.T., D.M. Ebert and P.W. Dodge. 1971. Acute toxicity and limits
of solvent residue for sixteen organic solvents. Toxicol. Appl. Pharmacol.
19:699-704.
Kirk-Othmer. 1981. C<| to Cg Alkanes. In Kirk-Othmer Encyclopedia of Chemical
Technology, 3rd ed. Wiley-Interscience. New York.
Krasavage, W.J., J.L. O'Donoghue, G.D. OiVincenzo and C.J. Terhaar. 1980.
The relative neurotoxicity of nethyl-n-butyl ketone, n-hexane and their
aetabolites. Toxicol. Appl. Pharnacol. 52:433-441.
Marks, ToA., P„w. Fisher and E„ Staples. 1980. Influence of n-hexane on
embryo and fetal development in mice. Drug and Chen. Toxicol. 3:393-406.
McCarty et al. 1979. Treatment for the control of trichloroethylene and
related industrial solvents in drinking water. U.S. Environmental
Protection Agency, Drinking Water Research Division. Cincinnati, Ohio.
McGuire, M.J. and l.H. Suffet. 1980. Activated carbon adsorption of organics
from aqueous phase: Vol. 2. Ann Arbor Science Publishers, Inc. Ann
Arbor, Michigan.
Nomiyama, I., and J. Nomiyama. 1975. The effects of the cutaneous absorption
of n-hexane on humans. Jpn. J. Hyg. 30:140. (Cited in NIOSH, 1977)
NIOSH. 1977. Kational Institute for Occupational Safety and Health. Criteria
for a recommended standard...occupational exposure to alkanes (C5-C8).
Washington, DC. Publication No. 77-151.
NIOSH. 1-978. National Institute for Occupational Safety and Health. Registry
of Toxic Effects of Chemical Substances (RTECS). 1978.
Perbellini, L., F. Brugnone and I. Pavan. 1980. Identification of the
metabolites of n-hexane, cyclohexane and their isomers in men's urine.
Toxicol. Appl. Pharmacol. 53:220-229.
Perry, R.H. and C.H. Chilton. 1973. Chemical Engineers Handbook. 5th
Edition. McGraw-Hill Book Company, pp. 3-56.
Quentin, K.E., L. Weil and H. Berger. 1977. U.S. Patent 4,028,233, June 7,
1977, assigned to A.G. Hoechst, Germany Industrial Wastewater Cleanup,
Noyes Data Corporation, 1979.
Raye, R. 1983. In vitro toxicity of n-hexane and 2,5-hexanedione using
isolated perfused rabbit heart. J. Toxicol. Environ. Health. 11:879-864.
Singley, J.E., anJ L.J. S.lcllo. 1981. Advances in the development of design
criteria for packed column aeration. Submitted to Journal AWWA, 1981.
Takeuchi, Y., y. Oho, N. Hisanaga, J. Kitoh and Y. Sugiura. 1980. A com-
parative study on the neurotoxicity of n-pentane, n-hexane and n-heptane
¦in the rat. Brit. J. Ind. Med. 37:241-247.
269
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n-Hexane
March 31, 1967
-14-
U.S. EPA. 1985. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, OHo,45268. June.
U.S. EPA. 1986. UoSo Environmental Protection Agency. Final guidelines for
carcinogen risk assessment. Federal Register. 51(185):33992-34003.
September 24.
Windholz, M. 1983. The Merck Index. 10th Edition. Merck and Co.. Inc.,
Rahway, N.J. p. 678.
270
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March 31, 195
METHYL ETHYL KETONE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODWJ, provides infoimation on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin-of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and lccal officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject .to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water,~ The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
271
-------
Methyl Ethyl Ketone March 31, 198"
-2-
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 78-93-3
Structural Formula
0
II
CH3-CH2-C-CH3
Synonyms
2-Butanone, butan-2-one, ethyl methyl ketone, MEK.
Uses
0 As a solvent in processes involving gums, resins, cellulose acetate,
ar,d cellulose nitrate
0 Used extensively in the synthetic rubber industry
0 In production of paraffin wax and high grade lubricating oil
c In household products such as surface coating compounds (lacquer and
varnishes), paint remover, and glues.
Properties
Chemical Formula C^gO
Molecular Weight 72.10
Physical State liquid
Boiling Point 79.6°C
Melting Point —
Density
Vapor Pessure 100 mm Hg at 25°C
Water Solubility 295 mg/L at 25°C
Log Octar.ol/Water Partition
Coeffficient
Taste Threshold
Odor Threshold
Conversion Factor 1 ppm ¦ 2.95 mg/1113
Occurrence
0 Methyl ethyl ketone (MEK) is a synthetic organic chemical which does
not occur naturally. Production of MEK in 1980 was approximately 600
million lbs (U.S. ITC, 1981).
0 No information on the environmental fate of MEK has been identified.
Based upon its reported vapor pressure and solublity, MEK is expected
to slowly volatilize from soil and water. Due to MEK's relatively
high solublity in water MEK is expected to be mobile in soil.
272
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Methyl Etnyi' Ketone
March 3', 19c.
-3-
° MEK has not been included in Federal and State surveys of drinking
water. However, a number of studies have reported that MEK does
occur in surface water systems (Scheiman et al., 1974; U.S. EPA,
1976; Coleman et al., 1976).
III. PHARMACOKINETICS
Absorption
* Munies and Wurster (1965) studied the dermal absorption of HEX in
humans under normal, hydrated and dehydrated skin conditions. MEK
was applied at 100 ml to the forearm using an absorption cell; the
duration of exposure was 8 hours. MEK was detected in the expired
air at 3.6 mg./L 15 minutes after exposure. A steady-state level of
6.5 to 6.6 mg/L in the expired air was attained within 2 to 3 hours
after exposure.
° DiVincenso and coworkers (1974) reported that levels of 11* of admini-
stered MEK and metabolites were found in the serum 1 hour following
a single intraperitoneal dose of 450 ag/kg in guinea pigs.
Distribution
° Dietz and Traiger (1979) determined the blood concentrations of
2-butanol, 2,3-butanediol and 3-hydroxy-2-butanone in rats after
a single oral dose of 355 mgAg MEK.. The blood concentrations of
MEK and metabolites 4 hours after dosing were as follows: MEK
(94.1 mg/100 ml), 2-butanol (3.2 mg/100 ml), 3-hydroxy-2-butanone
(2.4 mg/100 ml), and 2,3-butanediol (8.6 mg/100 ml).
Metabolism
0 No information was found in the available literature on the metabolism
of methyl ethyl ketone.
Excretion
0 Insufficient pharmacokinetic data for MEK are available to assess
distribution and elimination of MEK in animals.
IV. HEALTH EFFECTS
Humans
° Data regarding the effects of oral exposure to MEK on humans were not
located in tne available literature. However, Smith and Mayers
(1944) iie^orted tli.it two young women exhibited signs of severe intoxi-
cation, including convulsions and loss of consciousness, after exposure
to MEK and acetone (298 to 560 and 330 to 495 ppm, respectively).
273
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Methyl-Ethyl Ketone March 31, 19c"
-4-
Animals
Short-term Exposure
0 The acute LD50 and LD50 of MEK have been determined for several routes
of exposure:
Species
rat
rat
rabbit
Route
oral
inhalation
dermal
2.9 g/kg
5»S g/m3
(2t000 ppm/4 hr)
>8 gAg
Reference
Kinura et al., 1971
Carpenter et al», 1949
Smyth et al., 1962
D Kimura and co-workers (1971) also have determined the oral LDjq values
for weanling and newborn rats to be 2.5 and 0.8 g/kg, respectively.
° Patty and co-workers (1935) studied the toxic effeets of MEK inhalation
in the guinea pig. The animals were exposed to high concentrations
Df vapor: 3,300 ppm (997 g/m3), 10,000 ppm (29.5 g/m3), 33,000 ppm
(97.3 g/m3) or 100„000 ppm (295 g/m3) for various durations up to
14 hours. Pathologic examination was done on animals that died during
exposure, cn those immediately sacrificed after exposure and on'
animals sacrificed 4 and 8 days after termination of exposure. At
Levels of 10,000 ppm (29.5 g/m3), 33,J)00 ppm (97.3 g/m3) and 100,000
ppm (295 g/m3), MEK exposure produced irritation of the nose and
syes, tearirg, respiratory distress, incoordination and narcosis.
Exposure to MEK vapor at a concentration of 100,000 ppm (295 g/m3) to
guinea pigs for 30 minutes or more resulted in corneal opacity. This
condition improved gradually in guinea pigs that lived 4 and 8 days
following exposure; at the end of 8 days, the eyes were nearly
normal.- This condition was not observed in animals exposed to- lower
concentrations. The pathologic findings in animals that died during
exposure or were sacrificed immediately after exposure to MEK (at all
levels except 3,300 ppm) were congestion of the liver, kidney, lung -
and brain congestion and emphysema. Congestion of the visceral
organs was not observed in the animals sacrificed 4 and 8 days after
termination of MEK exposure.
0 Studies have assessed the hepatotoxic effect of MEK after acute
exposure (DiVincenzo and Krasavage, 1974). Guinea pigs were admini-
stered a single intraperitoneal dose of MEK (750, 1,500 or 2,000
mg/kg). Twenty-four hours after exposure, blood samples of animals
were analyzed for ornithine carbamyl transferase (OCT) activity and
liver tissues were examined for histopathological changes. Liver
effects observed were increased lipid content and elevated serum
ornithine carbamyl transferase activity, a sensitive enzymatic assay
for liver injury (Davidsohn and Wells, 1965). Elevated serum OCT
activity was observed 24 hours after administration of 2,000 mg/kg of
MEK. Lipid accumulation in cells of the animal was present at the
two higher dopes (1,500 and 2,000 mg/kg).
274
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Methyl Ethyl Ketone
March 3i, 19E7
-5-
Long-term Exposure
° LaBelle and Brieger {1955} compared the longer-term exposure of
composite solvent, containing 235 ppm (0.693 g/m3) HEK and seven
other solvents (total of 226 ppm) to MEK alone* In each case, 25
rats were exposed to the composite solvent vapors, MEK vapors or air
alone for 7 hours per day, 5 days per week .for 12 weeks. There were
no deaths or sign of toxicity observed in the animals. There were
also no significant gross or microscopic pathological changes observed
at autopsy upon examination of control or exposed animals.
0 Cavender et al. (1083) exposed rats of both sexes to methyl ethyl
ketone at concentrations of 0, 1,250, 2,500 or 5,000 ppm, 6 hours/day,
5 days/week, for 90 days. Mo animals died during the study« The
90-day exposures had no adverse effect on the clinical health or
growth of male or female rats except for a depression of mean body
weight in the 5,000 ppm exposure group. However, at necropsy,
increases in liver weight were noted in the 1,250 and 2,500 ppm group
of female rats. Increases in liver weight, liver weight/body weight
ratios and liver weight/brain weight ratios were observed in both
male and female rats at the dose level of 5,000 ppm methyl ethyl
ketone. In the male rats at the dose level of 5,000 ppm, kidney
weight/body weight ratios also were elevated. Spleen and brain
weights, and brain weight/body weight ratios were elevated in the
5,000 ppm female rats. Urine volumes in the 5,000 ppm male rats were
higher than control values. Mean corpuscular hemoglobin values in
male and female rats at the dose level of 5,000.ppm were elevated.
Serum glutamic-pyruvic transaminase activity in female rats at the
dose level of 2,500 ppm of HEK was elevated while female rats at the
dose level of 5,000 ppm MEK exhibited significantly decreased SGPT
activity. In addition, alkaline phosphatase, potassium and glucose
values for female rats at the dose level of 5,000 ppm were increased
relative to controls. While some of these changes were statistically
significant, they were considered incidental findings, without
toxicological significance.
0 Inhalation exposure of rats to methyl ethyl ketone at a level of 200
ppm, 12 hours/day, 7 days/week for 24 weeks resulted in slight neuro-
logical effects visible only at 4 months of treatment (Takeuchi et al.,
1983), but exposure of rats to 1,125 ppm continuously for 5 months
did not result in neuropathy (Saida et al., 1976). In both studies,
only a single toxicological endpoint, either motor nerve conduction
velocity, mixed nerve conduction velocities, or distal motor latency
(Takeuchi et al., 1983) or paralysis (Saida et al., 1976), was
examined. It was interesting to note in the study by Saida et al.
(1976) that rats exposed to the combination of methyl ethyl ketor.e
and methyl n-butyl ketone developed paralysis after 25 days, and
exposure to 225 ppm methyl n-butyl ketone alone produced paralysis
after 65 dayc (suggesting that methyl ethyl ketone shortened the
latency period for the onset of methyl n-butyl ketone-induced neuro-
pathy.
275
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Methyl Ethyl Ketone
-6-
March 31, 198"
Reproductive Effects
0 Data reported by Schwets and co-workers 11974) implicate MEK to be an
embryotoxie, fetotoxic and teratogenic agent in the rat. Pregnant
rats (Sprague-Dawley) were exposed to MEK vapor at a concentration of
1,126 ppm (3o3 g/m3) ©r 2,618 ppm (7.7 g/m3) for 7 hours/day on days
6 through 15 of gestation* The following parameters were evaluated:
maternal mortality, liver weight and behavior, number of corpora
lutea/dam, number of resorptions, number of implantations, fetal _
mortality, fetal weight and size, and skeletal and visceral anomalies
among the fetuses. MEK exposure at either dose level did not appear
to affect adversely the number of implantation sites, the number of
live fetuses/litter, or the number of corpora lutea/daac There was
evidence of fetotoxicity as indicated by a marked decrease in fetal
body weights following exposure to 1,126 ppm (3.3 g/m3). Decreased
fetal weight was not observed after exposure to 2,618 ppm (7.7 g/m3)
of MEK. Skeletal and visceral anomalies were acted after exposure to
MEK. The total incidence of skeletal anomalies (skull, vertebral,
and sternebral) was increased significantly (P
-------
Methyl Ethyl Ketone
March 31, 19 87
-7-
Carcinogenicity
8 No information was found in the available literature on the carcinc
genie effects of MEK exposure to humans or animals.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA e (NOAEL or LOAEL) x (BW) a ®g/L (__ ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect-Level
in mg/Kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF » uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day * assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
A One-day HA for MEK is calculated based upon findings reported by
DiVincenzo and Krasavage (1974). Guinea pigs were administered MEK at a
single intraperitoneal dose of 750, 1,500 or 2,000 mg/kg. Hepatotoxicity
in guinea pigs was measured in terms of increased serum ornithine carbamyl
transferase activity and lipid accumulation in the liver. Elevated serum
ornithine carbamyl transferase activity was observed 24 hours after admini-
stration of 2,000 mg/kg of MEK. Lipid accumulation in liver cells of animals
was noted also at the two higher doses (1,500 and 2,000 mg/kg). Therefore,
in view of demonstrated hepatotoxicity in terms of increased serum enzyme
activity (at dose level of 2,000 mg/kg) and lipid accumulation in the liver
cells at dose levels of 1,500 and 2,000 mg/kg of MEK, the lowest dose level,
750 mgAg as the NOAEL will be used in the development of a One-day HA.
The One-day HA for a 10 kg child is calculated as follows:
Cne-dav I1A = nso dfly) ^0 kg) = 75 /L „ 75000 u /L
(100)(1 L/day)
where:
750 mg/kg day = NOAEL based on absence of increase in enzyme activity
in guinea pigs.
277
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Methyl Ethyl Ketone
March 31, 1967
-8-
10 leg ¦ assumed body weight of a child.
100 ¦ uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NQ&EL from an animal study.
1 L/day - assumed daily water consumption of a child.
Ten-day Health Advisory
There are no data from which to derive a Ten-day HA directly. Therefore,
it is recommended that the HA can be determined by dividing the One-day HA by
10, resulting in a HA of 7500 ug/L for a 10 kg child.
Longer-term Health Advisory
Adequate duration-specific oral data are not available from which to
derive the Longer-term HA. However, the L&Belle and B?i@ger (1955) inhalation
study in rats may be considered for a longer-term HA. In this study, a group
of 25 rats was exposed to 235 ppm (693 mg/m3) MEK for 7 hours/day, 5 days/week
for 12 weeks. Without indicating the specific organs examined, the authors
reported that no significant pathological changes were observed either macro-
scopically or microscopically. The Longer-term HA is derived as follows:
Step 1: Determination of the Total Absorbed Dose (TAD)
TAD « (693 mg/m3)(1 a3/hr)(7 hr/day) (5/7) (0.5) _ 24.7 BgAg/day
70 kg
where:
693 mg/m3 = NOAEL of 235 ppm based on absence of pathological change
in rats.
1 m3/hr = respiratory rate of adult human (pulmonary rate/body weighi
ratio) assumed to be the same for humans and test animals.
7 hr/day * exposure duration..
5/7 K conversion from 5 days exposure to 7 days exposure.
0.5 " assumed fraction of MEK absorbed.
70 kg = assumed body weight of an adult.
Step 2: Determination of the Longer-Term HA
Longer-tern MA for a 10-kg child:
(24.7 mq/kg/day) (10 kg) = 2.5 mg/L (or 2500 ug/L)
(100) (1 L/day)
278
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Methyl Echvl Ketone
March 31, 1 5£~
-9-
where:
24.7 mgAg/day = TAD.
10 kg ¦ assumed body weight of a child.
100 * uncertainty factor, chosen" in accordance with NAS/ODK
guidelines for use with a NOAEL from an animal study.
1 L/day ¦ assumed daily water consumption of a child.
Longer-term HA for a 0—Jcgr adult:
(24.7 mg/kg/day) (70 kg) « 8.6 mg/L (or 8600 ug/L)
(100) (2 L/day)
where:
24.7 mg/kg/day = TAD.
70 kg » assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), -formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived fror,
the NOAEL (or LCAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Hater Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DUEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Lifetime HA for MEK may be derived based on LaBelle and Brieger (1955)
inhalation study in rats for 12 weeks. In this study, a NOAEL of 693 mg/m3
279
-------
Methyl Ethyl Ketone March 31, 1967
-1 0-
was identified. Animals were exposed to MEK for 7 hours/day, 5 days/week for
12 weeks. The Lifetime HA is derived as follows:
Total absorbed dose (TAD) of 24.7 mg/kg/day was determined as described
under Longer-term HA.
Step 1: Determination of the Reference' Dose (RfD)
RfD - 24.7 mg/kg/day « 0.0247 ng/kg/day
(1,000)
where:
24.7 agAg/day - TAD (NQAEL) based on absence of pathological changes.
1,000 ¦ uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of les3-than-lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DW2L = (0-0247 mg/kg/day) (70 kg) , 0>86 ng/L or 860 ug/L
2 L/day
where:
0.0247 mg/kg/day - RfD.
70 kg » assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA =• 0.86 mg/L x 20% - 0.17 mg/L (170 ug/L)
where:
0.86 mg/L « DWEL.
20% « assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
° No studies on the carcinogenic effects in animals to MEK have been
found in th« available literature.
° IARC has net made an assessment of MEK's carcinogenic potential.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), methyl ethyl ketone may be
280
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Methyl Ethyl Ketone
March 3i, 198-
-11-
classified in Group D: Not classified. This category is for agents
with inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDELINES AND STANDARDS
0 An occupational threshold limit value (TLV^of 200 ppm was set by
ACGIH (1980).
VII. ANALYTICAL METHODS
0 There is no standardized method for the determination of methyl ethyl
ketone in drinking water samples. However, methyl ethyl ketone may be
determined by purge and trap gas chromatographic-mass spectrometric
(GC-MS) procedure used for determination of volatile organic compounds
in industrial and municipal discharges (U.S. EPA, 1984). In this
method, a 5 mL water sample is spiked with an internal standard of an
isotopically stable analog of methyl ethyl ketone and purged with an
inert gas. The volatile compounds are transferred from the aqueous
phase into the gaseous phase where they are passed into a sorbent
column and trapped. After purging is completed, the trap is backflushed
and heated to aesorb the compounds on to a gas chromatograph (GC).
The compounds are separated by the GC and detected by a mass spectro-
meter (MS). The labeled compound serves to correct the variability
of the analytical technique. The method detection limit is dependent
upon the nature of interferences,•but it is estimated to be 50 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Because of its polarity and resulting miscibility in water, MEK is a
difficult compound to remove from contaminated potable water. The
conventional water treatment techniques of coagulation and sand
filtration are ineffective in MEK removal (McGuire et al., 1978).
0 Chlorination does cause some oxidative degradation of NEK. Treatment
with 100 mg/L chlorine for 12 hours reduced MEK by 5* (McGuire et al.,
1978). However, such treatment leads to the formation of trihalo-
methanol which makes chlorination an undesirable treatment. Oxidative
treatment with 100 mg/L potassium permanganate for 3 hours was com-
pletely ineffective in reducing MEK concentrations (McGuire, 1978).
0 MEK also is not a good candidate for removal by air stripping. It has
a low Henry's Law Constant of 3.4 x 10~5 atm m^/mole (McGuire et al.,
1978).
° Adsorption to granular activated carbon (GAC) offers the.best potential
for MEK removal. McGuire et al. (1978) reported a 95.% removal effi-
ciency using a l.l min detention time over a 1.2 hr treatment period.
However, in another laboratory investigation of removal of MEK (7.2
mg/L) by Fiitrasorb 400, breakthrough occurred after 3 hours of
treatment at a flow rate of 23 ml/min and a detention time of 2.1 mm
(McGuire et al., 1978).
2 81
-------
•Methyl Etnyl Ketor.e
March 3i
19s:
-12-
0 McGuire et al. (1978) also attempted laboratory isotherm studies using
GAC and 0.2' mm ortho-phosphate buffered glass distilled water as a
solvent for the MEK. These results also indicate that treatment with
SAC can be used to remove MEK.
0 Treatment with powdered activated carbon (PAC) however, does not seem
to be as effective (McGuire et alo, 1978; Kuo et al., 1977).
• Treatment technologies for the removal of methyl ethyl ketone from
water are available and have been reported te be effective. Selection
of individual or eombinations of technologies to achieve methyl ethyl
ketone reduction must be based on a case-by-case technical evaluation,
and an assessment of the economics involved.
° Positioning the chlorina^ion step in water treatment so that it occurs
after MEK removal also should be considered since MEK can serve as a
precursor for THM formation.
282
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Methyl Ethyl Ketone
March 3", 19S7
-1 3-
IX. REFERENCES
ACGIH. 1980. American Conference of Governmental Industrial Hygienists.
TLVs - Threshold limit values for chemical substances in workroom air,
_ adopted by ACGIH for 1980. Cincinnati, OH.
Carpenter, CiP., H.F. Smyth and U.C. Pozzani. 1949. The assay of acute
vapor toxicity, and the grading and interpretation of results on 96
chemical compounds. J. Ind. Hyg. Tox. 31(6)s343-346.
Cavender,- F.L., H.W. Casey, H. Salem, J.A. Swenberg and E.J. Gralla. 1983.
A 90-day vapor inhalation toxicity study of methyl ethyl ketone. Fund.
Appl. Toxicol. 3:264-270.
Chain, E.S.K. 1982. Oxidation of particular organics. Personal communication.
Coleman, W.E., R.D. Lingg, R.G. Melton and F.C. Kopfler. 1976. The occur-
rence of volatile organics in five drinking water supplies using gas
chromatography/mass spectrometry. Chapter 21. In: L.H. Keith, ed.
Identification and analysis of organic pollutants in water. Ann Arbor,
HI: Ann Arbor Science Publications, Inc.
Deacon, M.H., M.D. Pilny, J.A. John, B.A. Schwetz, F.J. Murray, H.O. Yakel
and R.A. Kuna. 1981. Embryo- and fetotoxieity of inhaled methyl ethyl
ketone in- rats. Toxicol. Appl. Pharmacol. 59:617-619.
Dietz, F.K., and G.J. Traiger. 1979. Potentiation of CCL4 of hepatotoxicity
in rats by a metabolite of 2-butanone: 2,3-butanediol. Toxicology.
14:209-215.
DiVincenzo, G.D., and N.J. Krasavage. 1974. Serum ornithine carbamyl trans-
ferase as a liver response test for exposure to organic solvents, km.
Ind. Hyg. Assoc. J. 35:21-29.
Duckett, S., N. Williams and S. Francis. 1974. Peripheral neuropathy associ-
ated with inhalation of methyl n-butyl ketone. Experientia. 30:1283.
Hites, R.A,, G.A. Jungclaus, V. Lopez-Avila and L.S. Sheldon. 1979. Poten-
tially toxic organic compounds in industrial wastewater and river systems:
two case studies. ACS Symp. Ser. 94:63-90. D. Schuetzle, ed., Moni-
toring Toxic Substances.
Kimura, E.T., D.E. Ebert and P.W. Dodge. 1971. Acute toxicity and limits
of solvent residue for sixteen organic solvents. Toxicol. Appl. Pharmacol,
19:699-704.
Kuo, P.P.K., E.S.K. Chain, F.B. DeWalle and J.H. Kim. 1977. Gas stripping,
sorption, and therr/.al desorption procedures for preconcentr&ting volatile
polar water-soluble organics from water samples for analysis by gas
chromatography. Analytical Chemistry. 6:1023-1029.
LaBelle, C.w., and H. Brieger. 1955. The vapor toxicity of a composite
solvent and its principal components. Arch. Ind. Health. 12:623-627.
283
-------
Methyl Ethyl Ketone
March 3', 15E~
-1 4-
Love, 0«T., and R.G. Eilers. 1981. Treatment for the control of trichloro-
ethylene and related industrial solvents in drinking water. U.S. Environ-
mental Protection Agency, Drinking Water Research Division. Cincinnati,
Ohio.
McGuire, M.J., I.H. Suffet and J.Vo Radziul. 1978° Assessment of unit
processes for the removal of trace organic compounds from drinking water.
JAMWA. 10:565-572.
Munies, R., and D.E. Wurster. 1965« Investigation of some factors-influ-
encing percutaneous absorption. Absorption of methyl ethyl ketone.
J. Pharm. Sci. 54:1281-1284.
NIOSH. 1980. National Institute for Occupational Safety and Health.
2=Butanone (MEK). In: Quarterly hazard summary report. Cincinnati,
OH; National Institute for Occupational Safety and Health.
Patty, F.A., HoHo Schrink and W.P. Yant. 1935. Acute response of guinea
pigs to vapors of some new commercial organic compeuads. U.S. Public
Health Reports. Vol. 50, pp. 1217-1228.
Saida, K., J.R. Mendell and H.Si Weiss. 1976. Peripheral nerve changes
induced by methyl n-butyl ketone and potentiation by methyl ethyl ketone.
J. Neuropath. Exp. Neurol. 35(3)t207-225.
Scheiman, M.A., R.A. Saunders and F.E. Sallfeld. 1974. Organic contaminants
of the District of Columbia water supply. BioMedical Mass Spectrometry.
Vol. 1. pp 209.
Schwetz, BoA., B.K.J. Leong and P.J. Gehring. 1974. Embryo- and fetotoxicity
of inhaled carbon tetrachloride, 1,1-dichloroethane and methyl ethyl
ketone in rats. Toxicolo Appl. Pharmacol. 28:452-464.
Shackelford, W., and L.H. Keith. 1976. Frequency of organic compounds
identified in water. Athens, GA: U.S. Environmental Protection Agency,
Environmental Research Laboratory. (EPA-600/4-76-062)
Singley, J.E., and L.J. Bilello. 1981. Advances in the development of design
criteria for packed column aeration. Submitted to Journal AWWA, 1961.
Smirasu, Y. 1976. Mutagenicity testing of pesticides. Kogia to Taisaku.
J. Environ. Pollu. Control. 12:407-412.
Smith, A.R., and M.R. Mayers. 1944. Poisoning and fire hazards of butanone
and acetone. Indust. Hyg. Bull., New York State Dept. Labor. 23:174.
(Cited in LaBelle, C.W., and Brieger, H., 1955 paper)
Smyth, H.F., C.P. Carpprter, C.S. Weil, U.O. Pozzani and J.A. Striegel.
1962. Range-find\na toxicity data: List VI. Am. Ind. Hyg. Assoc. J.
23:95-107."
284
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Methyl Ethyl Ketone
Marcn ji, 13c<
-1 5
Spencer, P.S., and H.H. Schaumburg. 1976. Feline nervous system response to
chronic intoxication with commercial grades of methyl n-butyl ketone,
methyl iso-butyl ketone, methyl ethyl ketone. Toxicol. Appl. Pharmacol.
30:301-311.
Takeuchi, Y., Y. Ono, N. Hisanga, M. Iwata, M. Aoyama, J. Kitoh, and Y. Sugiura.
1983. An experimental study of the combined effects of n-hexane and
methyl ethyl ketone. Brit. J. Ind. Med. 40:199-203.
Traiger, G.J., and J.V. Bruckner. 1976. The participation of 2-butanone in
2-butanol-induced potentiation of carbon tetrachloride hepatotoxicity.
J. Pharmacol. Exper. Therap. 196(2):493-500.
U.S. EPA. 1976. U.S. Environmental Protection Agency. Prequency of organic
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PB-265 470.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Method 1624 Revision
B. Volatile Organic Compounds by Isotope Dilution GC/MS. Federal
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U.S. EPA. 1986. U.S. Environmental Protection Agency. Final guidelines for
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September 24.
U.S. ZTC. 1981. United States International Trade Commission. Synthetic
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Wang, T.C., and J.C. Bricker. 1979. 2-Butanone and tetrahydrofuran contami-
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Windholz, K., ed. 1976. The Merok Index, 9th ed. Merck and Co., Inc.
Raihiway, N.J^ p. 5937.
Zakhari, S., P. Levy, M. Leibowitz and D.M. Aviado. 1977. Review of the
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environment. Cleveland, OH: CRC Press, Inc.
285
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STYREliL
Health Advisory
Office of Drinking water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODVJ), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
popula tion.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spalls or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based or. data describing noncarcinogenic end points of toxicity.
Health Advisories; do not quantitatively incorporate any potential carcinogenic
risk from suc/i exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime KAs are not recommended. The chemical concentration values for
Grou:; n or 3 carcinogens are correlated with carcinogenic risk estimate? by
employing a cancer potency (unit risk) value together with assumptions for
lifetime expcsjre and the consumption of drinking water. The cancer un:t
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stats?5. values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
286
-------
Sty rene
Karcr. 31
-2-
This Health Advisory (HA) is based on information presented in the
Office of Drinking Water's Health Effects Criteria Document (CD) for Styrene
(UoS. EPA, 1965a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult ,the CD. The CD is available
for review at each EPA Regional Office of Drinking Hater counterpart (e.g.,
Hater Supply Branch or Drinking Hater Branch), or for a fee from the National
Technical Information Service, U*S* Department of Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB # 86-110056/AS. She toll-free number is (800)
336-4700; in the Washington. D.C. area: (703) 487-4650*
GENERAL INFORMATION AND PROPERTIES
CAS No. 100-42-5
Structural Formula
CH . CH
2
Synonyms
Vinyl benzene, cinnamene, pheiylethylene, etheiylbenzene
Use
Styrene plastics
Properties (Hansch and Leo, 1979; Lewis et al., 1983)
Chemical Formula
Molecular Weight
Physical State
Melting Point
Density (20°C)
Vapor Pressure (20°C)
(25°C)
Water Solubility
Log Octanol/Water Partition
Coefficient
Conversion Factors
CoHo
104.16
Clear, colorless liquid with a
characteristically sweet and
pleasant odor
145°C
30*86 g/cm3
4.53 torr
6.18 torr
320 mg/L
2.95
1 mg/m3
1 ppm
0.235 ppm
4.26 mg/m3
Occurrence
Styrene is produced primarily from the dehydrogenation of ethylbenzene.
In 1962, the U.S production of styrene totaled 5.9 billion pounds.
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° National drinking water surveys indicate that styrene is an infrequent
contaminant. To date, the testing of 941 ground water supplies and
102 surface water supplies has failed to result in the detection oc
a single positive occurrence (Boland, 1981).
0 Contamination of drinking water by styrene, however, has been reported
occasionally by State programs.
III. PHARMACOKINETICS
Absorption
0 Available data indicate that the absorption of styrene from the
gastrointestinal tract of rats is rapid and virtually complete
(Plotnick and Weigel, 1979).
c Styrene uptake and absorption has been the subject of a number of
human innalation studies (Fiserova-Bergerova and Teisinger, 1 965;
Teramoto and Horiguchi, 1979). The findings of these studies indicate
that pulmonary retention of styrene is approximately 2/3 of the
administered concentration with considerable variation in measured
uptake between individuals and studies (mean uptakes ranged from
53 to 89%).
Distribution
° The distribution of styrene following oral administration was studied
in rats given single doses of 20 mg/kg 14C-styrene in corn oil by
gavage (Plotnick and Weigel, 1979). Peak tissue levels were reached
within 2 to *1 hours. The organs with the highest concentrations wsrs
kidney (-i'6 ug/g in males; 25 ug/g in females), liver (13 ug/g in
ma!e=; 7 u?/g in females) and pancreas (10 ug/g in males; -6 ug/g in
females) wit'.; lower concentration levels in lungs, heart, spleen,
adrenals, braiir, testes and ovaries.
0 Results fron- inhalation studies in rats indicate that distribution cf
styrene is widespread with relatively high concentrations in adipose-
tissue (Hithey and Collins, 1979).
° In humans, Dowty et al. (1976) found concentrations of transplacent-
aily transferred styrene to be somewhat higher than those of maternal
blood, which suggests a selective one-way transplacental transfer.
0 Pellizzari et al. (1982) detected styrene in each of 8 milk samples
collected from lactating women residing in various cities.
Metabolism
° The metabolic fate of styrene in mammals has been studied extensively.
There is limited information from human studies, but similarities to
the process m other mammals have been identified.
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0 Based on studies in rats administered styrene-7,8-oxide or styrene
glycol by intraperitoneal injection, Ohtsuji and Ikeda (1971) have
proposed that the metabolism of styrene proceeds via P-450 microsomal
oxidations to styrene oxide, styrene glycol, and then to mandelic
acid which is metabolized to either phenylglyoxylic acid or to benzoi
the hippuric acid.
Excretion
° Results £rcm a number of studies in rats (Withey and Collins, 1977,
1979; Ramstey and Young, 1978, 1980; Teramoto and Horiguchi, 1979)
indicate that styrene is eliminated relatively rapidly from all
tissues in test animals«
0 Twenty-four hours following oral administration of 20 mg/kg 14C-
styrene to rats, concentrations in a-11 tissues and organs examined we
less than 1 ug/a (Plotnick and Weigel, 1979).
° The elimination of styrene from the heart, brain, liver, spleen and
kidney of rats was described by biphasic log-linear kinetics after
intravenous injection of 4.0 mg/kg (Withey and Collins, 1977). Half-
lives ranged from 3.8 to 7.1 minutes for the alpha (fast) phase anc
from 20 to 37 minutes for .the beta (slow) phase.
0 Predictions based on a toxicokinetic model (parameters estimated fron
a human inhalation study) indicated that maximum concentrations of
styrene in both blood and fat of humans were reached after a few
repeated 8-hour daily exposures to 80 ppm styrene, suggesting no
tendency for long-term accumulation (Ramsey et al., 1980; Ramsey and
Young, "1976, 1980).
HEALTH EFFECTS
Humans
0 Results of controlled experiments using human volunteers indicate
that styrene administered by inhalation at relatively high doses
results in central nervous system (CNS) effects.
9 Drowsiness, listlessness and an altered sense of balance were
reported during a 4-hour exposure of two male subjects to styrene
at 3,407 mg/m^ (800 ppm) (Carpenter et al., 1944).
0 Stewart et al. (1968) reported that volunteers exposed to styrene by
inhalation at 217 mg/m^ (50 ppm) and 499 mg/m3 (117 ppm) for 1 and
2 hours, respectively, showed no signs of toxicity. The moderately
strong initial styrene odor diminished after 5 minutes. At 921 mg/ir.-
(216 ppn) nas*1 irritation resulted after 20 minutes. Eye and nose
irritation, strong odor and altered neurological function were report
for volunteers exposed to styrene at 1,600 mg/m3 (376 ppm) for 1 hour
Most volunteers exposed to this level exhibited reduced performance
in the Crawford Manual Dexterity Collar and Pin Test, the modi fiei
Romberg Test and the Flannagan Coordination Test. Six subjects wore
S 9 exposed to 422 mg/m3 (99 ppm) styrene vapor for seven hours. No
serious untowed effects were noted.
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0 Gamberale and Hultengren (1974) exposed 12 subjects to styrene by
inhalation at concentrations of 21 3, 639, 1 ,065 and 1,491 ng/n3 (50,
150, 250 and 350 ppm) during four consecutive 30-minute intervals.
A dose-related increase in single reaction time was evident. Reaction
time recorded during the final 30-minute exposure was significantly
increased (p <0.05).
0 Odkvist et al. (1982) studied the effects of styrene on the vestibulo-
oculomctor functions in 10 subjects exposed to styrene by inhalation
at 370 to 591 mg/m^ (88-140 ppm) for approximately 80 minutes. The
rate of movement of the eyes between two alternating light sources
(saccade) increased significantly (p <0.05) after exposure. Suppression
of the vestibule-oculomotor reflex was also affected.
0 There is suggestive evidence that the human fetus is more sensitive
than the adult to the toxic effects of styrene (Holmberg, 1977;
Hemminki et al., 1980).
0 The frequency of spontaneous abortions among Finnish chem-ical workers
was analyzed by Hemminki et al. (1980). Information on spontaneous
abortions (15,482 cases), induced abortions (71,235 cases) and births
(193,897 cases) for 1973-1976 was obtained from the Hospital Discharge
Registry oi the Finnish National Board of Health and linked by social
security number, to the membership of the Finnish Union of Chemical
Workers (approximately 900 female members). About 85% of the total
number of spontaneous abortions in Finland were reportedly listed in
tiie registry. The rate of spontaneous abortion was defined as the
number of spontaneous abortions x 100/number of births. The rates
of spontaneous abortion were 8.54% (N =. 52) and 15.0% (N = 6) among
the female union members and a subgroup in the styrene industry,
respectively. These rates were significantly higher (p<0.01) than
tine r<= sjiong all Finnish women (5.52%, 15,482 spontaneous abortions
The ratios of spontaneous abortion were 16 and 32 in the female union
workers and female styrene industry workers, respectively, which
wer» sicnificantlv higher (p<0.001) than the rate among all Finnish
women (8\ '.
0 The information on the work histories of 43 Finnish mothers of children
born with central nervous system (CNS) defects from June 1, 1976 to
March 1, 1977 were obtained through personal interviews (Holmberg,
1977). Two of these mothers had been employed in the reinforced
plastics industry with regular exposure to styrene, polyester resin,
organic peroxides and acetone during pregnancy. The defects in their
two children were anencephaly and congenital hydrocephaly. The
overall rates of anencephaly and congenital hydrocephaly were reported
to be 0.2 and 0.3, respectively, per 1000 live births in Finland.
Based on these estimates, there appeared to be more than a 300 fold
increasei rare ^5 these malformations in the reinforced plastics
industry -iuri-; the 9-month study period compared with the general
population (2/12 vs 0.5/1000).
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Animals
Short-term Exposure
° Wolf et al. (1956) reported an acute oral LD50 of greater than 5,000
mg/kg for rats treated with styrene by gavage. This indicates that
the acute toxicity of styrene is relatively low.
0 The lowest single oral dose of styrene (administered by oral intuba-
tion) causing 100% mortality in rats within two weeks of treatment
was 8,000 mg/kg, while 1,600 mg/kg was the maximum dose resulting in
no deaths (Spencer et al., 1942).
0 The effects of styrene administration at 250, 450 or 900 mg/kg orally
(method not stated) for 7 consecutive days on hepatic mixed function
oxidase (MF0) enzyme activities, glutathione content and glutathione-
s-transferase activity were reported by Das et al. (1981). Activities
of ary] hydrocarbon hydroxylase and aniline hydroxylase were signifi-
cantly enhanced at higher doses"of styrene (450 and 900 mg/kg). A
significant lowering of glutathione content accompanied with the
inhibition of glutathione-S-transferase activity was also noted at
the highest dose of styrene (900 mg/kg). Therefore, the NOAEL for
effects on hepatic enzymes in this study was 250 mg/kg/day.
° Agrawal et al. (1982) studied the effects of styrene on dopamine
receptor binding in rats. Styrene was administered at 200 or 400
mg/kg/day by gavage to groups of 6 eight-week old ITRC male albino
rats. Styrene was administered in a single dose or in up to 90 daily
doses over 90 days. Significant increases in the specific binding of
3H-spiroperidol to dopamine receptors in the corpus stratum were
r.oteJ at both levels after single or repeated exposure to styrene.
The L-0AE1 for this study was identified as 200 mg/kg/day.
Long-term Exposure
0 Changes in hepatic enzyme activity following oral exposure to styrene
•have been demonstrated by a number of investigators.
° Srivastava et al. (1982) administered styrene by gavage (at 200 or
400 mg/kg/day) to groups of 5 adult male albino ITRC rats, 6 days
per week for 100 days. These animals did not exhibit any changes in
weight gain or other overt signs of toxicity. There were significant
dose-dependent increases in hepatic enzymes (benzo[a]pyrene hydroxylase
and aminopyrine-N-demethylase) as well as decreases (glutathione-S-
transferase). There were significant decreases in some mitochondrial
enzymes as well. His topathological changes were seen only at the
high dose and these consisted of tiny areas of focal liver necrosis,
consisting of a few degenerated hepatocytes and inflammatory cells.
Therefore, the LOAEL for hepatic effects was 200 mg/kg/day.
0 Groups of ten female rats were administered styrene at 66.7, 133, 400
or 667 mg/kg/day by intubation, five days a week for six months (Wolf
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ilarc'". 3 ' , 1 S l ~
-7-
et al., 1956). At the two higher dose levels, decreased growth
weights and increased liver and kidney weights were observed without
hematologic or histopathologic effects. At the two lower dose levels,
no effects were noted on body weight, organ weight or pathology.
Therefore, the NOAEL for this study was 133 mg/kg/day and the LOAEL
was 400 mg/kg/day.
0 Beagle dogs were given styrene in a peanut oil suspension by gavage
7 days per week for 560 days (Quast et al., 1978). Dose levels were
200, 400 cr 600 mg/kg bw/day. The controls received peanut oil only.
At the two higher dose levels, minimal Jhijs^bopathologic effects were
noted in the liver (increased iron deposits within the reticulo-
endothelial cells} as well as hematologic effects that included
increased Heinz bodies in erythrocytes and a decreased packed cell
volume. At the lowest dose level, these effects were not noted.
Therefore, 200 mg/kg/day was identified as the NOAEL for this study
and 400 mg/kg/day can be designated as the LOAEL.
Reproductive Effects
° The reproauctive/teratogenic effects of styrene oxide were assessed
in Wistar rats (Sikov et al. 1981). The percentage of pregnant rats
was reduced significantly.
Developmental Effects
0 Investigators at the Dow Chemical Company administered styrene in
pcdr:ut o.l tc pregnant Sprague-Dawley rats (29 to 39 dams per group)
by gavage at dose levels of 0, 180 or 300 mg/kg/day (0, 90, 150 mg/kg
twice daily) on days 6 through 15 of gestation (Murray et al., 1976;
197b). Maternal toxicity was indicated by significantly reduced
(p <0.05) body weight gain and food consumption at the higher dose
level. There were no significant effects observed on maternal
nortality or percent pregnancy. No teratogenic or fetotoxic effects
were observed. Therefore, the NOAEL for maternal toxicity was 1£D
mg/kg/qs;/.
Hutaqenici t"
0 Results were negative for six mutagenicity tests using Salmonella
typhimurium test systems, both with and without S-9 metabolic activat-
ing system. Styrene was tested using the bacterial strains TA1535,
TA1537, TA98 and TA100. De Meester et al. (1977, 1981) and Vainio
et al. (1976) obtained positive results with mutant-strains sensitive
to base pair substitution while all tests were negative in strains
sensitive to frameshift mutagens.
° Styrene oxide, a major metabolite of styrene,, has been demonstrated
consistently to be mutagenic in S^. typhimurium TA1535 and TA100,
in t'u-j presence and absence of a mammalian metabolic activating
syster. (De Ilcester et al., 1977; 1981).
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Carcinogenici ty
0 Both positive and negative results have been reported in bioassays
of the potential carcinogenicity of styrene in experimental animals.
Most of the long-term bioassay results, however, are characterized by
inconsistent observations of elevated tumor formation and exqessive
mortality among treated animals (Jersey el al., 1978; Ponomarkov
and Tomatis, 1978; NTP, 1979; Maltoni et al., T982).
° Retrospective cohort mortality and ease-control studies have been con-
ducted on workers exposed to styrene in the styrene-polystyrene manu-
facturing industry and in the styrene-butadiene synthetic rubber indusc:
(McMichael et a2., 1976; Smith and Ellis, 1977; Meinhardt et al., 1973).
There are inadequate data at present to indicate that styrene is a
human carcinogen. However, an elevated incidence of tumors of the
hematopoietic and lymphatic tissues have been observed. The available
studies are limited because of relatively small cohort sizes or
multiple chemical exposures of workers (including exposure to benzene 1.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA. = (NOAEL or LOAEL) x (BW) = ___ mg/L ( ug/L)
(UF) x ( L/day)
whe re:
NOAElj or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
B'; = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/da'y = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The stv.dy of Stfwart et al. (1968) was seleted as the basis for calculati-u
the One-dv' H1 . The >st'jdy invloved a controlled styrene inhalation exposure
using nine healthy human male volunteers. No subjective or objective signs
of toxicity were noted following on? two hour exposures to 51 ppm (217
mg/m^) or 117 ppm (449 mg/m^) styrene respectively. To simluate a work
day, six subjects were exposed to 99 ppm (422 mg/m^) styrene vapor for seven
293
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-9-
hoars. From a subjective standpoint, no serious'untoward effects were noted ex:-;--
mild eye and throat irritation in three subjects. There were no objective
sigr.s of impairment of balance or coordination; however, three of the six
subjects did report that they were having intermittent difficulty in performing
the modified Romberg Test. In contrast, exposure to 376 ppm (1602 mg/m^)
styrene vapor for one hour resulted in abnormal neurological findings and
complaints of nausea and inebriation. The result of urinalysis, hematology
and blood chemistry studies were normal and unchanged from pre-exposur-~
values.
The results of another study (Odkvist et al., 1982) using human volunteers
exposed to similar styrene levels, indicate that the mean pulmonary styrene
uptake was 64% cf the inspired amount. Using a NOAEL of 99 ppm (422 mg/m3)
from a 7-hour exposure, the One-day Health Advisory for a 10-kg child can be
derived. First tl\e total absorbed dose (TAD) is determined.
TAD* = (422 ng/r3) .(20 rr3/day) (7 hours/24 hours) (0.64) « 22.5 mg/kg/day
70 kg
where:
TAD = total absorbed dose.
442 nig/m3 = NOAEL, based on the absence of adverse effects in
humans exposed to styrene by inhalation.
7 hours/24 hours = duration of exposure.
20 (r.^/Jay = assumed ventilation volume for 70-kg adult.
0.64 = estimated ratio of absorbed dose (Odkvist et al., 1982).
7C kg = weight of exposed individual (adult).
Tnerefore the C^.o-cay Health Advisory for a 10-kg child is as follows:
One-day HA = (22.5 mg/kg/day) (10 kg) = 22.5 mg/L
(10) (1 L/day)
where:
22.5 mg/kg/day, .= TAD.
10 kg = assumed body weight of a child.
10 = uncertainty factor, chosen in accordance with NAS/ODK
guidelines for use with a NOAEL from a study in humans.
' l/day = assumed daily water consumption of a child.
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Stvrfcr.T
;iarcn
-10-
Ten-day Health Advisory
No information was found in the available literature that was suitable
for deriving a Ten-day HA value for styrene. It is therefore recommended
that'the Longer-term HA for a 10-kg child (2 mg/L, calculated below) be
used at this time as a conservative estimate of the Ten-day HA value.
Longer-term Health Advisory
The Quast et al. (1978) study in dogs has been chosen to serve as the
basis for calculating the Longer-term HAs for styrene. In this study, beagle
dogs were administered styrene by gavage at 0, 200, 400 or 600 mg/kg/day,
7 days per week, for 560 days. At the two higher doses, minimal histopathologic
effects were noted in the liver (increased iron deposits within the reticulo-
endothelial cells) as well as hematologic effects that included increased
Heinz bodies in erythrocytes and a decreased packed cell volume. At the
lowest dose level, these effects were not noted with the possible exception of the
equivocal observation of low level occurrence of Heinz bodies in a single
female from this group.
Based on the NOAEL of 200 mg/kg/day determined in this study, the Longer-
term HAs are calculated as follows:
For a 10-kg child:
Longer-term HA =* (200 mg/kg/day) (10 kg) a 2 mg/L (2000 ug/L)
(100) (10) (1 L/day)
where:
200 mg/kg/day = NOAEL at which no decreased growth weights or increases
liver and kidney weights were observed in dogs.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with KAS/C'J'.:
guidelines for use with a NOAEL from an animal stud".
.10 = modifying factor for small group size (4 dogs per
treatment).
1 L/day = assumed daily water consumption of a child.
For a 70-kg adult:
Longer-term HA = (200 mg/kg/day) (70 kg) = 7 mq/L (7000 ug/L)
(100) (10) (2 L/day)
where all factors are
70 kg
2 L/day
the same except:
= assumed body weight
= assumed daily water
of an adult.
consumption of an adult.
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Styrene
March 31, 19S7
-11 -
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a' three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be de-cermined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived fror. the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step J by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical. For
Group C carcinogens, an additional safety- factor of 10 is added to the DWEL.
The Lifetime HA for a 70-kg adult has been determined on the basis of
the study in dogs by Quast et al. (1978) as described above.
Using the NOAEL of 200 mg/kg/day, as determined in that study, the
Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - (200 mg/kg/day) = 0>2 mg/kg/day
(1,000)
where:
200 mg/kg/day = NOAEL at which no decreased growth weights or increased
liver and kidney weights were observed in dogs.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0-2 mg/kg/day) (70 kg) = 7 mg/L (7000 ug/L)
(2 L/day)
2
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Styrene
March 31, 1997
-1 2-
where:
0.2 mg/kg/day = RfD.
70 leg » assumed body weight of an adult.
2 L/day - assumed daily water consumption of an adult
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA » [1 mg/L) (20%) ¦ 0.14 mg/L (140 ug/L)
(10)
where:
7 mg/L » DWEL.
20% =¦ assumed relative source contribution from water.
10 « additional uncertainty factor per ODW policy to
account for possible carcinogenicity.
Evaluation of Carcinogenic Potential
0 Data on an increased incidence of lung tumors (adenomas and carci-
nomas) in O20 strain mice (Ponomarkov and Tomatis, 1978) were used
for the quantitative assessment of cancer risk due to styrene.
Based on the data from this study and using the linearized
multistage model-, a carcinogenic potency factor (qi*) for humans of
1.34 (mg/kg/day)-1 was calculated from the data for male mice and a
q1 * of 2.47 (mg/kg/day)"1 was calculated from the data for female mice
(Ponomarkov and Tomatis, 1978). Because the data cannot accommodate
a tumor incidence of 100% when only a single dose is tested, the
tumor response for female mice was adjusted from 32/32 and the
transformed dose reduced by multiplying the calculated transformed
dose, 25.7 mg/kg/day, by the ratio 31/32 to arrive at an adjusted
transformed dose o£ 24.9 mg/kg/dayo The higher of the two q^* values
is the basis for the estimation of cancer risk levels. The doses
corresponding to increased lifetime cancer risks of 10~4, 10~5 and
10~6 for a 70-kg adult are 3 x 10~3, 3 x 10~4, 3 x 10~5 mg/kg/day,
respectively. Assuming a water consumption of 2 liters/day, the
corresponding concentrations of styrene in water are 1.4, 1.4 x 10"1
and 1.4 x 10~2 ug/L, respectively. These criteria., which reflect
lifetime exposure, are uncertain because of short exposure duration
(13% of lifetime) and the small number of animals in each dose group.
0 IARC evaluated styrene in February of 1979 and found insufficient
evidence to reach a conclusion as to its carcinogenicity'rating
(IARC, 1979).
0 Applying the criteria described in EPA's guideline for assessment of
carcinogenic risk (U.S. EPA, 1986), styrene may be classified in
Group C: Possible human carcinogen. This category is for agents with
— * ¦ ' -;ed evidence of carcinogenicity in animals in the absence of human
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ilarc'
ic:~
-1 3-
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The OSHA Standard for styrene is an 8-hour TWA concentration of 100 pp-,
a ceiling concentration of 200 ppm and a maximum peak concentration
(29 CFR 1910.1000; Table Z-2) of 600 ppm for 5 minutes or less in any
3-hour period.
" The ACGIH (1982) has established the TWA-TLV for styrene in workroom
air as 50 ppm with an STEL of 100 ppm. The TLV was reduced from 100
ppm in 1981 (ACGIH, 1981).
0 NIOSH (1983) recommended a styrene concentration limit in workplace
air of 50 ppm TWA for up to a 10-hour day, 40 hour work-week and a
ceiling concentration 100 ppn determined during any 15 minute sampling
period.
VII. ANALYTICAL METHODS
" Styrena content is determined by a purge-and-trap gas chromatographic
procedure used for the determination of volatile aromatic and unsat-
urated organic compounds in water (U.S. EPA, 1985b). This method
calif? for the bubbling of an inert gas through the sample and trapping
styrene on an adsorbant material. The adsorbant material is heated
tc "drive off styrene onto'a gas chromatographic column which is
temperature programmed to separate the method analytes which are then
detected by the photoionization detector. This method is applicable
to the measurement of styrene over a concentration range of 0.05 to
1,500 ug/L. Confirmatory analysis for styrene is by mass spectrometry
which has a detection limit of 0.3 ug/L (U.S. EPA, 1985c).
viii. treat:'.e::t tech'.;olo;Ie?
c In:ori.-.aticr, is available on the removal of styrene from water by air
stripping, adsorption and oxidation. Styrene has a Henry's La^
Constant of 12 atm which makes it suitable for removal from water by
air stripping (U.S. EPA, 1985d).
0 Decarbonaters which have some aeration function have been evaluated
for their efficacy in styrene removal. When the influent styrene
concentration was 0.076 ug/L, the decarbonators tested were able to
remove 51.3% (U.S. EPA, 1985d).
0 Tests evaluating adsorption of styrene by granular activated carbon
showed that an average of 40% was removed over a 10-month period
(U.S. EPA, 1985d). The influent styrene concentration was 0.03 ug/L.
0 The Pthenyl double bond found in the styrene molecule makes it amend-
able to oxidation. It is, therefore, possible that oxidative tech-
niques may be effective in removing styrene from potable water. Bench
scale evaluations of ozone treatment of styrene-contaminated water
conducted by Avigne (1983, as cited by U.S. EPA, 1985b) indicate
that the reaction rate constant for a 0.007 mM styrene solution (p-:
2) is 300,000 L/mole-sec. The pH was maintained at 2 to inhibit the
29£
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-1 4-
decomposition of ozone. Oxidation of styrene to benzaldehyde and
hydrogen peroxide was reported by Legube (1983, as cited by U.S. Zrk,
1985b). Using an ozone application rate of 107 mg/hr at 12 L/hr
O.S moles ozone per mole of styrene was required to completely oxiciz
the styrene. The initial styrene concentration was 1.1 x 10~4 mole/1
It was suggested that further oxidation of benzaldehyde to benzoic
acid might occuro
0 It is possible that other oxidizing agents such as permanganate could
be effective in oxidizing styrene. However, no studies of tests of
these alternative oxidizing situations were available.
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IX. REFERENCES
ACGIH. 1981. American Conference of Governmental Hygienists. TLVs. Threshold
limit values for chemical substances and physical agents in the workroo-.
environment with intended changes for 1981. Cincinnati, OH. p. 50.
ACGIH. 1982. American Conference of Governmental Hygienists. TLVs. Threshold
limit values for chemical substances and physical agents in the Workroom
environment with intended changes for 1982. Cincinnati, OH. p. 29.
Agrawal, A.K., S.P. Srivastava and P.K. Seth. 1982. Effect of styrene on
dopamine receptors. "ull. Environ. Contain. Toxicol. 29(4):400-403.
Boland, P.A. 1981. National screening program for organics in drinking
water. EPA contract 68-01-4666. SRI International.
Carpenter, O.P., C.B. Shaffer, C.S. Weil and H.F. Smyth. 1944. Studies on
the inhalation of 1,: 3-butadiene with a comparison tb its narcotic effect
with benzol, toluol and styrene, and a note on the elimination of styrene
by the human. J. Ind. Hyg. Toxicol. 26(3)s69-78.
Das, M., R. Dixit, M. Mushtaq, S.P. Srivastava and P.K. Seth. 1981. Effect
of styrene on hepatic mixed function oxidasaes, glutathione content and
glutathione-S-transferase activity in rats. Drug Chem. Toxicol.
4(3):219-227.
De Meester, C., F. Poncelet, M. Roberfroid, J. Rondelet and M. Mercier. 1977.
Mutagenicity of styrene and styrene oxide. Mutat. Res. 56(2):147—152.
De Mecster, C., Durverger-Van Bogaert, M. Lambotte-Vandepaer, M. Mercier
and F. Poncelst. 1981. Mutagenicity of styrene in the Salmonella
typhimuriur. test system. Chen. Biol. Interact. 20(2) s 1 63-1 70.
Dowty, B.J., J.L. Laseter and J. Storer. 1976. Transplacental mig-aticr. arc
accur.jiatic-, ir. blood of volatile organic constituents. Pediatr. Res.
10:696-701.
Fiserova-Dergerova, V., and Teisinger. 1965. Pulmonary styrene vapor retention.
Ind. Med. Surg. 34:620-622.
Gamberale, F., and r-i. Hultengren. 1974. Exposure to styrene. II. Psycholog-
ical functions. Work Environ. Health 11(2):86-93.
Hansch, C., and A.J. Leo. 1979. Substituent constants for correlation
analysis in chemistry and biology. John Wiley and Sons, New York, NY.
Hemminki, K., E. Franssila and H. Vainio. 1980. Spontaneous abortion anonj
female cheriral workers in Finland. Int. Arch. Occup. Health 45:123-126.
Holmberg, P.C. 1977. Central nervous defects in two children of mothers
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Work Environ. Health 5:333-335.
300
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-16-
IARC. 1979. International Agency for Research on Cancer. IARC monographs
on the evaluation of the carcinogenic risk of chemicals to humans. Sor.-.
monomers, plastics and synthetic elastomers, and acrolein. 19, 97-115.
Jersey, G., M. Balmer, J. Quast et al. 1978. Two year chronic inhalation
toxicity and carcinogenicity study on monomeric styrene in rats. Dow
Chemical study for Manufacturing Chemical Association. December 6.
Lewis, P.J., C. Hagopian and P0 Koch. 1983. Styrene. In; Kirk-Othmer
Encyclopedia of Chemical Technology, 3rd ed. M. Grayson and D. Eckroth,
eds. John Wiley and Sons, Inc. New York. Vol. 21, pp. 770-801.
Maltoni, C., A. Cilberti and D. Carrietti. 1982. Experimental contributions
in identifying brain potential carcinogens in the petrochemical industry.
Ann. New York Acad. Sci. 381:216-249.
IlcMichael, A.J., R0 Spirtas, J.F. Gamble and P.M. Tousey. 1976. Mortality
among rubber workers: Relationship to specific jobs. J. Occup. Med.
18 s 1 78-185.
Meinhardt, T., R. Young and R„ Hartle. 1978. Epidemiologic investigations
of styrene-butadiene rubber production and reinforced plastic production.
Scand. .7. Work Environ. Health. 8(4): 250-259.
Murray, F.J., J.A. John, H.D. Haberstoh et al. 1976. Teratologic evaluation
of styrene monomers administered rats by gavage. Dow Chemical Study for
Manufacturing Chemical Association. August 26.
Murray, F.J„, J.A. John, M.F. Balmer and B.A. Schwetz. 1978. Teratologic
evaluation -of styrene given to rats and rabbits by inhalation or by
gavage. Toxicology 11(4):335-343.
NIOSH. 1983. National Institute for Occupational Safety and Health. Criteria
for a recommended standard ... occupational exposure to styrene. DHH^
(NIOSH) Publ. No. 83-119. U.S. DHHS, Cincinnati, OH.
NTF. 1979. National Toxicology Program. National Cancer Institute Carcino-
genesis Technical Report Series No. 185. Bioassay of styrene for possible
carcinogenicity.
Odkvist, L.M., B. Larsby, R. Tham et al. 1982. Vestibulo-oculomotor disturb-
ances in humans exposed to styrene. Acta Oto-Laryngol. 94(5-6):487-492.
Ohtsuji, M., and M. Ikeda. 1971. Metabolism of styrene in the rat and the
stimulatory effect of phenobarbital. Toxicol. Appl. Pharmacol.
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Pellizzari, E.D., T.D. Hartwell, B.S.H. Harris, R.D. Waddell, D.A. Whitaker
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Bull. Enviro;.. Contam. Toxicol. 28(3): 322-328.
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1 **-C-styrene in male and female rats. Res. Commun. Chem. Pathol. Pnarrriacoi
24(3):51 5-524 .
301
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Ponomarkov, V.I., and L. Tomatis. 1978. Effects of long-term oral administra-
tion of styrene to mice and rats. Scand. J. Work Environ. Health.
4(Suppl. 2):127-135.
Quast, J.F., R.P. Kalnins, K.J. Olson, et. al. 1978. Results of a toxicity
study in dogs and teratogenicity studies in rabbits and rats administered
monpmeric styrene. Toxicol. Appl. Pharmacol. 45:293-294.
Ramsey, J.C., and J.D. Young. 1978. Pharmacokinetics of-inhaled styrene in
rats and humans. Scand. J. Work and Health 4(SuppI.2):84-91.
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styrene in rats and humans. _In: Proc. lO^1 Conference on Environmental
Toxicology, OH. November, 1979. AFAMRL-TR-79-121. Wright Patterson Air
Force Base, OH. pp. 103-117.
Ramsey, J.C., J.D. Young, H.J. Karbowski, M.B. Chenoweth, L.P. McCarty and
w.H. Braun. 1980. Pharmacokinetics of inhaled styrene in human
volunteers. Toxicol. Appl..Pharmacol. 53(1);54-63.
Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery and D.W.
Phelps. 193":. Teratologic Assessment of butylene oxide, styrene oxide
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302
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Withey, J«R0, and F.G. Collins. 1979. The distribution and pharmacokinetics
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303
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March 31, 1 9£ 7
TETRACHLOROETHYLENE (PCE)
Health Advisory
Office of Drinking Water
O.S. Environmental Protection Agency
INTRODUCTION
The Health Advisory {HA} Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing vith the
contamination of drinking water* Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population,
Health Advisories serve as Informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur* They are not to be
construed as legally enforceable Federal standards* The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an Individual's lifetime} and Lifetime
exposures baaed on data describing noncarclnogenlc end points of toxicity.
Health Advisories do not quantitatively Incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water* The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Problt models. There is no current
understanding of the biological mechanisms Involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
30
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Tetrachloroethyiene
March 31, 1967
-2-
This Health Advisory (HA) is based on information presented in the
Office of Health and Environmental Assessment Criteria Document (CD) for
Tetrachloroethylene (U.S. EPA, 1985a). Individuals desiring further informa-
tion on the toxicological data base or rationale for risk characterization
should consult the CD<> The CD is available for a fee from the National
Teehnical Information Service, U.S. Department of Commerce, 528S Port Royal
Rd.„ Springfield, VA, 22161. The toll-free number la (800) 336-4700; in the
Washington, D.C. areas (703) 487-4650*
SI. GENERAL INFORMATION AMD PROPERTIES
CAS Ho. 127-18-4
Structural Formula
Solvent for many organic substances
In drycleanlng processes
Metal degreaser
Intermediate in the synthesis of certain fluorocarbons
In the textile industry (Fuller, 1976)
Properties (Verschueren, 1977; Torkelsen and Rowe, 1981; Wlndholz, 1983)
CI - C » C - Cl
Cl Cl
Synonyms
PCE, Percbloroethylene, 1,1,2,2-Tetrachloroethylene, Perc
Uses
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Specific Gravity
Water Solubility
C2C14
165.85
liquid
121o2#C
19 am Hg
1.623
150 ag/L (25»C>
Log Octanol/Water Partition 2.86
Coefficient
Taste Threshold —
Odor Threshold (water)
1 ppm In air
Conversion Factor
300 ug/L
6.78 mg/m3
305
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Tetrachloroetnyiene
March 31, 195?
-3-
Occurrence
* Tetrachloroethylene (PCE) is a synthetic chemical with no natural sources.
* Production of PCE was 550 million pounds in 1982 (U.S. ITC, 1983).
° The majority of PCE is not consumed during its various uses, but is
released directly to the atmosphere. Tetrachloroethylene that does
not evaporate during use becomes heavily contaminated with grease and oil
and Is disposed of in the forms of solid and liquid wastes. During
disposal, PCE is dlschrarged directly to land and surface water.
E?:_.-se metal and fabric cleaning industries are widely dispersed,
PCE releases occur nationwide. x
* PCE released to air degrades in a matter of days or weeks. PCE
releases to water degrades slowly; volatilisation appears to be the
major transport process for removal of PCE from aquatic systems (U.S.
EPA, 1975). it is very mobile in soil and readily migrates to ground
water. In ground water, where volatilization does not occur, PCE
remains for months or years. Under certain conditions, PCE in ground
water has.been reported to degrade to trlchloroethylene and then to
dichlormethylene and vinyl chloride (Parsons et al., 1984? Vogel and
McCarty, 1985).
° Tetrachloroethylene is ubiquitous in the air with levels in the ppt
to ppb range. It is also a common contaminant in ground and surface
waters with higher levels found in ground water. Surveys of drinking
water supplies have found that 3* of all public systems derived from
well water contain PCE levels of 0.5 ug/L or higher. K small
number of systems (0.7%) have levels higher than 5 ug/L. Public
systems derived from surface water have also been found to contain
tetrachlorethylene but at lower levels.
' The major sources of exposure to tetrachloroethylene are from contami-
nated water and to a lesser extent air. Tetrachloroethylene has beer,
reported to occur In some foods in the ppm range, but food is considered
only a minor source of exposure (U.S. EPA, 1983).
III. PHARMACOKINETICS
Absorption
* Single oral doses of (36Cl)-PC£ were absorbed completely when admini-
stered to rats at a concentration of 189 mgAg (Daniel, 1963) as were
doses of (">4c)-pce administered to mice at a dose of 500 mgAg (Schu-
mann et al., 1980).
* Human volunteers at rest absorbed about 25 percent of PCE admini-
stered by Inhalation exposure at 72 or 144 ppm over a four-hour
period. The compound initially was absorbed rapidly, with decreasing
uptake as exposure continued. Absorption was determined by measuring
PCE and Its metabolites (trlchloroethanol, trichloroacetic acid) In
exhaled air, blood and urine (Monster, 1979; Monster et al., 1979;
Monster and Houtkooper, 1979).
306
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Tetrachioroethylene
March 31, 19£7
-4-
Dlstribution
* Cnce In the bloodstream, PCE tends to distribute to body fat. In
human tissue at autopsy, ratios o£ fat to liver concentrations are
greater than 6:1 (McConnell et al., 1975). The fat to blood ratio
Is about 90 and the half-life for saturation of the fat to 50% of its
equilibrium concentration is about 25 hours (Moastar, 1*979).
0 In rats exposed via Inhalatione FCE levels rise more or less continue
ously with duration of exposure In brain, lungs, and fat, but tend to
level off in blood and liver after a 3-hour exposure. Brain cerebrum
concentrations of PCE exceed blood levelsfBy a^out four-fold, and
brain cerebellum by about three-fold, independent of the duration of
exposure (Savolalaen et al., 1977).
Metabolism
* Only small amounts of PCE (less than 4% of the estimated absorbed dose;
are metabolized and excreted as trichloroacetic acid in humans (Ogata
et al., 1971; Fernandez et al., 1976).
0 Oxidative metabolism is proposed to proceed via an epoxide intermediate
which can lead to the major metabolite, trichloroacetic acid. (U.S.
EPA, 1985a). Zn humans, PCE is metabolized to trichloroethanol,
trichloroacetic acid and unidentified chlorinated products (Ike
-------
Tetrachloroethylene
March 31, 1-98 7
-5-
although they suggest that PCE is relatively nontoxic bv the oral
route at these doses.
c Stewart et al. (1974) exposed 19 volunteers to PCE (20 to 150 ppm) for a
5-week period and noted deleterious effects (decreased odor perception,
diminished response on the modified Romberg test) at 100 ppm but not
at 20 ppm.
Animals
Short-term Exposure
* Zn mice, the 24-hcur LD5qs/LC5o« uei 6*8 to 10.8 g/kg by the oral
route (Wenzel and Gibson, 1951), 5,200 ppm with 4 hours Inhalation
exposure (Frlberg et al,, 1953) and 4.7 g/kg intraperitoneal (Klaassen
and Plaa, 1966).
8 Ir. rats, the 24-hour LD5QS/LC5QS are 13 g/kg -oral (Smyth et al., 1969)
and 4,000.ppm with four hours inhalation exposure (Carpenter et al.,
1949).
0 Single oral gavage doses of 2,158 mgAg PCE to rabbits resulted in a
50% increase in serum lipoprotein levels and mild transient elevations
of serum enzymes (alkaline phosphatase, SGOT, SGPT) which were indica-
tive of liver damage (Fujll, 1975).
0 A dose-response related increase in fatty Infiltration of the livers
of mice was observed after four hours of exposure to 200 to 3,000 ppm
(1400 to 20,000 mg/m3) via inhalation (Kylln et al., 1963). Decreased
hepatic ATP and Increased total lipid and triglyceride levels were
observed In mice exposed to 800 ppm PCE In air for three hours (Ogata
et al., 1968).
0 Schumann, et al. (1980) administered tetrachloroethylene in corn oil
to rats and mice via gavage for 11 consecutive days at does of 100,
250, 500 and 1000 mgAg» For mice, histopathological changes (centrllobu-
lar swelling) were observed at all dose levels and increased body weight/
liver weight ratios were observed at doses of 250 ng/kg/iay and higher.
Rats were more resistant with toxicity (increased liver weight and
serum enzyme levels) apparent only at the highest dose. A LOAEL of
100 mgAg/day was identified based on histopathological changes in
mice.
Longer-term Exposure
0 Rats were exposed to 70, 230 or 470 ppm PCE (470, 1600, or 3200 mg/m3)
by inhalation 8 hours/day, 5 days/week for 150 days. No significant
changes were observed at 70 ppm; renal and liver congestion and swelling
were observed al 230 and 470 ppm (Carpenter, 1937).
8 Rats, rabbits and monkeys were exposed via inhalation to PCE at 400 ppm
(2700 mg/m3) 7 hours/day, 5 days/week for up to 179 days (Rowe, et
al., 1952). Histopathological examination of the liver, kidney and spleen
revealed no significant changes at this exposure level.
3
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Tetrachloroethylene
March 31, 198"'
-6-
0 Guinea pigs showed a dose dependent increase in liver weight and
fatty infiltration of the liver when exposed to 100, 200 or 400 ppm
(680, 1400, or 2700 mg/m^) for up to 169 exposures over 236 days
(Rowe et al., 1952) •
• Kylin et al. (1965) observed fatty infiltration in livers of mice
exposed to 200 ppo (1400 mg/m3)c 4 hours/day, 5 days/week for 8 months.
" In a study by Buhen and 0'Flah@£ty (1985;, nale Swiss-Cox mice were
exposed to tatraehloroethylane in corn oil via gavage at doses of 0,
20, 100, 200, 500, 1000, 1500, and 2000 mgAg* 5 days/week for 6 weeks.
Liver toxicity was evaluated by several parameters including liver weight
/body weight ratio, hepatic triglyceride concentrations, DNA content,
histopathological evaluation and serum enzyme levels. Increased
liver triglycerides were first observed in mice treated with 100 mgAg«
Liver weight/body weight ratios were significantly higher than controls
for th 100 mgAg group, and slightly higher than controls in the 20
mgAg groupo A NOAEL of 20 mgAg/day was identified based on the
absence of hepatotoxic effects.
° Toxic nephropathy was observed in mice exposed to 386 and 1072 mgAg
in corn oil via gavage, 5 days/week, for 78 weeks (NCI, 1977).
Reproductive Effects
° Rabbits showed liver enzyme changes and renal function alterations
following 200 to' 300 ppm exposures (1400 to 20,000 mg/m^), 4 hours/day,
5 days/v/eek for 9 weeks (Brancacclo et al., 1971; Mazza, 1972).
• Pregnant rats exposed to 300 ppm PCE (20,000 mg/m^) for 7 hours/day,
on days 6 through 15 of gestation had 4 to 5% reduction in body weight
and twice the number of resoprtions per implantation compared with
controls (Schwetz et al. (1975).
Developmental Effects
° Schwetz et al. (1975) assayed for reproductive and developmental
effects in rats and mice exposed to 300 ppm PCE (20,000 mg/m3) by
inhalation for 7 hours/day on gestational days 6 through 15. Pregnant
mice exhibited a significant Increase in the mean relative liver
weights and their fetuses weighed significantly less than controls.
In the mouse pups, significant subcutaneous edema, delayed skull
ossification and 1fhe presence of split sternebrae were observed.
• Offspring of rats exposed to PCE (900 ppm 16100 mg/m^], days 7-13
of gestation; 900 ppm, days 14-20 of gestation; 100 ppm [680 mg/m3],
days 14-20 of gestation) were evaluated with respect to brain histo-
pathology and biochemistry and several behavioral parameters. No
significant differences were found between controls and the 100 ppm
dose groap. differences in neurotransmitter levels and some altera-
tions on behavioral tests were noted in the 900 ppm dose groups.
09
-------
Tetrachloroethyiene March 31, 1967
-7-
Mutaqenlclty
° Several mutagenicity studies have been performed on PCS which employ
the Ames Salmonella/mlcrosome test or modifications of this test.
Most tests reveal little or no evidence of mutagenic activity by PCE
except at concentrations which result in greater than 90% bacterial
toxicity (U.S. EPA, 1985a).
Carcinogenicity
* PCE contsinlng stabilizers was concluded by NCI (1977) to be a liver
carcinogen in B6C3Fi nice administered 386 to 1,072 mgA? by gavage
for 78 weeks. No conclusion concerning the effects on Osborne-Mendel
rats administered 471 to 949 ag/kg by gavage could be made because of
high mortality rates (median survival for treated animals was less than
68 weeks compared to greater than 88 weeks for controls).
0 In the NTP (1985) inhalation bloassay, rats and nice of both sexes
were exposed to 0, 200 and 400 ppm (rats) and 0, 100 and 200 ppm
(mice) tetrachloroethylene. Male rats exhibited a significantly
Increased Incidence of mononuclear cell leukemia, and an increased
incidence of renal tubular adenomas/carcinomas (combined). PCE
induced hepatocellular carcinomas in male and female mice at both
doses. Classification of PCS as carcinogenic in the rat is contro-
versial. The Science Advisory Board's Halogenated Organlcs Subcommittee
(U.S. EPA, 1987) has questioned the relevance of mononuclear leukemia
to man, a species not susceptible to this type of leukemia, and the
validity of combining renal adenomas/carcinomas to achieve .statistical
significance to the results*
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarclnogenlc end point of toxicity.
Die HAs for noncarclnogenlc toxicants are derived using the following formula:
HA » (NOAEL or LOAEL) x (BW) „ « (
(UF) x ( L/day)
where:
NOAEL or LOAEL ¦ No- or Lowest-Observed-Adverse-Bffeet-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF =¦ uncertainty factor (10, 100 or 1,000), In
accordance with NAS/0DW guidelines.
L/day = assumed dally water consumption of a child
310
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Tetrachloroethylene
March 31, 1987
-8-
One-day Health Advisory
The available studies were not considered sufficient for derivation of a
One-day HA. It Is recommended that the value for the Ten-Day HA, 2 mg/1, be
used at this time as a conservative estimate for the One-Day HA.
Ten-day Health Advisory
Hepatotoxiclty in nice exposed to tatrachloroethylene was selected as the
basis for calculating the Tan-day HA 'value. Schumann et ai» (1980) administered
PCE In corn oil to rats and nice via gavage for 11 consecutive days at doses
of 0, 100, 250, 500 and 1000 mg/kg. For mice, histopathological changes
(centrllobular hepatocellular swelling) were observed in all treated animals,
and increased liver weight/body weight ratios were observed in animals exposed
to doses of 250 mg/kg and higher. The lowest dose, 100 ng/kg/6ay, represents
the LOAEL for the study. This value is consistent with the estimated LOAEL
(based on altered hepatic lipid and triglyceride content) of 160 mg/kg/day
for mice exposed to 200 ppm for 4 hours (Kylin et al, 1i§3; see appendix),
and could be used as the basis for the Ten»Day Health Advisory with the
application of an uncertainty factor of 1000. This uncertainty factor is In
accordance with NAS/ODW guidelines for derivation of the HA based on a LOAEL
from an animal study. Data froa longer<°tsrs studies indicates that an uncer-
tainty factor cf 1000 may be overly conservative in this ease.
Buben and O'Flaherty (1985) treated alee with doses ranging from 20 to
2000 mg/kg, 5 days/week for 6 weeks and observed a slight increase.in liver
weight in mice treated with 20 mgA9f at 100 ®9Ag» increases were significantly
different from controls. From this study, a dose of 20 sg/kg was identified as
a NOAEL and 100 mg/kg was identified as a LOAELo Basing %he Ten-day HA on the
NOAEL of 20 mg/kg with an uncertainty factor of 100 is consistent with the
protection of humans from the CNS effects observed by Stewart et al. (1980)
at 100 ppm for 7 hours (approximately 20 mg/kg, see appendix).
The value was calculated as follows:
Ten-day HA = (20 mg/k?/day) (10 kg) . 2>0 ^ _ 2 000 ug/L
(100) (1 L/day)
where:
20 mgAg/day » NOAEL based on the absence of effects on liver weight
of alee exposed to tetrachloroethylene via gavage.
10 kg - assumed body freight of child.
100 ¦ uncertainty factor, chosen in accordance with NAS/ODW
guidelines" for use of a NOAEL from an animal study~
> L/day * assumed dally water consumption for a child.
311
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Tetrachioroethyiene
March 3*, 19S~
-9-
Longer-term Health Advisory
The study by Suben and O'Flaherty was also selected as the basts for the
longer-term HA. Lifetime carcinogenicity bioassays did not provide an indicatior.
of toxicity at the low dose range (MCI, 1977; 1985). The NOAEL of
20 mgA9/day and the LOAEL of 100 mg/kg/day identified in the study by Buben
and O'Flaherty are consistent with estimates of LOAELs from Inhalation studies*
A LOAEL of 63 mgA9/day (based on increased liver height and fatty infiltration
of the liver) was estimated from chronic exposure of guinea pigs to 100 ppm
for 7 hours/day (Rowe et al., 1952; see appendix), and a LOAEL of 160 mgAg/day
(based on fatty infiltration of the liver) from mice exposed to 200 ppm for 4
hours (Kylin et al, 1965). The Longer-tarn HA value for a 10-kg child was
calculated as follows:
Longer-term HA ¦ (20 mg/kg/day)(5/7)(10 kg) m mg/L m 1*400 ug/L
(100) (1 L/day)
where:
20 mg/k9/day ¦ NOAEL baaed on the absence of effects on liver weight
for mice exposed to tetrachioroethyiene via gavage.
5/7 » factor to convert 5 day/week exposure to daily exposure.
10 kg * assumed weight of child*
100 ¦ uncertainty factor chosen in accordance with NAS/ODW
guidelines for used of a NOAEL from an animal study•
1 L/day <• assumed water consumption for a 10 kg child.
The Longer-term HA value for a 70-kg adult was calculated as follows:
Longer-term - (20 mg/kg/day)(5/7)(70 kg) . 5.0 mg/L « 5 000 u /L
(100) (2 L/day)
where:
20 mgAg/day * NOAEL based on the absence of effects on liver weight
for mice exposed to tetrachioroethyiene via gavage.
5/7 * factor to convert 5 day/week exposure to daily exposure.
100 - uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use of a NOAEL from an animal study.
70 kg * assumed weight of adult.
2 L/day - assumed water consumption for 70 kg adult.
312
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Tetrachicroethylene
March 31, 19£7
-1 0-
Llfetlme Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
clnogenlc adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process« Step 1 determines the Reference Dose
(R£D); formerly called the Acceptable Daily Intake (ADZ). Die RfD is an esti-
mate of a dally exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the HOAEL (or LOAEL), identified from a chronie (or subehronle) study, divided
by uncertainty factor(s)* From the RfD, a Drinking Water Equivalent Level
(SftEL) can be determined (Step 2)» A DWEL is a Medina*-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure fros that medium, at
which adverse*, neacarclnogenie health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed dally water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring In other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicalso If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
No suitable chronic oral or-lifetime oral studies were located in the
literature to serve as the basis for the Lifetime HA value. NOAELs were not
identified in the NCI (1977) study in which LOAELs were identified at high
doses (386 mgAg/day, mice, 471 mgA?/day, rats). The NTP (1983) study in
which lower doses were tested has not been validated.
Approximate NOAELs and LOAELs calculated from chronic and lifetime inhalation
studies give less conservative estimates of toxic doses than the six-week
oral study of Buben and O'Flaherty (1985) <> LOAEL estimates of 63 mgAg/day
for guinea pigs exposed to 100 ppm, 7 hrs/day (Rowe et al., 1952), 400 mgAg/day
for rats exposed to 475 ppm for 7 hr/day (Carpenter, 1937) and 160 mgAg/day
for mice exposed to 100 ppm for 6 hr/day (NTP, 1985) are consistent with the
NOAEL of 20 mgAg/day and LOAEL of 100 mgA9/day. identified in the study by
Buben and 0'Flaherty<> In this study, mice were treated with doses of 20 to
2000 mgAg/day, 5 days/week for 6 weeks. A slight Increase in liver weight
was observed at 20 mgA9? 100 ag/kg, liver weight and hepatic triglyceride
levels were significantly increased over controls. Using the NOAEL of 20
B9A9/day and an uncertainty factor of 1000 consistent with the use of data
from less than lifetime studies, the Reference dose and DWEL were calculated
as follows:
Step 1: Determination of the Reference Dose (RfD)
Reference Dose ¦ ngAg/day) (5/7) m 0.0143 mgAg/day
1000 * 1
where:
20 mgAg/day ¦ NOAEL based on the absence of effects in liver weight
for mice exposed to tetrachloroethylene via gavage.
313
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Tetrac'nloroe thy iene
March 31, 15:¦
-11-
5/7 = factor to convert 5 day/week exposure to daily exposure.
1000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study of
less-than-lifetime duration*
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL - (0.0143 mgAg/day) (70 kg) . 0.5 Bg/L . 500 ug/L
(2 L/day)
where:
0.0143 mg/kg/day » RfD.
70 kg = assumed body weight of an adult.
2 L/day » assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
A lifetime HA is not recommended for PCS because of its classification as
group B2: probable human carcinogen (US EPA, 1986). TCie estimated excess
cancer risk associated with lifetime exposure to drinking water containing
tetrachloroethylene at 500 ug/L is approximately 1 x 10~*. This estimate
represents the upper 95% confidence limit from extrapolations prepared by
EPA's Carcinogen Assessment Group using the linearized, multistage model.
The actual risk is unlikely to exceed this value, but there is considerable
uncertainty as to the accuracy of risks calculated by this methodology.
Controversy surrounds the classification of PCE. TOie Science Advisory
Board, Halogenated Organics Subcommittee has recommended a classification of
Group C: possible hunan carcinogen (U.S. EPA, 1987). This committee
concluded that the animal evidence of carcinogenicity was limited and
questioned grouping rat renal adenomas/carcinomas for statistical analysis
and extrapolating mouse mononuclear cell leukemia to man, a species which is
not susceptible to this type of leukemia. In contrast to group B2 carcinogens
for which no lifetime HA values are recommended, lifetime HA values are
calculated for group C carcinogens as follows:
Lifetime HA = 500 ug/L x 20% = ug/L
10
where:
500 ug/L = DWEL.
20% = assumed relative source contribution from water.
10 = additional uncertainty factor per ODW policy to
account for possible carcinogenicity.
J14
-------
Tetrachioroe thyler.e
March 31, 19S~
-12-
Evaluatlon of Carcinogenic Potential
° The National Academy of Sciences (NAS, 1977, 1980) and EPA's Carcinogen
Assessment Group (Anderson, 1983) have calculated drinking water con-
centrations that would be estimated to increase the risk by one excess
cancer per million (10~6) and per one hundred thousand (10~5). Assuming
consumption of 2 liters of water/day by a 70 kg adult over a 70 year
lifetime, NAS calculated drinking water concentrations of 3.5 ug/L and
35 ug/L for 10"® and 10"® risks, respectively. CAG calculated concen-
trations of 66, 6.6 and 0.7 ug/L for 10~4, 10"^ and 10"® risks, respec-
tively. Each group employed the linearized, non-threshold multistage
model, extrapolating from data obtained in the 1977 NCI bioassay in
mice.
0 The linear multistage model is only one method of estimating carcino-
genic risk. It is possible to estimate carcinogenic risk with the
probit, logit or Weibull models, but for PCE the data are inadequate
for calculating reasonable risk estimates using these techniques.
While recognized as statistically alternative approaches, the range of
risks described by using any of these modelling approaches has little
biological significance unless data can be used to support the selection
of one model over another» In the interest of consistency of approach
and in providing an upper bound on the potential cancer risk, the
Agency has recommended use of the linearized multistage approach.
0 I ARC (1979) stated that there is limited evidence to conclude that it
is a carcinogen In mice, and placed it in Group 3.
° The US EPA Carcinogen Assessment Group (CAG) classified tetrachloroethylene
in Group B2: Probable human carcinogen (U.S. EPA, 1986). This classifica-
tion has been questioned by the Science Advisory Board, Halogenated Orgar.irs
Subcommittee, which has recommended a classification of Group C:
Possible human carcinogen (U.S. EPA, 1987).
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS '
° The World Health Organization has recommended a tentative guideline
value of 10 ug/L for PCE in drinking water, based on carcinogenic
properties (WHO, 1984).
° The National Academy of Sciences (NAS, 1980) calculated 24-hour and
7-day SNARLS. The 24-hour SNARL was 172 mg/L, based on a 490 mgAg
LOAEL following i.p. administration, a 100-fold uncertainty factor,
and a 70 kg adult drinking 2 L/day of drinking water. A 7-day SNARL
of 24.5 mg/liter was calculated by dividing the 24-hour SNARL by seven.
VII. ANALYTICAL METHODS
° Analysis of tetrachloroethylene is by a purge-and-trap gas chromato-
graphic procedure used for the determination of volatile organohalides
in drinking water (U.S. EPA, 1985b). This method calls for the
315
-------
Te t'rachloroe thyiene
March 3", IS"
-1 3-
bubbling of an inert gas through the sample and trapping tetrachloro-
ethyiene on an adsorbant material. The adsorbant material is heated
to drive off the tetrachloroethyiene onto a gas chromatographic
column. This method is applicable to the measurement of tetrachloro-
ethylene over a concentration range of 0.03 to 1500 ug/L. Confirmatory
analysis for tetrachloroethyiene is by mass spectrometry (U.S. EPA,
1985c). The detection limit for confirmation by mass spectrometry is
0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
° Treatment technologies which will remove tetrachloroethyiene from
water include granular activated carbon adsorption (GAC), aeration
and boiling.
° Dobbs and Cohen (1980) developed adsorption curves for several organic
chemicals including PCE. It was reported that Filtrasorb® 300 carbon
exhibited adsorptive capacities of 51 mg, 14 mg, 3.9 mg and 1.1 mg
PCE/gm carbon at equilibrium concentration of 1,000, 100, 10 and 1
mg/L respectively. USEPA-DWRD installed pilot-scale adsorptiion
columns in New Jersey and Rhode Island. In Rhode Island, a Filtrasorb9
400 GAC column maintained a concentration of PCE below 0.1 mg/L for
11 weeks of operation and below for 20 weeks of operation in the
effluent, given an influent concentration that ranged from 600 to
2,500 mg/L (Love and Eilers, 1982). In New Jersey, PCE concentration
ranging from 60 to 205 mg/L were reduced to less than 0.1 mg/L by
GAC over a 58-week study period (Love and Eilers, 1982).
0 PCE is amenable to aeration on the basis of its Henry's Law Constant
of 1,100 atm (Kavanaugh and Trussell, 1980). In a pilot-scale packed
tower aeration study, removal efficiencies of 72 to 99,8% for PCE
were achieved using air-to-water ratios of 5-80, respectively (ESE,
1985).
° In diffusea-air aeration pilot-scale studies using either spiked
Cincinnati tap water (17-1,025 mg/L PCE) or actual PCE contaminated
New Jersey groundwater (94 mg/L PCE), diffused aeration removed 90%
of PCE at an air-to-water ratio of 4 for the latter and 98+* for the
Cincinnati water at air-to-water ratios of 8, 16 and 20 (Love and
Eilers, 1982).
0 Air stripping is an effective, simple and relatively inexpensive
process for removing PCE and other volatile organics from water.
However, use of this process then transfers the contaminant directly
to the air stream. When considering use of air stripping as a treat-
ment process, it is suggested that careful consideration be given to
the overall environmental occurrence, fate, route of exposure and
various other hazards associated with the chemical.
316
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Tetrachloroethvlene
March 31, 196 ~
-1 4-
IX. REFERENCES
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"Latest Cancer Risk Rate Estimates." March 22.
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Buben, JoAc, and E. O'Flaherty. 1985. Delineation of the role of metabolism
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Carpenter, C.P., M.F. Smyth, Jr. and O.C. Pozzanl. 1949. The assay of
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Daniel, J.W. 1963. The metabolism of ^^Cl-labelled trichloroethylene and
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Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organlcs. EPA 600/8-80-023. Office of Research and Development, MERL,
Wastewater Treatment Division, Cincinnati, Ohio.
ESE. 1985. Environmental Science and Engineering. Draft technologies and
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Federal Register. 1986. Guidelines for carcinogen risk assessment. 51 (185):
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Fernandez, J., E. Guberan and J« Caperos. T976. Experimental human exposures
to tetrachloroethyiene vapor and elimination in breath after inhalation.
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Fernando, P.B., M. D'Sllva, G.K.B. Stork and G.R. Slnnatamby. 1939. Tetra-
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Friberg, L., B. Kylln and A. Nystrom. 1953. Toxicities of trichloroethylene
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Fujll, T. 1975. The variation in the liver function of rabbits after admini-
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March 31, 198 7
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Fuller, B.B. 1976. Air pollution assessment of tetrachloroethylene MTR-7143,
McLean, Virginia, Mitre Corporation. EPA Contract No. 68-02-1495.
Hake, C.L., and R.D, Stewart. 1977. Human exposure to tetrachloroethylene:
Inhalation and skin contact. Environ. Health Perspect. 21:231-238.
Xkeda,-M. 1977. Metabolism of trichloroethylene and tetrachloroethylene in
human subjects. Environ. Health Perspect* 21/*239-245.
Ikeda, M., and T. Xmamura. 1973. Biological half-life of trichloroethylene
and tetrachloroethylene In human subjects. Int. Arch* Arbeitsmed.
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Ikeda, H., and He Ohtsujl. 1972. A. comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents
given trlchloro- or tetrachloro- derivatives of ethane and ethylene.
Brit. J. Ind. Med. 29:99-104.
Ikeda, M., H. Ohtsujl, T. Xmamura and Y. Komoike. 1972. Urinary excretion
of total trlchloro compounds, trichloroethanol and trichloroacetic acid
as a measure of exposure to trichloroethylene and tetrachloroethylene.
Brit. J. Ind. Med. 29:328-333.
XARC. 1979. International Agency for Research on Cancer. IARC monographs
on the evaluation of the carcinogenic risk of chemicals to man. Some
monomer, plastic and synthetic elastomes and acrolein. 19:377-401.
Kavanaugh, M.C., and R.R. Trussell. 1980. Design of aeration towers to
strip volatile contaminants from drinking water. JAWWA.
Kendrick, J.F, 1929. The treatment of hookworm disease with tetrachloro-
ethylene. Amer. J. Trop. Med. 9:483-488.
Klaassen, C.D., and G.L. Plaa. 1966. Relative effects of various chlorinated
hydrocarbons on liver and kidney function in mice. Toxicol. Appl. Pharma-
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Kylln, B., H. Reichard, X. Sumegl and S. Yllner. 1963. Hepatotoxlclty of
Inhaled trichloroethylene, tetrachloroethylene and- chloroform. Single
exposure. Acta Pharmacol. Toxicol. 20:16-26.
Kylln, B., I. Sumegi and S. Yllner. 1965. Hepatotoxlclty of Inhaled tri-
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Margard, W. 1978. In v* t.ro bloas3ay of chlorinated hydrocarbon solvents.
Battelle Laboratories. Unpublished proprietary document for Detrex
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318
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Tetrach^oroethyiene
March 31, 19c~
-1 6'
Mazza, V. 1972. Enzymatic changes in experimental tetrachloroethylene poison-
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Monster, A.C. 1979. Difference In uptake* elimination and metabolism In
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Monster, AeC., G. Boersma and H. Steenweg. 1979. Kinetics of tetrachloro-
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Xht. Arch. Occup. Environ, Health. 42:303-309.
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NAS. 1980. National Academy of Sciences. Drinking Water &ad Health. Volume 3.
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NCX. 1977. National Cancer Institute. Bloassay of tetrachloroethylene for
possible carcinogenicity. DHEW Publication No. NIH 77-813, O.S. Depart-
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PB-272 950, NTIS.
NTP. 1983. Bloassay on tetrachloroethylene in female B6C3Fi mice. Draft.
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19
-------
Tetrachioroethyiene
March 31, 1987
-1 7-
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3 *>
KJ
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Te trachloroe thylene
March 31, 19??
-18-
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321
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Te trachlcroethvlere
March 31, 19S7
-19-
Appendix
Estimation of absorbed dose based on inhalation exposure
Approx.
Approximate
Time of
Approximate
weight
minute vol.
tPCE]
Exposure
dose
Species
(kq)
(liter/nir.)
(ppm)
(hr/day)
(mg/kg/day)a
Reference
Human
70.0
10.0
100
7
20
Stewart et al, 1977
Guinea
0.50
0.222
100
7
63
Rowe et al, 1952
pig
Rat
0.25
0.132
200
6
130
Savolainen et al, V
400
6
260
Savolainen et al, 1
230
8
200
Carpenter, 1937
470
8
400
Carpenter, 1937
Mouse
0,025
0.024
100
6
120
NTP, 1985
200
6
230
NTP, 1985
200
. 4
160
Kylin, 1963, 1965
aDose =« [PCEtmg/L)][min. vol. (L/hr)][Time(hr/day)][50% absorption]/[bw(kg)]
where:
[PCE(mg/L]
[mino vol.(L/hr)]
[PCE(ppm)] x (6.78 mg/m3 - ppm) x (1 L/1000 m3)
[min. vol.(L/min)l x (60 min/hr)
3 2
fin)
-------
March 31, 19S /
TOLUENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
Io IKTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinxing
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology chat would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. Hie HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. Hie chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime expcsure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. Hiere is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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This Health Advisory is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for Toluene
(U.S. EPA,-1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for review at each EPA Regional'Office of Drinking Hater counterpart (e.g.,
Hater Supply Branch or Drinking Water Branch), or for a fee from the National
Technical Information Service, U.S. Department of Sommerce, 5285 Port Royal Rd.,
Springfield, VA 22161, PB # 86-117975/REB. The' toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650*
II. GENERAL INFORMATION AND PROPERTIES
CAS So. 108-88-3
Structural Formula
ch3
Synonyms
0 Methylbenzene, phenylmethane, toluol, methylbenzol. methacide
Uses
e Raw material in the production of benzene and other organic solvents
Solvent (especially for paints, coatings, gums, oils and resins)
Gasoline additive to elevate octane ratings
Properties (Amoore and Hautala, 1983; Cier, 1969; Sutton and Calder, 1975;
Tute, 1971; Weast, 1977; Zoeteman et al., 1971)
Chemical Formula, C7H8
Molecular Weight 92.15
Physical State (room temp.) Clear, colorless liquid
Melting Point -94.98C
Boiling Point 110.6°C
Vapor Pressure 28.7 mm Hg at 25°C
Specific Gravity 0o8623 at 15.6°C
Water Solubility
Fresh Water 535 mg/L
Sea Water 379 mg/L
Log Octancl/Water Partition 2.69
Coefficient
Taste Threshold (water) 0.04 mg/L; 1 mg/L
Odor Threshold (water) 0.04 mg/L; 1 mg/L
Odor ThreshyV.i (air) 0.6-140 mg/m^
Conversion Factor 1 ppm «* 3.77 mg/ra^
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March 31, 19-'
-3-
Occurrence
° Toluene occurs naturally as a component of petroleum oil.
0 Toluene is produced in large amounts (5.1 billion lbs in 1981).
Toluene also is produced indirectly in large volumes during gasoline
refining and other operations. Toluene content of gasoline can be as
high as several percent.
9 Releases of toluene to the environment are mainly to air due to toluene's
volatile nature, with smaller amounts to water and soil. Releases of
toluene to water are due to spills and leaks of gasoline and other
petroleum products and from the disposal of waste from paints, inks
and other products containing toluene. Because of the widespread use
of petroleum products, releases of toluene occur nationwide.
° Toluene degrades rapidly in air with a half life of a few days (Mabey
et al., 1981). Toluene released to surface water rapidly volatilizes
to air. Toluene released to the ground binds- somewhat to soil and
slowly migrates with ground water. Toluene is biodegraded readily in
soils and surface waters. In the absence of biodegradation, toluene
is expected to be stable in ground water (Marion and Malaney, 1963;
Lutin et al., 1965; Price et al., 1974; Bridie et al., 1979;
Patterson and Kodukala, 1981; Tabak et al., 1981).
0 Toluene occurs at low levels in drinking water, food and air. Toluene
occurs in both ground and surface public water supplies, with higher
levels occurring in surface water supplies. Based upon EPA's Ground
Water Supply Survey (U.S. EPA, 1963), approximately 1% of all ground
water-derived public drinking water systems have levels greater than
0.5 ug/L. The highest level reported in ground water was 1.4 ug/L.
Based upon EPA's National Screening Program Survey, approximately 3%
of .all surface water-derived drinking water systems are contaminated
it levels higher than 0.1 ug/L. None of the systems were reported to
contain levels higher than 1.4 ug/L. Toluene is found in"foods as a
naturally occurring compound at ppb levels and in the air of urban
and suburban, areas at levels of approximately 10 ppb. Toluene has
been reported to occur in indoor air at levels higher than outside.
Based upon the available data, the major source of toluene exposure
is from air.
III. PHARMACOKINETICS
Absorption
0 Studies in humans showed that toluene is absorbed quickly through the
respiratory tract (Astrand et al., 1972; Astrand, 1975). Toluene
was detected in arterial blood within the first 10 seconds after
exposure to 100 or 200 ppm toluene (Astrand et al., 1972).
0 In humans, inhalation exposure at 115 ppm (430 mg/m3) resulted in a
pulmonary absorption of 57% after 1 hour which decreased to a stable 37h.
of inspired dose after 2-4 hours of exposure (Nomiyama and Nomiyar.a,
1974).
3 2 5
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Toluen?
Mp r r'n ^ 1
•4-
0 Absorption from the GI tract in male rats was relatively rapid, with
maximal blood-toluene levels being reached within 2 hours after
gastric intubation with 100 uL toluene in 400 uL peanut oil. The oil
may have slowed absorption (Pyykko et al., 1977).
0 Dermal absorption of aqueous toluene (180 to 600 mg/L} across human hanc
skin was 160 to 600 ug/cm^/hour. Absorption was related directly to
concentration (Dutkiewicz and Tyras, 1968a,b)»
Distribution
0 Little is known about the tissue distribution of toluene in humans.
Due to its lipophilic nature and low water solubility, toluene would
be expected to distribute to and accumulate in lipid tissue (U.S.
EPA, 1985a).
0 In male rats, tissue distribution of toluene and its metabolites is
similar following inhalation of high concentrations of toluene (17,340
mg/m3) or oral administration of a single dose of labelled toluene
(100 uL in 400 uL peanut oil) (Pyykko et alo, 1977; Bergman, 1979).
Toluene is distributed throughout the body with greatest accumulation
in lipid tissues (adipose, bone marrow).. Toluene and its metabolites
also were found in relatively high concentration in tissues active in
ics metabolism and excretion (i.e., liver and kidney).
Metabolism
0 Toluene is metabolized in humans, rats and rabbits by side-chain
hydroxylation to benzyl alcohol, which is conjugated with glycine to
form hippuric acid (70% of the dose) and then excreted in the urine
(Oaley et al., 1968; Ogata et al*, 1970).
0 In rats dosed orally with toluene, minor amounts of toluene undergo
ring hydroxylation, probably via arene oxide intermediates, to forr-
o-cresol and p-cresol (0.04-1.0% of the dose) which are excreted in
the urine as sulphate or glucuronide conjugates (Bakke and Scheline,
1970; Angerer, 1979).
Excretion
° Following oral or inhalational exposure in both humans and animals,
toluene is excreted rapidly as the unchanged compound in expired air
and mainly as the metabolite, hippuric acid, in the urine (Smith
et al., 1954; El Masri et al., 1956; Ogata et al., 1970).
0 Most of the urinary excretion of toluene occurs within 12 hours of
the termination of exposure. Hie concentration of toluene in exhaled
air of human subjects declined rapidly as soon as inhalation exposure
was terminated (Astrand et al., 1972).
° The supply of glycine needed to conjugate with toluene in hippuric
acid formation may be a limiting factor in the rate of toluene
excretion. Riihimaki (1979) suggested that toluene at 780 ppm (2,940
326
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March 21. 1 r-
-5-
mg/m3) during light work or 270.ppm (1,010 mg/m3) during heavy work
would saturate the capacity for glycine conjugation in humans.
IV. HEALTH EFFECTS
Humans
° Exposures of humans to toluene are usually the result of inhalation
of toluene vapors in experimental or occupational settings of during
episodes of intentional abuse.
0 Acute exposure to toluene at approximately 200^ ppm (754 mg/m3) for
8 hours caused symptoms indicating CNS toxicity (fatigue, headache,
nausea, muscular weakness, confusion and incoordination (von Oettingen
et ai., 1942a,b; Carpenter et al., 1944). Iftese effects generally
increased in severity with increases in toluene concentration (von
Oettingen et al., 1942a,b). Toluene vapor at 100 ppm for 8-hour
exposures appeared to be the NOAEL for these effects (von Oettingen
et al., 1942a,b).
8 Subacute occupational exposure to toluene (for 1 to 3 weeks) at
levels of 50 to 1500 ppm (189 to 5660 mg/m3) resulted in symptoms
similar to those seen in acute exposure studies and which were related
to level of exposure (Wilson, 1943).
8 Chronic exposure to toluene vapors at levels of approximately 200
to 800 ppm have been associated primarily with CNS (von Oettingen
et al., 1942a,b) and, possibly, peripheral nervous system effects
(Matsushita et al., 1975; Seppalainen et al., 1978). Disturbances in
memory, thinking, psychomotor skills, visual accuracy and sensorimotor
speed were reported in a significant number of workers exposed to 200
to 803 ppm for "many years" (Munchinger, 1964). Hanninen et al.
(1976) reported many differences in performance test results between
non-exposed workers and painters exposed to approximately 30.6 ppr.
toluene for an average of 14.8 years. Effects indicative of cerebral
and cerebellar dysfunction, such as ataxia, tremors, equilibrium
disorders, impaired speech, vision and hearing, and impaired memory
and coordination have been reported in chronic abusers of toluene
(Knox and Nelson, 1966; Boor and Hurtig, 1977; Sasa et al., 1978).
° Chronic abuse of and occupational exposures to toluene (approximately
200 to 800 ppm) for periods ranging from 2 weeks to 6 years have been
associated with hepatomegaly and hepatic function changes (Greenburg
et al., 1942; Grabski, 1961). Renal function also appears to be
affected in chronic abusers of toluene (Kroeger et al., 1980; Moss
et al., 1980).
Animals
Short-terr, Exposure
0 The oral toxicity of toluene is relatively low, with an LD50 between
6.4 and 7.53 g/kg in adult rats (Wolf et al., 1956; Smyth et al.,
327
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Toluene
March 31, 1?2"
-6-
1969; Kimura et al., 1971). The earliest observable sign of acute
oral toluene toxicity in adult rats is inhibition of the functions
of the CNS, which become evident at approximately 2.0 gAg (Kimura
et al., 1971 ).
9 The LC^q for inhaled toluene is 4,618 ppm (17,400 mg/m3) after a
6-hour exposure in rats (Bonnet et alc; 1982). No effects were
reported after acute exposures to 620 or 1,100 ppm (2,340 or 4,150
mg/m3) toluene, but 1250 ppm (4710 mg/m3) affected coordination and
irritated the mucous membranes in rats.
* The dermal LD50 in rabbits is 12.2 gAg (Smyth et al., 1969).
Long-term Exposure
0 Subchronic oral administration of toluene to female rats at 118, 354
or 590 mg/kg/day for 193 days (5 days/week for 138 total doses)
resulted in no effects at any level (hematological, clinical, gross
or histopathological) and a NOAEL >590 mg/kg/day (Wolf et al., 1956).
0 Subchronic inhalation of toluene for 6 weeks resulted in slight
pulmonary irritation in rats exposed at 200 ppm (754 mg/m3) for 7
hours/day, 5 days/week (von Oettingen et al., 1942a). Renal effects
were evident in rats treated at 600 ppm (2260 mg/m3) for 7 hours/day,
5 days/week for 6 weeks.
e Chronic inhalation of toluene was studied in F344 rats exposed to 30,
100 or 300 ppm (113, 377 or 1,130 mg/m3) toluene 6 hr/day, 5 days/wee:-;
for 24 months (CUT, 1980). Reduced hematocrit values were reported
in females exposed to 100 and 300 ppm. Increased corpuscular hemoglobin
concentration was reported in females exposed to 300 ppm.
Reproductive Effects
0 Data regarding the reproductive effects of toluene have not been
located.
Developmental Effects
° Based on data reported in an abstract, oral administration of 1.0 mL/kg
toluene in cottonseed oil to pregnant CD-I mice, 3 times daily on
days 6 through 15 of gestation, resulted in a statistically signifi-
cant increase in the incidence of cleft palate (Nawrot and Staples,
1979). Maternal toxicity was not seen after exposure to toluene but
a significant increase in embryonic lethality occurred at doses of
0.3 ml/kg and up.
0 Inhalation exposures to 1,000 mg/m3 by pregnant rats for 8 hours per
day on gestational days 1 t-.roogh 21 resulted in a significant increase
in signs o^ skeletal retardation but did not cause internal or external
malformations (Hudak and Ungvary, 1978).
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March 31, 1&"'~
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Mutagenici ty
° Toluene has been tested for mutagenicity by many investigators using
various assay methods (reverse mutation, mitotic gene conversion and
mitotic crossing-over) and has not been demonstrated to be genotoxic
or mutagenic.
Carcinogenici ty
0 CUT (1980) concluded that exposures to 0, 30, 100 or 300 ppm toluene
for 24 months did not produce an increased incidence of neoplastic,
proliferative, inflammatory or degenerative lesions in F344 rats.
However, the highest dose used did not approach the Maximum Tolerated
Dose (KTD) and, therefore, it has been suggested that toluene may not
have been adequately tested for carcinogenicity (Powers, 1979).
0 Other studies suggest that toluene is not carcinogenic when applied
topically (twice weekly applications of 0.1 ml toluene for 20 weeks)
to the shaved skin of mice (Frei and Stephens, 1968).
0 No evidence of a promotion effect was noted when toluene (0.1 ml)
was painted on the skin of mice twice weekly for 20 weeks following
initiation with 7,12-dimethyl-benz(a)anthracene (Frei and Kingsley,
1968; Frei and Stephens, 1968).
0 Toluene is used extensively as a solvent for lipophilic chemicals
being tested for carcinogenic potential. Negative control studies
employing 100% toluene were negative.
V. QUANTIFICATION OF T0XIC0L03ICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-tern (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxic:t
The HAs for noncarcinogenic toxicants are derived using the following formal
HA = (NOAEL or LOAEL) x (BW) = mg/L 1 ug/L)
(UF) x ( . L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF a uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
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March 31, 19"
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One-dav Health Advisory
The effects of single inhalation exposures of humans to toluene for
periods up to 8 hours have been reported by several investigators (von
Oettingen et al., 1942a,b; Carpenter et al., 1944; Ogata et al., 1970;
Gamberale and Hultengren, 1972). Based on the consistent dose-response data
from a combination of these studies, it is evident that toluene at approxi=
mately 100 ppm for up to 8 hours/day causes no apparent adverse effects in
humans. Complaints of headache and drowsiness were reported by one volunteer
exposed to 50 and 100 ppm, while consistent toluene-induced effects (fatigue,
muscular weakness, incoordination) were evident in persons exposed to 200 ppm
for 8 hours. Gamberale and Hultengren (1972) reported that a 20-minute
exposure to 100 ppm toluene was a no-effect level when determined by perceptual
speed and reaction time tests. At 200 ppm, toluene was noted as clearly
causing toxic effects such as incoordination, exhilaration and prolonged
reaction time (von Oettingen et al., 1942a,b; Carpenter et al., 1944; Ogata
et al., 1970). These data substantiate the selection of 100 ppm (377 mg/m3)
toluene as the NOAEL in humans exposed for up to 8 hours.
Using a NOAEL of 100 ppm (377 mg/m3), a One-day HA is calculated as
follows:
Step 1: Determination of the Total Absorbed Dose (TAD)
TAD = (377 mg/n3)(20 m3/day H0.6) (8 hr/24 hr) ^ 2US mgAg/day
where:
377 mg/m3 a NOAEL (converted from 100 ppm) for absence of
toxic effects in humans (von Oettingen et al.,
1942a,b).
8 hours/24 hours » duration of exposure in one day.
20 m3/day » assumed daily ventilation volume for 70 kg adult
0.6 = estimated ratio of dose absorbed (Nomiyama and
Nomiyama, 1974).
70 kg a assumed body weight of an adult.
Step 2:
The One-day HA for a 10-kg child is derived from the TAD as follows:
One-day HA = (21.5 mg/kg/day)(10 kg) a 21.5 mg/L (21,500 ug/L)
(10) (1 L/day)
where:
21.5 ma/kg/day = TAD
3 0
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rciuer.f
March 31, 19t~
-9-
10 kg = assumed body weight of a child.
10 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from a human study.
1 L/day ® assumed daily water consumption of a child«
Ten-day Health Advisory
Mo information was found in the available literature that was suitable
for determination of a Ten-day HA value. It is therefore recommended that
the DWEL, adjusted for a 10 kg child (3.46 ag/L), be used at this time as a
conservative estimate of tne Ten-day HA value.
Longer-term Health Advisory
No information was found in the available literature that was suitable
for determination of the Longer-term HA values. It is therefore recommended
that the DWEL, adjusted for a 10 kg child (3.46 mg/L), be used at this time
as a conservative estimate of the Longer-term HA values.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (AOI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse,. noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The study by CUT (1980) is the most appropriate from which to derive
the Lifetime Health Advisory. Rats were exposed to toluene via inhalation at
0, 113, 337 or 1130 mg/m3 for 6 hrs/day 5 days/wk for two years. All parameters
measured at the end of the study, -o include clinical chemistry, hematology
and urinalysis, were normal with the exception of a decreased hematocrit in
females exposed at 100 and 300 ppm (377 and 1130 mg/m^, respectively) and an
increased corpuscular hemoglobin concentration in the high-dosed females.
331
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Toluene
March 31,
-1 0-
Similar changes did not occur in the males nor were they related to any patho-
logical findings. From these results, a NOAEL of 300 ppm (1130 mg/kg) was
identified.
Using this NOAEL, the Lifetime Health Advisory is derived as' follows:
Step 1: Determination of the Total Absorbed Dose (TAD)
TAD - {113° <6 hours/24 hours) (20 a3/day) (5/7) (0,6) „ 34>6 mgAg/day
70 kg
where:
1130 mg/m3 « NOAEL from animal data.
6 hours/24 hours * exposure duration in one day.
20 m3/day = assumed daily respiratory volume of an adult*
5/7 » conversion of 5 day/week dosing regimen to 7 day/wee
continuous exposure.
0.6 « estimated ratio of dose absorbed (Nomiyama and
Nomiyama, 1974).
70 kg » assumed body weight of &n adult.
Step 2: Determination of the Reference Dose (RfD)
RfD = (34.6 mg/kg/day) =, 0.346 mgAg/<3ay
ISO
Where:
28.8 mg/kg/day = TAD.
100 = uncertainty factor, chosen in accordance with NAS/ODv;
guidelines for use with a NOAEL from an animal study.
Step 3: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.346 mg/kg/day) (70 kg) = 12#1 ng/L (12,100 ug/L)
(2 L/day)
where:
0.346 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
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March 31, T?"~
-1 1-
Step 4: Determination of the Lifetime Health Advisory
Lifetime HA = (12.1 mg/L) (201) » 2.42 mg/L (2,420 ug/L)
where:
12.1 mg/L « DWEL.
20% « assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 IARC (1982) has not classified toluene into various categories of
carcinogenic risk to humans.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), toluene may be classified in
Group D: Not classified. This category is for agents with inadequat
animal evidence of carcinogenicity.
0 The chronic (106-week) bioassay of toluene in F-344 rats of both
sexes resulted in no carcinogenic effects (CUT, 1980). Gross and
microscopic examination of tissues and organs revealed no increase
in neoplastic tissue or tumor masses among rats treated at 30, 100 or
300 ppm when compared with controls. This bioassay, however, could
have been performed at higher exposure levels, since the highest dose
administered (300 ppm) was not a Maximum Tolerated Dose (MTD)»
0 Prechronic carcinogenicity testing of commercial toluene administered
by gavage to F344 rats and B6C3F^ mice has been conducted, but a
technical report on the data has not been issued (NCI, 1983). The N'T
(NCI, 19S3) also has started a chronic bioassay of commercial toluene
in rats and mice exposed by inhalation. Testing is in progress, but
neither preliminary nor final data are available. The assessment of
the carcinogenic potential of toluene must await the completion of
these, tests.
OTHER CRITERIA, GUIDANCE AND STANDARDS
° TLV = 100 ppm ( 375 mg/m3); STEL « 150 ppm ( 560 mg/m)3 for skin
(ACGIH, 1981).
0 EPA's ambient water quality criterion for toluene is 14.3 mg/L (U.S.
EPA, 1980).
° The EPA has proposed a Recommended Maximum Contaminant Level (RMCL)
of 2.0 ing/L based upon the Adjusted Acceptable Daily Intake (AADI) of
10.1 mg/L for noncarcinoge.-.ic effects assuming 20% contribution fro;:.
drinking water (U.S. EPA, 1985d).
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Tciuer.e
March 31, 19 7'
-1 2-
VII. ANALYTICAL METHODS
° Analysis of toluene is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile aromatic and unsaturated organic
compounds in water (U.S. EPA, 1985b). This method calls for the
bubbling of an inert gas through the sample and trapping toluene on an
adsorbant material. The adsorbant material is heated to drive off
toluene onto a gas chromatographic column. The gas chromatograph is
temperature programmed to separate the method analytes which are then
detected by the photoionization detector. This method is applicable to
the measurement of toluene over a concentration range of 0.02 to 1500
ug/L. Confirmatory analysis for toluene is by mass spectrometry (U.S.
EPA, 1985c). The detection limit for confirmation by mass spectrometry
is 0.2 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Treatment options for removing toluene from drinking water sources
include aeration and adsorption onto granular activated carbon (GAC).
Conventional treatment methods have been found to be ineffective for
the removal of toluene from drinking water (ESE, 1982).
® The Henry's Law Constant for toluene (288 afem at 20°C) indicates it
is amenable to removal by aeration. In a pilot-scale study, a packed
column aerator, operated at 50 to 90% of its flooded condition,
removed toluene from contaminated water (ESE, 1982). A field study
by Cummins (1985) also demonstrated the efficacy of aeration treatment
Water containing 62 ug/L toluene from a gasoline spill was decontami-
nated successfully by air stripping (air to water ration was 30:1 or
greater). The process was less effective at lower air to water
ratios (i.e., 8:1) but even at this ratio about 70% of the toluene
was removed.
0 Air stripping is an effective, simple and relatively inexpensive proce:
for removing toluene and other volatile organics from water. However,
use. of this process then transfers the contaminant directly to the
air stream. When considering use of air stripping as a treatment
process, it is suggested that careful consideration be given to the
overall environmental occurrence, fate, route of exposure-and various
hazards associated with the chemical.
0 Carbon adsorption isotherms developed by Dobbs and Cohen (1980) showed
that GAC can remove toluene from water effectively. However, with
Freundlich constants of 26 for K and 0.44 for 1/n, carbon usage rates
would be relatively high (U.S. EPA, 1985b). Toluene was also success-
fully removed from a light hydrocarbon cracking quench using GAC.
The solution treated contained 8.3 mg/L toluene. Breakthrough on a 6
f-_ x 1 inch G,v; column (Filtrasorb® 300) occurred after the processing
of aoojt. 1 , 200 gallons. Suffet et al., as cited by ESE ( 1982) found
that GAC (Filtrasorb® 400) adsorbed toluene from water containing a
mixture of contaminants. However, in this pilot study, breakthrough
occurred after 10 weeks, whereas levels of the other contaminants
remained below detection for 18 weeks.
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IX. REFERENCES
ACGIH. 19B4. American Conference of Governmental Industrial Hygienists.
Toluene. Documentation of threshold limit values for substances in
workroom air. 3rd ed. Cincinnati, OH. p. 400.
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety:
Odor threshold compared with threshold limit'values and volatilities for
214 industrial chemicals in air and water dilution. J. Appl. Tox.
3:272-290.
Angerer, J. 1979. Occupational chronic exposure to organic solvents. VII.
Metabolism of toluene in man. Int. Arch. Occup. Environ. Health. 43(1):
63-67.
Astrand, I. 1975. Uptake of solvents in the blood and tissues of man. A
review. Scand . J. Work Environ. Health. 1(4)s199-218.
Astrand, I., H. Ehrner-Samuel,' A. Kilbom and P. Ovrum. 1972. Toluene
exposure. I. Concentration in alveolar air and blood at rest and
during exercise. Work Environ. Health. 72(3):119-130.
Bakke, O.H., and R.R. Scheline. 1970. Hydroxylation of aromatic hydrocarbons
in the rat. Toxiccl. Appl. Pharmacol. 16s691-700«
Bergman, K. 1979. Whole-body autoradiography and applied tracer techniques
in distribution and elimination studies of some organic solvents.
Benzene, toluene, xylene, styrene, methylene chloride,, chloroform, carbon
tetrachloride and trichloroethylene. Scand. J. Work Environ. Health.
5: Suppl. 1 . (263 pp.).
Bonnet, P., V. Morele, G. Raoult, D. Zissu and D. Gradiski. 1982. Determi-
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335
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Toluene
March 31, 19"
-1 4-
Cummins, M.D. 1985. Field evaluation of packed column air stripping. U.S.
Environmental Protection Agency, Office of Drinking Water, Technical
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Daley, J., D. Jerina and B. Witkop. 1968. Migration of deuterium drinking
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Frei, J.v., and w.F. Kingsley. 1968. Observations on chemically induced
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Frei, j.v., and P. Stephens. 1968. The correlation of promotion of tumor
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Gamberale, F., and M. Hultengren. 1972. Toluene exposure. II. Psychophysio-
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1973).
Grabski, D.A. 1961. Toluene sniffing producing cerebellar degeneration.
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Greenburg, L., M.R. Mayers, H. Heimann and S. Moskowitz. 1942. The effects
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Hudak, A., and G. Ungvdiy. 1978. Emtryotoxic effects of benzene and its
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336
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Toiuer.-
Ma rc
1 9 :
-1 5-
Kimura, E.T., D.M. Ebert and P.W. Dodge. 1971. Acute toxicity and limits
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Matsushita, T., Y. Arimatsu, A. Ueda, K. Satoh and S. Nomura. 1975. Hema-
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Ogata, M.( K. Tomokuni and Y. Takatsuka. 1970. Urinary excretion of hippuric
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337
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Toluene
March 31, 1
¦16-
Patterson, J.W., and P.S. Kodukala. 1981. Biodegradation of hazardous
organic pollutants. Chem. Eng. Prog. 77(4):48-55.
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8
-------
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Karch 31, 1 9cT
1,1,1-TRICHLOROETHANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Viater (ODW), provides information on the health effects, analytical method-
ology and treatment technology -that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory-
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. 'The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
340
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1,1,1 -Trichloroethane
March 3:
19
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This Health Advisory is based on information presented in the Office of
Drinking Water's Health Effects Criteria Document (CD) for 1,1,1-Trichloro-
ethane (U.S. EPA, 1984a}. The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxieological data base or
rationale for risk characterization should consult the CD. The CD is available
for review at each EPA Regional Office of Drinking Hater counterpart (e.g.,
Water Supply Branch or Driaking Water Branch), or for a fee-from the National
Technical Information Service, U.S. Department of Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB # 86-118130/AS. The toll free cumber is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PEOPERTIES
CAS Mo. 71-55-6
Chemical Structure
H CI
l-l
H-C-C-Cl
I I
H CI
Synonyms
0 1,1,1-TCA, methyl chloroform, ethane, '1,1,1-trichloro and
methyltrichloromethane.
Uses
0 In the cleaning and vapor degreasing of fabricated metal parts
0 In the synthesis of other organic chemicals
° As a spot remover and film cleaner
0 As an additive in metal cutting oils
Properties (U.S. EPA 1984)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Densi ty
Vapor Pressure
Water Solubility (25°C)
Log Octanol/Water Partition
Coeff icierct.
Taste Threshold
Odor Thresnold
Conversion Factor
C2H3C13
133.41
colorless, nonflammable liquid
74 °C
4.6
100 mm Hg (25°C)
44 mg/L
5.4 mg/m^
341
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1,1,1 -Trichloroerhaj;c
March 3"i, 'SI
-3-
Occurrence
0 1,1,1-Trichloroethane is a synthetic chemical with no nataral sources.
0 Production of 1,1,1-trichloroethane was 600 million lbs in 1982
(U.S. ITC, 1983). About 70% of all 1,1,1-trichloroethane is used in
metal cleaning.
0 The major source of 1,1,1-trichloroethane released to the environment
is from-its use as a metal degreaser. Since 1,1,1-trichloroethane is
not consumed during degreasing operations, the majority of all
1,1,1-trichloroethane production is released to the environment.
Most of the releases occur to the atmosphere by evaporation. However,
1,1,1-trichloroethane which is not lost to evaporation becomes heavily
contaminated with grease and oil and is disposed of by burial in
landfills or dumping on the ground or into sewers. Because metal
working operations are performed nationwide, 1,1,1-trichloroethane
releases occur in all industrialized areas. Releases of 1,1,1-tri-
chloroethane from other uses also may be significant.
0 1,1,1-Trichloroethane released to the air degrades slowly with an
estimated half life of from 1 ° * ~*8. 1,1,1-Trichloroethane
released to surface waters migrates to the atmosphere in a few days
or weeks. 1,1,1-Trichloroethane which is released to the land does
not sorb onto soil and migrates readily to ground water. 1,1,1-Tri-
chloroethane slowly hydrolyzes in water with an estimated half-life
of greater than 6 months. 1,1,1-Trichloroethane, unlike other chlori-
nated compounds, does not bioaccumulate in individual animals or food
chains.
° Because of the large and dispersed releases, 1,1,1-trichloroethane
occurs widely in the environment. 1,1,1-Trichloroethane is ubiquitous
in the air with levels in the low ppb range, and is a common contami-
nant in ground and surface waters with higher levels found in ground
water. Surveys of drinking water supplies have found that 3% of all
public systems derived from well water contain 1,1,1-trichloroethane
at levels of 0.5 ug/L or higher. A small number of systems (0.1%)
have levels higher than 100 ug/L. Public systems derived from surface
water also have been found to contain 1,1,1-trichloroethane but at
lower levels. 1,1,1-Trichloroethane has been reported to occur in
some foods in the ppb range.
° The major sources of exposure to 1,1,1-trichloroethane are from con-
taminated water and, to a lesser extent, air. Food is only a minor
source.
III. PHARMACOKINETICS
Absorption
0 While inhalation of 1,1,1-TCA vapor through the lungs is the common
route of entry into the body, 1,1,1-TCA also is absorbed rapidly and
completely fri>m the gastrointestinal tract (Stewart et al., 1969).
342
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1,1, 1-Tnchloroethar.e March 31, TSI
-4-
0 Stewart and Andrews (1966) reported an observation of non-lethal acute
intoxication after oral ingestion of a liquid ounce of 1,1,1-TCA
(0,6 g/kg bw). The concentration of 1,1,1-TCA in the expired air was
measured serially and found to be equivalent to an inhalation exposure
of 500 ppm (2,700 sng/m3) by experimental subjects.
° Monster et al. (1979) and Humbert and Fernandez (1977) reported
•1,1,1-TCA retention in subjects exposed to 70 (378 mg/m3) or 140 ppm
(756 »g/m3) respectively, to be 30 percent of the inspired air
concentration at equilibriua after 4 hours of exposure.
Metabolism
e 1,1,1-TCA is metabolized to a very limited extent by animals and humans
(Monster et alo, 1979). The metabolites include trichloroethanol,
TCA-glucuronide and trichloroacetic acid which are excreted primarily
in urine; very small amounts of trichloroethanol (1 percent), however,
are excreted unchanged by the lungso
° Hake and his coworkers (1960), using C14-labelefi 1,1,1-TCA, determined
that less than 3% of 1,1,1-TCA is metabolized by rats following a
single intraperitoneal injection of 1,1,1-TCAo
0 More recently, estimates of the extent of metabolism in the human
have been made from controlled inhalation exposure with unlabeled
1,1,1-TCA (Seki et al., 1975; Humbert and Fernandez, 1977; Monster
et al., 1979). From the experimentally determined retained dose and
the amounts of 1,1,1-TCA metabolites excreted into the urine, no more
than 6% of the dose is estimated to be metabolized.
0 The metabolic fate of inhaled 1,1,1-TCA in rats and mice is not
altered upon repeated exposures (Schumann et al., 1982).
Excretion
0 Unchanged 1,1,1-TCA is primarily excreted via lungs.
IV. HEALTH EFFECTS
Humans
0 Acute pulmonary congestion and edema typically are found in fatalities
resulting from inhalation of 1,1,1-TCA (Capalan et al., 1976;
Bonventre et al., 1977). Fatty vacuolation in the livers of the
exposed subjects also has been observed (Capalan et al., 1976).
Animals
Short-term Exposure
° The acute oral LD50 for 1,1,1-TCA, as determined in several species
of animals, ranges from 5.7 to 14.3 g/kg (Torkelson et al., 1958).
343
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1,1, 1-Trichioroeth<=.\e
March 51, 19:~
-5-
0 Vainio et al. (1976) found that a single oral dose of approximately
1.4 g/kg depressed some hepatic microsomal metabolic indices in rats
(including cytochrome P-450 and epoxide hydratase).
0 Bruckner et al. (1985) observed that there was relatively little
evidence of toxicity in a short-term study by gavage in rats receiving
1,1,1-TCA at 0.5 g/kg 9 days. Higher doses of 5 and 10 g/kg
caused transient hyperexcitability and protracted narcosis, as well
as fatalities.
Long-term Exposure
0 Bruckner et al. (1985) administered 1,1,1-TCA to rats by gavage 5
times weekly for up to 12 weeks at 0, 0.5, 2.5 or 5.0 g/kg. Rats
given 2.5 or 5.0 g/kg exhibited reduced body weight gain and CNS
effects. Approximately 35% of these rats died during the first
50 days of the experiment, but only the 5.0 g/kg group showed an
increase in serum enzyme levels indicating an alteration in index
of toxicity. Ingestion of 0.5 g/kg for 12 weeks did not result ir
alterations in indices of toxicity.
° McNutt et al. (1975) exposed mice continuously by inhalation to
1,1,1-TCA at 250 (1,365 mg/m3) or 1,000 ppm (5,400 mg/m3) for 14 weeks
Serial sacrifice of exposed and control mice from 1 to 14 weeks demon-
strated significant changes in the centrilobular hepatocytes as well
as evidence of triglyceride accumulation in the livers of the 1,000
-ppm exposure group.
0 In the NCI (1977) study, diminished body weight gain and decreased
survival time were observed in both rats and mice. Male and female
rats were given 7 50 or 1,500 mg/kg 1,1,1-TCA in corn oil by gavage
5 times weehiy for 78 weeks. Similarly, male and female mice received
approximately 2,800 or 5,600 mg/kg for 78 weeks.
• In the NTP bioassay (1983), rats and mice were gavaged 5 times weekly
with 1,1,1-TCA in corn oil at doses of 375 or 750 mg/kg body weight
(rats) and 1 ,500 or 3,000 mg/kg body weight (mice), respectively, for
103 weeks.
Reproductive Effects
0 There appeared to be no dose-dependent effects on fertility, gestation
viability indices in mice exposed to 1,1,1-TCA at dose levels of 100,
300 or 1,000 mg/kg for 35 days (Lane et ale, 1982).
Developmental Effects
0 There appeared to be no dose-dependent effects on viability indices
in mice exposec to 1,1,1-TCA at dose levels of 100, 300 or 1,000 mg/kg
for 35 d-nys (Lane et al., 1982).
-------
1,1,1 -Tnchloroeihane
March 31, i9c
-6-
Mutageni ci ty
0 Simmon et al. (1977) reported that 1,1,1-TCA was mutagenic in vanojs
strains of S_. typhimuriua, with metabolic activation.
# Loprieno et al» (1979) stated that 1,1,1-TCA was not mutagenic in
Saecharomyees cerevisiae or Schizosaccharcayes bombe.
Carcinogeni ci ty
* NTP (1983) has reported a significant (P <0.05) dose response trend
and increased incidences of hepatocellular carcinomas in the low- and
high-dose male and in the high-dose female mice exposed to 1,1,1-TCA
for 103 weeks. However, it should be noted that these findings are
based on the draft report and may change pending the outcome of the
ongoing NTP audit of the study.
V. QUANTIFICATION OF TOXICOLOSICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term {approximately 7 years) and Lifetime exposures if adequate data .
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA ¦ (NOAEL or LOAEL) x (BW) _ mg/L (« ug/L)
-------
1,1,i-Trichloroethane
March 31, 19c"
-7-
One-dav HA = H .4 g/kg/day) (10 kg) = , 40 -,L or noOOO ug/L
(100) (1 L/day)
where:
1.4 g/kg/day - NOAEL based on absence of changes in hepatic microsomal
metabolic indices in rats.
10 kg » assumed body weight of a child.
100 « uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Ten-day Health Advisory
Insufficient toxicoloigical data are available to derive a Ten-day HA for
1,1,1-TCA. However, in order to provide a health guidance level for 1,1,1-TCA
for this duration of exposure, it is recommended that the Longer-term HA for
the 10 kg child be used (35 mg/L or 35,000 ug/L).
Longer-term Heal'cn Advisory
A subchronic oral toxicity study in rats by Bruckner et al. (1985) is
used for the Longer-term HA. .In this study, rats (2Q0 to 250 g) were given
1,1,1-TCA 5 times weekly by gavage for 12 weeks at 0, 0.5, 2.5 or 5 g/kg.
Rats given 2.5 cr 5.0 g/kg exhibited reduced body weight gain and CNS effects
including transient.hyperexcitability and protracted narcosis. Approximately
35% of these rats died during the first 50 days of the experiment, but only
the 5.0 g/kg group showed an increase in serum enzyme levels. Ingestion of
0.5 g/kg for 12 weeks did not result in alteration in indices of toxicity
(serum enzyme levels, organ weights or histopathological changes in the liver
and kidney).
Using 0.5 g/kg/day as a NOAEL, a Longer-term HA for the 10 kg child is
calculated as follows:
Longer-term HA " ,(500 mg/.^g/day^—(10 kg) (5/7) m 35 mg/L <35,000 ug/L)
(100) (1 L/day)
where:
0.5 g/kg/day *>
10 kg =
5/7 *
100 =
1 L/day
346
NOAEL in a 12-week study based on absence of various
parameters of toxicity in rats.
assumed body weight of a child.
conversion of 5 day/week exposure to daily exposure.
uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal stjdy.
assumed daily water consumption of a child.
-------
1,1,1-Trichloroethane
March 31, 19S7
-8-
Longer-term HA for 70 kg adult:
Longer-term HA = (500 mg/kg/day) (70 kg) (5/7) „ 125 mg/L (125,000 uq/L)
(100) (2 L/day)
where:
0.5 g/kg/day ¦ NOAEL in a 12-week study based on absence ©f various
parameters of toxicity in rats.
70 kg « assumed body weight of an adult.
5/7 • conversion of 5 day/week exposure to d&ily exposure.
100 ¦ uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day « assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure, ttie Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADZ). The RfD is an esti-
mate of a gaily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or.LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinkinc
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classifed as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
In the absence of suitable ingestion toxicological data to derive a
Lifetime HA, an inhalation study in mice is considered for a Lifetime HA.
McNutt ai. (1975) exposed male mice continuously via inhalation to
1,1,1-TCA at 2 50 (1,365 mg/m^) or 1,000 ppm (5,460 mg/m^) for 14 weeks. Con-
trol mice were exposed to room air. Serial sacrifice of exposed and control
mice from 1 to 14 weeks demonstrated significant changes in the centrilobular
hepatocytes of animals in the 1,000 ppm (5,460 mg/m^) group. These changes
consisted of vesiculation of the rough endoplasmic reticulum with loss of
347
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1,1,1-Tnchloroetnane
attached polyribosomes, increased smooth endoplasmic reticulum, microbodies
and triglyceride droplets. A NOAEL could not be identified but a LOAEL of
250 ppm (1,365 mg/m3) from this study can be used with appropriate uncer-
tainty factors. A Lifetime HA based upon these data is derived as follows:
Step 1: Determination of the Total Absorbed Dose (TAD)
TAD » (1,365 ag/m3) (1 a3/hr) (6 hrs) (0.3) „ 35 Bc/fcg/day
(70 kg) "
where:
1,365 mg/m3 (250 ppm; - LOAEL based on histological changes in liver
of animals.
1 m3/hr » ventilation volume for a 70 kg adult.
6 hrs ¦ Exposure assumed to be saturable; thus, 6 hrs
is considered equivalent to exposure for a
24-hour period.
0.30 = ratio of administered dose absorbed.
70 kg ¦ assumed body weight of an adult.
Step 2: Determination of the Reference Dose (RfD)
RfD = <35 mg/kg/day) & 0#035 ng/fcg/day
(1,000)
where:
35 mg/kg/day = TAD and LOAEL based on histological change in liver of
animals
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
Step 3: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0«035 mg/kg/day) (70 kg) „ -| ,0 ng/L (1 000 ug/L)
(2 L/day)
where:
0.035 pg/kg/day = PfD.
70 kg <= assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
348
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1,-1,1 -Tnchloroe thane
March 31, 19:
-10-
Step 4: Determination of the' Lifetime Health Advisory
Lifetime HA * 1 mg/L x 0.20 = 200 ug/L
where:
1 mg/L - DWEL.
0o20 ¦ assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 IARC (1982) has "classified 1,1,1-trichloroethane in Group 3:
Inadequate data to evaluate.
9 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), 1,1,1-trichloroethane is
classified in Group Ds Not classified (inadequate aniaml evidence
of carcinogenicity).
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 NAS (1980) has calculated a chronic SNARL of 3.8 mg/L for an adult
consuming 2 liters of water and contribution from water being 20%.
0 An ambient water quality criterion of 18.7. mg/L was calculated for an
adult consuming 5 liters of water daily (U.S. EPA, 1980).
VII. ANALYTICAL METHODS
0 Analysis of 1,1,1-trichloroethane is by a purge-and-trap gas chromato-
graphic procedure used for the determination of volatile organohalides
in drinking water (U.S. EPA, 1985a). This method calls for the
bubbling of an inert gas through the sample and trapping 1,1,1-tri-
chloroe thane or. an adsorbant material. The adsprbant material is
heated to drive off the 1,1,1-trichloroethane onto a gas chromato-
graphic column. This method is applicable to the measurement of
1,1,1 -trichloroethane over a concentration range of 0.03 to 1500 ug/L.
Confirmatory analysis for 1,1,1-trichloroethane is by mass spectrometry
(U.S. EPA 1985b). The detection limit for confirmation by mass
spectrometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
° Treatment technologies which will remove 1,1,1-trichloroethane from
water include granular activated carbon (GAC) adsorption, aeration
and boiling.
0 Dobbs and Cohen (1980) developed adsorption isotherms for several
organic chemicals including 1,1,1-TCA. It was reported that
349
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1/1,1-Trichloroethane
Ma r ch 31, 19"~
-1 1-
Filtrasorb® 300 carbon exhibited adsorption capacities of 1.1 mg and
0.5 mg 1,1,1-TCA/gm carbon at equilibrium concentrations of 100 and
10 ug/L, respectively. U.S. EPA installed pilot-scale adsorption
columns in Connecticut and New Jersey. In Connecticut, contaminated
well water with 1,1,1-TCA concentrations ranging from 10 to 50 ug/L
was passed through a Filtrasorb® 400 GAC column. Breakthrough occurred
after 11,360 bed volumes (BV) or approximately 12 weeks of continuous
operation. In New Jersey, contaminated groundwater with an average
of 300 ug/L of 1,1,1-TCA was passed over a Witcarb* 950 GAC column.
Breakthrough occurred after 16,800 bed volumes (BV) or approximately
30 weeks of continuous operation. A similar study assessed the
effects of differing contact time and carbon adsorption of 1,1,1-TCA
(Love and Eilers, 1982). Zt was reported that 1,1,1-TCE concentrations
of 100 ug/L were reduced to 0.5 ug/L when loadings of 0.26 mg, 0.51 mg
and 0o74 sig 1r1,1-TCA/gm of Filtrasorb® 400 carbon for contact times
of 7.5, 15 and 22,5 minutes, respectively, were used.
0 1,1,1-TCA is amenable to aeration on the basis of its Henry's Law
Constant of 400 atm (Kavanaugh and Trusell, 1980). In a pilot-scale
diffused aeration column, removal efficiency of 90% of 1,1,1-TCA was
achieved from an initial concentration of 237 ug/L at an air-to-water
ratio of 4:1 (Love and Eilers, 1982). In a pilot-scale packed tower
aeration study, removal efficiencies of 74-97* were achieved for
42-110 ug/L , 1, *t -TCA for a broad spectrum, of operating parameters
(Love and Eilers, 1982).
0 Boiling also is effective for removing 1,1,1-TCA from water on a short-
term, emergency basis. Studies have shown that 5 minutes of vigorous
boiling will remove 96% of 1,1,1-TCA originally present (Love and
Eilers, 1982).
0 Air stripping is an effective, simple and relatively inexpensive
process for removing 1,1,1-TCA and other volatile organics from
water. However, use of this process then transfers the contaminant
directly to tho air stream. When considering use of air stripping as
a treatment process, it is suggested that careful consideration be
giver, to the overall environmental occurrence, fate, route of exposure
and various other hazards associated with the chemical.
350
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1,1, 1-Trichloroethane
12-
March 31, 19 £
IX. REFERENCES
Bonver.tre, J., 0. Brennan, D. Jason, A. Henderson and M.L. Bastos. 1977.
Two deaths following accidental inhalation of dichloromethane and 1,1,1-
trichloroethane. J. Analyt. Toxicol. 4i158-160.
Bruckner, J.V., S. Muralidhara, W.F. Mackenzie, G.M. Kyle and R. Luthra.
1985. Acute and subacute oral toxicity studies of 1,1,1-trichloroethane
(TRI) in rats. The Toxicologist. 5(1):100.
Caplan, Y.J., R.C. Backer and J.Q. Whitaker. 1976. 1,1,1-Trichloroethane:
report of a fatal Intoxication. Clin. Toxicol. 9:69-74.
Dobbs, R.A., and J.N. Cohen. 1980. Carbon adsorption isotherms for toxic
organics, EPA 600/8-80-023, Office of Research and Development, HERL,
Wastewater Treatment Division, Cincinnati, Ohio.
ESE. 1984. Environmental Science and Engineering. Technologies and costs for
the removal of volatile organic chemicals from potable water supplies. ES
No. 84-912-0300 prepared for U.S. EPA Science and Technology Branch,
CSO, ODW, Washington, DC.
Hake, C.L., D. Waggoner, N. Robertson and V.K. Rowe, 1960. The metabolism
of 1,1,1-trichloroethane by rat. Arch. Environ. Health. 1:101-105.
Humbert, B.E., and J.G. Fernandez. 1977. Exposure to 1,1,1-trichloroethane:
contribution to the study of absorption, excretion and metabolism in
human subjects. Arch. Mai. Prof. 38:415-425.
IARC. 1962. International Agency for Research on Cancer. IARC Monographs
on the evaluation of carcinogenic risk to men. Suppl. 4.
Kavanaugh, M.C., and R.R. Trussell. 1980. Design of aeration towers to
strip volatile contaminants from drinking water. Journal AWWA. December.
Lane, R.W., B.L. Riddle and J.F. Qorzelleca. 1982. Effects of 1,2-dichloro-
ethane and 1,1,1-trichloroethane in drinking water on reproduction and
development in mice. Toxicol. Appl. Pharmacol. 63:409-421.
loprieno, N., r.a.M. Rossi, S. Fumero, G. Meriggi, A. Mondino and S. Silvest.
1979. In vivo mutagenicity studies with trichloroethylene and other
solvents. Preliminary results. Institute di ricerche biomediche.
Ivrea, Italy.
Love, O.T., Jr., and R.G. Eilers. 1982. Treatment of drinking water contain-
ing trichloroethylene and related industrial solvents. Journal AWWA.
August.
McNutt, N., R. Amster, E. McConnell and F. Morris. 1975. Hepatic lesions in
mice after continuous inhalation exposure to 1,1,1-trichloroethane.
Lab. Invest. 32:642-654.
351
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1,1,1-Tnchloroe thane
March 31, 1 SE
-13-
Monster, A.C., G. Boersma and M. Steenweg. 1979. Kinetics of 1,1,1-trichloro-
ethane in volunteers; influence of exposure concentration and workload.
Int. Arch. Occup. Environ. Health". 42:293-301.
NAS. 1980. National Academy of Sciences. Drinking Water and Health. Volume 3.
National Academy Press. Washington, DC
NAS. 1983. National Academy of Sciences. Drinking Water and Health. Vol. 5.
National Academy Press. Washington, DC.
NCI. 1977. National Cancer Institute. Bioassay of 1,1,1-trichloroethane
for possible carcinogenicity. CAS No. 71-55-6. Technical Report Series
No. 3. January 1977.
NTP. 1983. National Toxicology Program. Carcinogenesis bioassay of 1,1,1-
trichlorethane in F344/N rats and B6C3F1 mice.
Perry, R.H., and C.H. Chilton. 1973. Chemical Engineers Handbook. 5th
Edition. McGraw Hill Book Company.
Schumann, A.M., T.R. Fox and P.G. Watanabe. 1982. A comparison of the fate
of inhaled methyl chloroform (1,1,1-trichloroethane) following single or
repeated exposure in rats and mice. Fund. Appl. Toxicol. 2:27-32.
Seki, Y., Y. Urashima, H. Aikawa, H. Matsumura, Y. Ichikawa, F. Kiratsuka,
Y. Hoshioka, S. Shimbo and M. Ikeda. 1975. Trichloro-compounds in the
urine of humans exposed to methyl chloroform at sub-threshold levels.
Int. Arch. Arbeitsmed. 34:39-49.
Simmon, V.F., A. Kaunanen and R.G. Tardiff. 1977. Mutagenic activity of
chemicals identified in drinking water. In; Scott, Bridges and Sobels,
eds. Progress in Genetic Toxicology. Developments in Toxicology and
Environmental Toxicology. Developments in Toxicology and Environmental
Science, Vol. 2, Elsevier, North Holland, Amsterdam, pp. 249-258.
Stewart, R.D., H.H. Gay," A.W. Schaffer, D.S. Erley and V.K. Rowe. 1969.
Experimental human exposure to methyl chloroform vapor. Arch. Environ.
Health. 19:467-474.
Stewart, R.D., and J.T. Andrews. 1966. Acute intoxication with methyl
chloroform vapor. JAMA. 195:705-706.
Torkelson, T.R., F. Oyen, D. McCollister and V. Rowe. 1958. Toxicity of
1,1,1-trichloroethane as determined on laboratory animals and human
subjects. Am. Ind. Hyg. Assn. J. 19:353-362.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water quality
criteria for chlorinated ethanes. NTIS PB81-117400.
U.S. EPA. 198-;. U.S. Environmental Protection Agency. Draft health effects
criteria document for 1,1,1-trichloroethane. Office of Drinking Water.
352
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1,1,1 -Tr:chloroethane
March 31, 19c
-1 4-
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory, Cin-
cinnati, Ohio 45268, June 1985.
UoS. EPA. 1985b. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268, June 1985.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register. 51(185) 33992-34003.
September 24.
U.S. XTC. 1983. U.S. International Trade Commission. Synthetic organic
chemicals, United States production, 1983.
Vainio, H., M„A. Parkki and J.A. Marniemi. 1976. Effects of aliphatic
chlorohydrocarbons on drug-metabolizing enzymes in rat liver _in vivo.
Xenobiotica. 6:599.
353
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March 31,-1987
TRICHLOROETHYLENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing- with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. Biey are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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Trichloroethylene
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March 31, 195 7
This Health Advisory is based upon information presented in the Office
of Drinking Hater's Health Effects Criteria Document (CD) for Trichloroethylene
(U.S. EPA, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for review at each EPA Regional Office of Drinking Water counterpart (e.g.i
Hater Supply Branch or Drinking Water Branch), or for a fee from the National
Technical Information Service, U.S. Department of Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB * 86-118106/AS. The toll free number is (800)
336-4700; in Washington, D.C. areas (703) 487-4650.
II. general information and properties
CAS No. 79-01-6
Structural Formula
C1-HCC-C12
Triehlor©ethylene
Synonyms
TCE, trichloroethene, acetylene trichloride, Tri, Trilene
Uses
Industrial solvent and degreaser for metal components
Properties (Torkelson and Rowe, 1981; Hindholtx, 1983)
Chemical Formula
Molecular Height
Physical State
Boiling Point
Vapor Pressure
Density at 25#C
Water Solubility
Odor Threshold (water)
Odor Threshold (air)
Organoleptic Threshold (water)
Conversion Factor
C2HC13
131.40
Colorless liquid
86«7*C
77 mm (25»C)
1.4 g/mL
0.1 g/100 mL (20*C)
0.5 mg/I>
2.5-900 mg/m3
0.31 mg/L (Amoore and Hautala, 1983)
1 ppm ¦ 5.46 ng/m3
Occurrence
° Trichloroethylenb (TCE) is a synthetic chemical with no natural
sources.
O
Production of TCE was 200 million lbs in 1982 (U.S. ITC, 1983)
° The major source of TCE released to the environment is from its use
as a metal degreaser. Since TCE is not consumed during this use, the
majority of all TCE production is released to the environment. Most
355
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Trichloroethylene
March 31, 1987
-3-
of the releases occur to the atmosphere by evaporation. However, TCE
which is not lost to evaporation becomes heavily contaminated with
grease and oil and has been disposed of by burial in landfills, dumping
on the ground or into sewers. Because metal working operations are
performed nationwide, TCE releases occur in all industrialized areas.
Releases of TCE during production and other uses are relatively minor.
0 Trichloroethylene released to the air is degraded in a matter of a few
days. Trichloroethylene releaaed to surface waters migrates to the
ataosphere in a few days or weeks where it also degrades. Photo-
oxidation appears to be the predominant fate of this compound (U.S.
EPA, 1979)o Trichloroethylene which is released to the land does not
degrade rapidly, migrates readily to ground water and remains in
ground water for months to years. Under certain conditions, TCE in
groundwater appears to degrade to dichloroethylene and vinyl chloride.
Trichloroethylene also may be formed in ground water by the degradation
of tetrachloroethylene (Parsons et al., 1984; Vogel and McCarty,
1985). Trichloroethylene, unlike other chlorinated compounds, does not
bioaccumulate in individual aniaals or food chains*
0 Because of the large and dispersed releases, TCE occurs widely in the
environment. Trichloroethylene is ubiquitous in the air with levels
in the ppt to ppb range. Trichloroethylene is a common contaminant
in ground and surface waters with higher levels found in ground
water. Surveys of drinking water supplies have found that 3% of all
public systems derived from well water contain TCE at levels of 0.5
ug/X. or higher. A small number of systems (0.04%) have levels higher
than 100 ug/L. Public systems derived from surface water also have
been found to contain TCE but at lower levels. Trichloroethylene has
been reported to occur in some foods in the ppm range.
0 The major sources of exposure to TCE are from contaminated water and
to a lesser extent airj food is only a minor source of TCE exposure
(U.S. EPA, 1983).
III. PHARMACOKINETICS
Absorption
s Data on absorption of ingested TCE are limited. When a dose of 200
mg/kg of 14C-TCE in corn oil was administered to rats, 97% of the
dose was recovered during 72 hours after dosing (DeKant et al., 1984).
Distribution
0 Doses of 0, 10, 100 or 1,000 mg TCE/kg/day were administered by gavage
to rats five days/week for six weeks (Zenick et al., 1984). Marginal
increases in TCE tissue levels were detected in the 10 mg/kg/day and
100 mg/kg/day dose groups. Compared to controls, a marked increase
in TCE levels in most tissues was observed in the highest dose group.
Trichloroethylene was distributed in all tissues examined with the
highest concentrations in the fat, kidney, lung, adrenals, vas
deferens, epididymis, brain and liver.
356
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Trichloroethylene
March 31, 19f
-4-
Metabolism
0 Studies indicate that TCE is metabolized to trichloroethylene oxide,
trichloracetaldehyde, trichloroacetic acid, monochloroacetic acid,
trichloroethanol and trichloroethanol glucuronide (U.S. EPA, 1985a).
Excretion
* Trichloroethylene audits metabolites are excreted in urine, by
•xhalation and, to a leaser degree, In sweat, feces and saliva
(Soucek and Vlachova, 1959).
HEALTH EFFECTS
Humans
Short-term Exposure
0 Oral exposure of humans to 15 to 25 ml (21 to 35 g) quantities of TCE
resulted in vomiting and abdominal pain, followed by transient uncon-
sciousness (Stephans, 1945).
Long-term Exposure
9 Studies of humans exposed occupationally have shown an increase in
serum transaminases, which indicates damage to the liver parenchyma
(Lachnit, 1371). Quantitative exposure levels were not available.
Animals
Short-term Exposure
° The acute oral LD50 of~TCE in rats is 4.92 g/kg
(NIOSH, 1980).
Long-term Exposure
• Rats exposed to 300 mg/m3 (55 ppm) TCE five days/week for 14 weeks
had elevated liver weights (Kimmerle and Eben, 1973).
Reproductive Effects
° Mo data were available on the reproductive effects of TCE.
Developmental Effects
e No data were available on the developmental effects of TCE.
Mutagenicity
0 Trichloroethylene was mutagenic in Salmonella typhimurium and in the
B^. coli K-12 strain, utilizing liver microsomes for activation (Grein
5 7 et al., 1975, 1977) .
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Trichloroethylene
-5-
March 31, 19t
Carcinogenicity
9 Technical TCE (containing epichlorohydrin and other compounds) was
found to induce a hepatocellular carcinogenic response in B6C3Fi mice
(NCI, 1976). Under the conditions of this experiment, a carcinogenic
response was not observed in Osborne-Mende^. rats. The "time-weighted"
average doses were 549 and 1,097 mg/kg for both male and female rats.
The time-weighted average daily doses were 1,169 and 2,339 mg/kg for
male mice and 869 and 1,739 mg/kg 'or female alee.
• E^ichlorohydrin-free TCE was reported to be carcinogenic in B6C3F^
mice when administered in corn oil at 1,000 mg/kg/day, 5 days/wk, for
103 weeks (NTP, 1982)'. It was not found to be carcinogenic in female
Fischer 344 rats when administered in corn oil at S00 or 1,000 mg/kg/day,
5 days/wk, for 103 weeks. The experiment with male rats.was considered
to be inadequate since these rats received doses of TCE that exceeded
the maximum tolerated dose.
° TCE has been shown to be carcinogenic in mice utilizing the inhalation
as well as the oral route of exposure. The National Cancer Institute
(1976) and the National Toxicology Program (1982) each conducted an
oral gavage study with TCE, one contaminated with epichlorohydrin and
the other free of epichlorohydrin, respectively. Zn these studies,
as described above, B6C3Ff mice were used, and the results were
unequivocally positive, showing liver neoplasms.
0 In an inhalation study, Henschler at al. (1980) reported dose-related
malignant lymphomas in female mice exposed to 100 or 500 ppm TCE vapor
6 hrs/day, 5 days/wk, for 18 months (HANtNMRI strain). However, the
authors downplayed the significance of this observation, indicating
that this strain of mice has a high incidence of spontaneous lymphomas.
0 Fukuda et al. (1983) found pulmonary adenocarcinomas in female .ICR
mice on exposure to TCE vapor.
• Henschler et al. (1984) tested Swiss (ICR/HA) mice and reported that
when the animals were treated by gavage with TCE in corn oil, no
statistical differences were observed in the incidence of cancers.
The results of this study can be questioned because the dose schedule
was often interrupted even with half of the original dose. Therefore,
it is very difficult to assess the exposure. A slight increase in
tumors was found in all groups treated with TCE but did not approach
statistical significance.
0 The Van Duuren study (1979) with skin applications of TCE in ICR/HA
mice does net negate the positive findings with other strains of mice
and other routes of exposure.
V. QUANTIFICATION Or TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
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March 31, 19S7a
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA ¦ (NOAEL or LOAEL) x (BW) _ mg/L 1 ug/L)
(UF) x ( L/day)
where*
NQAEL or LOAEL • No- or Lowest-Observed-Advarse-Effeet-Level
in ag/kg bv/day.
BW - assumed body weight of a child (10 kg) or
an adult (70 kg).
UF ¦ uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day - assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day and Ten-day Health Advisory
Suitable data were not available to estimate One-day and Ten-day Health
Advisories.
Longer-term Health Advisory
No suitable data are available from which to calculate a Longer-term
Health Advisory.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NQAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in bther sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
-------
Trichloroethylene
-7
March 31, 19&"a
Trichloroethylene may be classified in Group B: Probable Hunan Carcinogen,
according to EPA's weight-of-evidence scheme for the classification of carcino-
genic potential (U.S. EPA, 1986). Because of this, caution must be exercised
in making a decision on how to deal with possible lifetime exposure to this
substance. The risk manager must balance this assessment of carcinogenic
potential against the likelihood of occurrence of health effects related to
non-carcinogenic end-points of toxicity. In order to assist the risk manager
in this process, drinking water concentrations associated with estimated
excess lifetime cancer risks over the range of one in ten thousand to one
in a million for the 70 kg adult, drinking 2 liters of water"per day, are
provided in the following section. In addition, in this section, a Drinking
Water Equivalent Level .(DWEL) is derived. A DWEL is defined as the medium-
specific (in this case, drinking water) exposure which is interpreted to be
protective for non-carcinogenic end-points of toxicity over a lifetime of
exposure. The DWEL is determined for the 70 kg adult, ingesting 2 liters of
water per day. Also provided is an estimate of the excess cancer risk that
would result if exposure were to occur at the DWEL over a lifetime.
Xeither the risk estimates nor.the DWEL take relative source contribution
into account. The risk manager should do this on a case-by-case basis,
considering the circumstances of the specific contamination incident that has
occurred.
The study by Kimmerle and Eben (1973)is the most appropriate from which
to derive the DWEL. Ibis study evaluated the subacute exposure to trichloro-
ethylene vie inhalation by adult rats for some 14 weeks following exposure to
55 ppm (300 mg/m3), five days a week. Indices of toxicity include hemato-
logical investigation, liver and renal function tests, blood glucose and organ/
body weight ratios. Liver weights were shown to be elevated while other test
values were not different from controls. The elevated liver weights could be
interpreted to be the result of hydropic changes or fatty accumulation. The
no-observed-effect level was not identified since only a single concentration
was administered. From these results, a LOAEL of 55 ppm (300 mg/m3) was
identified. Using the LOAEL, the DWEL is derived as follows:
Step 1: Determination of the Total Absorbed Dose (TAD)
TAD = (300 mg/m3) (8^m3/day) (5/7) (0.3) . 7>35 ng/kg/day
where:
300 mg/m3 ¦ LOAEL for liver effects in rats
8 m3/day = Volume of air inhaled during the exposure period
5/7 " Conversion factor for adjusting from 5 days/week exposure
tc * daily dose
0.3 = Ratio of the dose absorbed.
7 0 kg = Assumed weight of adult.
360
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Trichloroethylene
-8-
March 31, 1~
Step 2: Determination of the Reference Dose (RfD)
RfD - I:35 mg/ko/day , 0.00735 mg/kg/day
(100) (10)
whores
7.35 mg/kg/day ¦ TAD.
1,000 ¦ uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LQAEL from an animal study.
Step 3: Determination of the Drinking Hater Equivalent Level (DUEL)
DWEL « (0.00735 ngAq/day) (70 kg) . 0.26 mg/L (260 ug/L)
2 L/day
where:
0.00735 mg/kg/day
70 kg
2 L/day
- RfD.
¦ assumed body weight
m assumed daily water
of an adult.
consumptiion of an adult.
The estimated excess cancer risk associated with lifetime exposure to
drinking water containing TCE at 260 ug/L is approximately 1 X 10~4. This
estimate represents the upper.95% confidence limit from extrapolations prepared
by EPA's Carcinogen Assessment Group using the linearized, multistage model.
The actual risk is unlikely to exceed this value, but there is considerable
uncertainty as to the accuracy of risks calculated by this methodology.
Evaluation of Carcinogenic Potential
• ZARC (1982) has classified TCE in Group 3.
0 Trichloroethylene has been classified in Group B2i Probable Human
Carcinogen. This classification for carcinogenicity was determined
by a technical panel of EPA's Risk Assessment Forum using the EPA
risk assessment guidelines for carcinogens (U.S. EPA, 1986). This
category is used for agents for which there is "sufficient evidence"
for human carcinogenicity from animal studies and for which there is
"inadequate evidence" or "no data" from human studies.
9 Using the improved multistage linearized model, it can be estimated
that water with TCE concentrations of 280 ug/L, 28 ug/L or 2.8 ug/L
may increase the risk of one excess cancer per 104, 105 or 106 people
exposed, respectively. These estimates were calculated from the 1976
NCI bioassay da<.&, which utilized TCE contaminated with epichlorohydrin.
Since then, ar. NTP (1982) bioassay utilizing epichlorohydrin-free TCE
has become available; the data from this bioassay have been reviewed
and evaluated for carcinogenicity, and epichlorohydrin-free TCE has
been reported to be carcinogenic in mice.
361
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Trichloroethylene
9-
inarcn ji , 17c/
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 ACGIH (1984) has recommended a threshold limit value (TLV) of 50 ppm
(/««-«270 mg/m3) and a short-term exposure limit (STEIi) of 150 ppm
{ 805 mg/m3.
* The NAS (1980) recommended One- and Seven-day SNARLS of 105 and 15 mg/L,
respectively.
0 The WHO (1981) recommended a drinking water guidance level of 30 ug/L
based on a carcinogenic end point.
0 The efa (U.S. EPA, 1980) recommended a water quality criterion of
6.77 mg/L for effects other than cancer.
• Die EPA (U.S. EPA, 1985d) has promulgated a Recommended Maximum
Contaminant Level (RMCL) of zero based upon its classification as a
known or probable human carcinogen and has proposed a Maximum Contami-
nant Level (MCL) of 0.005 mg/L based on Its RMCL and appropriate
feasibility studies.
VII. ANALYTICAL METHODS
0 Analysis of TCE is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile organohalides in drinking water
(U.S. EPA, 1985b). This method calls for the bubbling of an inert
gas through the sample and trapping ICE on an adsorbant material.
The adsorbant material is heated to drive off the TCE onto a gas
chromatographic column. This method is applicable to the measurement
of TCE over a concentration range of 0.01 to 1500 ug/L. Confirmatory-
analysis for TCE is by mass spectrometry (U.S. EPA, 1985c). The
detection limit for confirmation by mass spectrometry is 0.2 ug/L.
VIIIo TREATMENT TECHNOLOGIES
° Treatment technologies which will remove TCE from water include,
granular activated carbon (GAC) adsorption, aeration and boiling.
0 Dobbs and Cohen (1980) developed adsorption isotherms for several
organic chemicals including TCE. It was reported that Fibrasorb®
300 carbon exhibited adsorptive capacities of 7 mg, 1.6 mg and 0.4 mg
TCE/gm carbon at equilibrium concentrations of 100, 10 and 1 mg/L,
respectively. USEPA-DWRD installed pilot-scale adsorption columns
at different sites in New England and Pennsylvania. In New England,
contaminated veil water with TCE concentrations ranging from 0.4 to
177 mc,/L was passcf through GAC columns until a breakthrough concen-
tration of 0.1 mg/L was achieved with empty bed contact time (EBCT)
of 18 and 9 minutes, respectively (Love and Eilers, 1982). In
Pennsylvania, TCE concentrations ranging from 20 to 130 mg/L were
reduced to 4.5 mg/L by GAC after 2 months of continuous operation
(ESE, 1985).
362
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Trichloroethylene
¦1 0-
March 31,- 1&:7
• TCE is amenable to aeration on the basis of its Henry's Law Constant
of 550 atm (Kavanaugh and Trussell, 1980). Zn a full plant-scale
(3«78 MGD) redwood slat tray aeration column, a removal efficiency of
50-60% was achieved from TCE initial concentrations of 8.3-39.5 mg/L
at an air=to-water ratio of 30:1 (Hess et ale, 1961). In another
full plant-scale (6.0 MGD) multiple tray aeration column study, TCE
removal of 52% was achieved from 150 mg/l/ (Hess et al., 1981). A
full plant-scale packed tower aeration column removed 97-99% of TCE
from 1,500-2, 000 mg/L contaminated groundwater at air-to-water ratio
of 25:1 (ESE, 1985).
* Boiling also is effective in eliminating TCE from water on a short-term,
emergency basis. Studies have shown 5 minutes of vigorous boiling
will remove 95% of TCE originally present (Love and Eilers, 1982).
° Air stripping is an effective, simple and relatively inexpensive process
. for removing TCE and other volatile organics from water. However, use
of this process then transfers the contaminant directly to the air
stream. When considering use of air stripping as a treatment process,
it is suggested that careful consideration be given to the overall
environmental occurrence, fate, route of exposure and various other
hazards associated with the chemical.
363
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Trichloroethylene
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Marcn 31, 1^27
REFERENCES
ACGIH. 1984. American Conference of Governmental Industrial Hygienists.
Documentation of the threshold limit values. 4th ed« 1980-1984 Supplement4
pp. 406-408.
/
Amoore, J„E., and E. Hautala. 1983. Odor as an ail to chemical safety:
Odor thresholds compared with threshold limit values and volatilities
for 214 industrial chemicals in air and water dilution. J* Appl. Tbx.
3j 272-290.
deKant, W. Metzderm and D. Henschler. 1964. Novel metabolites of trichloro-
ethylene through dechlorination reactions in rats, mice and humans.
Biochem. Pharmacol. 33:2021-2027.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
orgaaics. EPA 600/8-80-023, Office of Research and Development, MERL,
Wastewater Treatment Division, Cincinnati, Ohio.
ESE. 1985. Environmental Science and Engineering. Draft technologies and
costs for the removal of volatile organic chemicals from potable water
supplies. ESE No. 84-912-0300 prepared for D.S. EPA, Science and Technology
Branch, CSD, ODW, Washington, D.C.
Fukuda, K., K. Takemoto and H. Tsuruta. 1983. Inhalation carcinogenicity of
trichloroetnvlene in mice and rats. Ind. Health* 21i243-254.
Greim, H., D. Bimboes, G. Egert, W. Giggelmann and M. Kramer. 1977. Muta-
genicity and chromosomal aberrations as an analytical tool for in vitro
detection of mammalian enzyme-mediated formation of reactive metabolites.
Arch. Toxicol. 39:159.
Greim, H., G. Bonse, Z. Radwan, D. Reichert and D. Henschler. 1975. Muta-
genicity mi vitro and potential carcinogenicity of chlorinated ethylenes
as a function of metabolic oxirane formation. Biochem. Pharmacol.
2 4:201 3.
Henschler, D., W. Romen, H.M. Elsasser, D. Reichert, E.Eder and Z. Radwan.
1980. Carcinogenicity study of trichloroethylene by long-term inhalation
in the animal species. Arch. Ibxicol. 43:237-248.
Henschler, D., H. Elsasser, W. Romen and E. EUer. 1984. Carcinogenicity
study of trichloroethylene, with and without epoxide stabilizers, in
mice. J. Cancer Res. Clin. Cticol. 104:149-156.
Hess, A.F., J.E. Dyksen and G.C. Cline. 1981. Case study involving removal
of organic chemical conpounds from ground water. Presented at Annual
American Water Works Association Conference, St. Louis, Missouri.
IARC. 1982. IARC monographs on the evaluation of the carcinogenic risk of
chemicals to humans. Supplement 4, Lyon, France..
364
-------
Trichloroethylene
-12-
March 31, 1957
Kavanaugh, M.C., and R.R. Trussell. 1980. Design of aeration towers to
strip volatile contaminants from drinking water. JAWWA. December.
Kimmerle, G., and A. Eben. 1973. Metabolism, excretion and toxicology of
trichloroethylene after inhalation* 10 Experimental exposure on rats.
Archo Toxicol. 30:115.
Lachnit, V. 1971. Halogenated hydrocarbons and the liver. Wien. Klin.
Wochenschr. 83(41)>734.
Love, O.T., Jr., and R.6. Silers. 1982. Treatment of drinking water containing
trichloroethylene and related industrial solvents. JAWWA. August.
NAS. 1980. National Academy of Sciences. Drinking Water and Health. Volume 3.
National Academy Press. Washington, DC.
NCI. 1976. National Cancer Institute. Carcinogenesis bioassay of trichloro-
ethylene. UoS. Department of Health, Education and Welfare, Public
Health Service, CAS No. 79-01°>6, February.
NIOSH. 1980. Registry of Toxic Effects of Chemical Substances. U.S. Depart-
ment of Health and Human Services. DHHS (NIOSH) 81-116.
NTP. 1982. National Toxicology Program. Carcinogenesis bioassay for tri-
chloroethylene. CAS * 79-01-6. No. 82-1799. (Dsaft).
Parsons, F., P«R0 Wood and J. DeMarco. 1984. Transformation of tetrachloro-
ethene and trichloroethene in microcosms and groundwater. JAWWA,
26(2)156f.
Soucek, B., and D. Vlachova. 1959. Metabolites of trichloroethylene excreted
in the urine by man. Pracoc. Lek. 11:457.
Stephens, C.A. 1945. Poisoning by accidental drinking of trichloroethylene.
Brit. Med. J. 2:218.
Torkelson, T.R., and V.K. Rowe. 1981. Halogenated aliphatic hydrocarbons.
In: Industrial Hygiene and Toxicology. 3rd ed. Vol. 2B. John Wiley
and Sons, New York. p. 3553.
U.S. EPA. 1979. U.S. Bivironmental Protection Agency. Water Related Environ-
mental Fate of 129 Priority Pollutants, Office of Water Planning and
Standards, E>A-440/4-79-029.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water quality
criteria document for trichloroethylene. Office of Water Research and
Standards. Cincinnati, Ohio.
U.S. EPA. 1983. U.S. Environmental Protection Agency. Trichloroethylene
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. The drinking water
criteria document on trichloroethylene. Office of Drinking Water.
365
-------
Crichloroethylene
-13-
March 31, 1S-S"
U.S. EPA. 1985b. Method 502.1. Volatile Halogenated Organic Compounds in
Water by Purge and Trap Gas Chromatography, Environmental Monitoring and
Support Laboratory, Cincinnati, Ohio 45268.
U.S. EPA. 1985c. Method 524.1. Volatile Organic Compounds in Water by Purge
and^Trap Gas Chromatography/Mass Spectrometry, Environmental Monitoring
and Support Laboratory, Cincinnati, Ohio 45268.
U.S. EPA. 1985d. U.S. Environmental Protection Agency. National primary
drinking water regulations; Volatile synthetic organic chemicals; final
rule and proposed rule. Federal Register 50(219)i46880-46933.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register 51(185)i33992-34003.
September 24.
U.S. XTC. 1983. United States International Trade Commission. Synthetic
organic chemicals. United States production, USITC Publication 1422.
Washington, O.C. 20436.
van Duuren, B.L., B.M. Goldschmidt, G. Lowengart, A.C* Smith, S. Melchionne,
I. Seldman and D. Roth. 1979. Carcinogenicity of halogenated olefinic
and aliphatic hydrocarbons in mice. J. Natl* Cancer Inst. 63:1433-1439.
Vogel, T., and P. McCarty. 1985. Biotransformation of tetrachloroethylene
to trichioroethylene, dichloroethylene, vinyl chloride, and carbon dioxide
under methanogenic conditions. Appl. Environm. Microbiol. 49(5).
WHO. 1981. World "Health Organization. Guidelines for drinking water quality.
Vol. I. Recommendations. Geneva, Switzerland, pp. 63, 66.
Windholz, M. 1983. The Merck Index. 10th edition. Merck and Co., Inc.
Rahway, NJ. p. 1378.
Zenick, H., K. Blackburn, E. Hope,' N. Richards and M.K. Smith. 1984. Effects
of trichloroethylene exposure on male reproductive function in rats.
Toxicology. '31;237.
366
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Marc'-. 21, 19?"
VINYL CHLORIDE
Health Advisory Draft
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. Kiey are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures bases' on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure ana the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. Tms provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess .cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
367
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Vinyl Cnlonie
Marc
31, 19S"
¦2-
This Health Advisory (HA) is based on information presented in the
Office of Drinking Water's Health Effects Criteria Document (CD) for vinyl
chloride (U.S. EPA, 1985a). The HA and CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Hater
counterpart (e.g., Water Supply Branch or Drinking-water Branch), or for a
fee from the National Technical Infermation Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB # 86-118320/AS. The
toll-free number is (800) 336-4700; in the Washington, D.C» area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 75-01-4
Structural Formula
H-C-C-Cl
I I
H H
° Monochloroethylene, chloroethene
Uses
0 Vinyl chloride and polyvinyl chloride (PVC) are used as raw materials
in the plastics, rubber, paper, glass and automotive industries.
In addition, vinyl chloride and PVC are used in the manufacture of
electrical wire insulation and cables, piping, industrial and household
equipment, medical supplies, food packaging materials and building
and construction products. Vinyl chloride copolymers and PVC are
distributed and processed in a variety of forms, including dry resins,
plastisol (dispersions in plasticizers), organosol (dispersions in
plasticizers plus volatile solvent), and latex (a colloidal dispersior,
in water used to coat paper, fabric or leather) (U.S. EPA, 1985a).
Properties (U..S. EPA (1"985a)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Specific Gravity
Water Solubility
Taste Tnreshola (water)
Odor Threshold (water)
Conversion Factor (air)
H2CCHCI
62.5
Gas
-13.3°C
2,530 mmHg at 20°C
0.91
1.1 g/L water at 28°C
not available
3.4 mg/L*
1 ppm = 2.6 mg/m3
*Amoore and Hautala (1983)
368
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March 31 , . 1 9^ -
-3-
Occurrence
0 Vinyl chloride is a synthetic chemical with no natural sources.
0 Since 1979, yearly production of vinyl chloride has been approximately
7 billion lbs (U.S. ITC, 1983). Vinyl chloride is polymerized, and
little is released to the environment. Environmental releases will
be limited to the areas where vinyl chloride is produced and used.
0 Vinyl chloride released to the air is degraded in a matter of a few
lrours (U.S.EPA, 1980a). Vinyl chloride released to surface waters
migrates to the atmosphere in a few hours or days where it undergoes
photochemical oxidation. Vinyl chloride which is released to the
ground does not adsorb onto soil and migrates readily to ground
water. Evidence from laboratory studies suggests that vinyl chloride
in ground water may degrade to CO2 and CI" (Vogel and McCarty, 1985).
Vinyl chloride is expected to remain in ground water for months to
years. Vinyl chloride has been reported to be a degradation product
of trichloroethylene and tetrachloroethylene in ground water (Parsons,
1984). Vinyl chloride does not bioafccuoulate in individual animals
or food chains.
0 Vinyl chloride does not occur widely in the environment because of
its rapid degradation and limited release. Vinyl chloride is a
relatively rare contaminant in ground and surface waters with higher
levels found in ground water. Hie Ground Water Supply Survey of
drinking water supplies have found that less than 2% of all ground
water derived public water systems contain vinyl chloride at levels
of 1 ug/L or higher. Vinyl chloride almost always co-occurs with
trichloroethylene. Public systems derived from surface water also
have been found to contain vi'nyl chloride but at lower levels. No
information on the levels of vinyl chloride in food have been identi-
fied. Based upon the limited uses of vinyl chloride and its physical
cnemicai properties, little or no exposure is expected from food,
vinyl chloride occurs in air in urban areas.and near the sites of its
production and use. Atmospheric concentrations are in"the ppt
range (U.S. EFA, 1979).
0 Tne major source of exposure to vinyl chloride is from contaminated
water.
III. PHARMACOKINETICS
Absorption
0 Vinyl chloride is absorbed rapidly in rats following ingestion and
inhalation (Withev, 1976; Duprat et al., 1977).
0 Usi.-g a'-aristical modeling, Withey and Collins (1976) concluded that,
for rats, a total liquid intake containing 20 ppm (wt/wt) vinyl
chloride would be equivalent to an inhalation exposure of about 2 ppr;
(vol/vol) for 24 hours.
369
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Distribution
° Upon either inhalation or ingestion of 14C-vinyl chloride in rats, the
greatest amount of 14C activity was found 72 hours after treatment
in liver followed by kidney, muscle, lung and fat (Watanabe et al.,
1976a,b). Another study of inhalation exposure of rats to 14c-vinyl
chloride showed the highest 14C activity immediately after treatment
in liver and kidney, followed by spleen and brain (Bolt et al., 1976).
Metabolism
° Bartsch and Montesano (1975) reported two possible metabolic pathways
for vinyl chloride, one involving alcohol dehydrogenase, the other
involving mixed function oxidase. Hefner et alo (1975) concluded
that the dominant pathway at lower exposure levels probably involves
alcohol dehydrogenase.
° Vinyl chloride metabolism is saturable (Hefner et al., 1975; Watanabe
et al., 1976a; Bolt et al., 1977).
° Chlorcethylene cxide, presumably through mixed-function oxidase, may
be the main metabolite capable of alkylating intracellular macro-
molecules (Laib and Bolt, 1977).
Excretion
° Rats administered vinyl chloride by ingestion or inhalation exhale
' greater amounts of urimetabolized vinyl chloride as the dose is
increased (Watanabe et al., 1976a, b).
0 Vinyl chloride metabolites are excreted mainly in the urine. In
rats, urinary metabolites include N-acetyl-S-(2-hydroxyethylcysteinei
and thiodiglycolic acid (Watanabe et al., 1976a).
HEALTH EFFECTS
Humans
° Cancer findings in humans are described under Carcinogenicity.
° Mutagenic effects in humans are described under Mutagenicity.
0 Developmental studies in humans are described under Developmental
Effects.
° At high inhalation exposure levels, e.g., 40-900 ppm (104-2,344 mg/m3),
workers have experienced dizziness, headaches, euphoria- and narcosis
(U.S. EPA, 1985?).
0 Symptoms of chronic inhalation exposure of workers to the vinyl
chloride-polyvinyl chloride industry include hepatotoxicity (Marstellar
et al. 1975), acro-osteolysis (Lilis et al., 1975), central nervous
370
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. 1 Cr.lor: ;
Ma r en
1 9:
-5-
system disturbances, pulmonary insufficiency, cardiovascular toxicity,
and gastrointestinal toxicity (Miller et al., 1975; Selikoff and
Hammond, 1975; Suciu et al., 1975). Data on dose-responses in humans
are scarce because few measurements of ambient vinyl chloride levels
in the workplace were made before 1975 (Mancuso, 1975).
Animals
Short-term Exposure
• Inhalation exposure to high levels (ca. 100,000 ppm or 260,417 mg/m3)
of vinyl chloride can induce narcosis and death, and, to lower doses,
ataxia, narcosis, congestion and edema in lungs and hyperemia in
liver in several species (U.S. EPA, 1985a).
Long-term Exposure
0 Administration of vinyl chloride monomer to rats by gavage for 13
weeks resulted in hematologic, biochemical and organ weight effects
at doses above 30 ag/kq (Feron et al., 1975).
0 Inhalation exposure of rats, guinea pigs, rabbits and dogs to 50 ppm
(130 mg/m3) vinyl chloride, 7 hours/day, 130 exposures in 189 days,
did not induce toxicity as judged by appearance, mortality, growth,
hematology, liver weight and pathology. Rats exposed to 100 ppm
(260 rag/m3) 2 hours/day for six months, had increased liver weights
(Torkelson et al., 1961).
Reproductive Effects
0 Potential effects on reproductive capacity have not been studied.
Developmental Effects
° Infante et al. (1976a,b) reported an association between human
exposure to vinyl chloride and birth defects and fetal loss, but this
association was contradicted by Edmonds et al. (1975) and Hatch et
al. (19S1).
0 Inhalation exposure of rats and rabbits to vinyl chloride concentrations
as high as 2,500 ppm (6,500 mg/m3) on days 6 to 15 (rats) and 6 to
18 (rabbits) of gestation and mice to vinyl chloride levels as high as
500 ppm (1,300 mg/m3) on days 6 to 15 of gestation did not induce
teratogenic effects but did increase skeletal variants in high dose mice
(John et al., 1977).
0 A developmental effects study with vinyl chloride in rats exposed by
inhalation to 600 or 6,000 ppm (2,160 or 21,160 mg/m3).4 hours daily
on gestation days 9 through 21 was negative for teratogenicity and
inconclur.J ve for fetotoxicity (Radike et al., 1977).
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Vinvl Chloriie
1 95'
-6-
Mutagenicity
° Chromosomal effects of vinyl chloride exposure in workers is conflicting
in that positive (Ducatmann et al., 1975; Purchase et al.f 1975) ana
negative (Killian et al., 1975; Picciano et al., 1977) results have
been reported. Picciano et al. (1977) reported exposures of 0.13 to
15.2 ppm (0.34 to 40 mg/m3, time-weighted averages) for 1 to 332
months.
® Vinyl chloride is mutagenic, presumably through active metabolites in
various systems including metaboIleally activated systems with £. typhi-
murium (Bartsch et al., 1975); coli (Greim et al., 1975); yeast
(Loprieno et al., 1977); germ cells of Drosophila (Verburgt and
Vogel, 1977); and Chinese hamster V79 cells (Hubermann et al., 1975).
0 Dominant lethal studies with vinyl chloride in CD-1 mice were negative
(Anderson et al., 1976).
Carcinogenicity
0 Increases in trie occurrence of liver angiosarcomas as well as in tumors
of the brain, lung, and hematopoietic and lymphopoietic tissues have
been associated with occupational exposure to the vinyl chloride-
polyvinyl chloride industry in humans (XARC, 1979). The initial
report of a link between vinyl chloride exposure and cancer in humans
by Creech and Johnson (1974), as well as subsequent reports by others,
indicates the nigh risk and specificity of association with liver
angiosarcoma, a very rare tumor in humans.
° Ingestion of vinyl chloride monomer in the diet by rats at feeding
levels as low as 1.7 and 5 mgAg/day over .their lifespan induced
hepatocellular carcinomas and liver angiosarcomas, respectively, as
well as other adverse hepatic effects (Feron et al., 1981). Til
et al. (19S3) extended the Feron et al. (1981) work to include lower
doses and did not find a significant (P<0.05) increase in carcinogenic
effects at feeding levels as high as 0.13 mg/kg/day. Administration
of vinyl chloride monomer by gastric intubation for at least 52 weeks
resulted in carcinogenic effects in liver and other tissue sites in
rats (Feron et al., 1981; Maltoni et al., 1981).
° Chronic inhalation of vinyl chloride has induced cancer in liver and
other tissue sites in rats and mice (Lee et al., 1977, 1978; Maltoni
et al., 1981).
V. QUANTIFICATION" OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-tern (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
372
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HA = JJ^0A£L_J3£_L0AELJ_^x__(BW^ _ mg/L (___ ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in nig/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF » uncertainty factor (10, 100 or 1,000), i
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
There are insufficient data for calculation of a One-day Health Advisory.
The Ten-day HA of 2.6 mg/L is proposed as a conservative estimate for a
One-day HA.
Ten-day Health Advisory
Inhalation data by Torkelson et al. (1961) were not selected for the
Ten-day HA caJculation because of preference for studies with oral exposure.
Feron et al. (1975) reported a subchronic toxicity study in which vinyl
chloride monomer (VCM) dissolved in soybean oil was administered by gavage to
male and female Wistar rats, initially weighing 44 g, at doses of 30, 100 or
300 mg/kg once daily, 6 days per week for 13 weeks. Several hematological,
biochemical and oroan weight values were significantly (P<0.05 or less)
different in both mid- and high-dose animals compared to controls. The NOAEL
in this study wis identified as 30 mg/kg.
Tne Ten-day HA, as well as the One-day HA, for a 10-kg child is calculated
as follows:
Ten-day HA = (30 mg/kg/day (6/7) (10 kg) = 2.6 mg/L (2,600 ug/L)
(100) (1 L/day)
NOAEL based on absence of biochemical and organ weight
effects in rats exposed orally to vinyl chloride.
expansion of 6 days/week treatment in the Feron et al.
(1975) study to 7 days/week to represent daily exposure.
assumed body weight of a child.
uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
assumed daily water consumption of a child.
where:
30 mg/kg/day =
6/7 =
1 0 k 9 -
1 00 =
1 L/day =
373
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Vin ¦: Chlcrii:
31, 1
-8-
Longer-term Health Advisory
The Longer-term HA can be calculated from the lifetime feeding study in
rats by Til et al. (1983). Til et al. (1983) have extended the earlier work
by Feron et al. CI 981) to include lower doses with basically the same protocol
used in the latter study. Carcinogenic and noncarcinogenic effects were evi-
dent with a vinyl chloride dietary level of 1.3 mgAg/day. At dietary levels
of 0.014 and 0.13 mg/ltg/day, increased incidences of basophilic foci of cellu-
lar alteration in the liver of female rats were evident. However, basophilic
foci by themselves are concluded not to represent an adverse effect on the
^iver In the absence of additional effects indicative of liver^lesions such
as those found in the 1.3 mgA9/day group; and a dose-related increase in
basophilic foci was not evident. Therefore, the dose of 0.13 mgAg/day is
identified as the NOAEL for noncarcinogenic effects for the Longer-term HA
calculation.
Using the C.13 mgAg/day NOAEL from the Til et al. (1983) study, the
Longer-term HA for a.10-kg child is calculated as follows:
Longer-term HA = (0.13 mgAg/day) (10 kg) » 0#013 mg/L (13 Ug/L)
(100) (1 L/day)
where:
0.13 mgAg/day = NOAEL based on absence of adverse liver effects
in rats.
10 eg = assumed body weight of a child.
1 00 » uncertainty factor, chosen in accordance with NAS/0l>
guidelines for use with a NOAEL from an' animal study
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (0.13 mg/kg/day) (70 k?) , 0<046 /L (46 /ZJ
(100) (2 L/day)
where:
0.13 mgAg/day = NOAEL based on absence of adverse liver effects
in rats.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODi."
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
374
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Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). Hie RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). Prom the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are hot available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing tne risks associated with lifetime exposure to this chemical.
Because vinyl chloride is classified as a human carcinogen (XARC Group 1
and EPA Group A), a Lifetime Health Advisory is not recommended.
Evaluation of Carcinogenic Potential
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), vinyl chloride may be classified
in Group A: Human carcinogen. This category is for agents for which
there is sufficient evidence to support the causal association betwee:-.
exposure to the agents and cancer.
0 The IARC (1979) has concluded that there is sufficient evidence to
classify vinyl chloride as a human carcinogen in its Category 1.
0 EPA's Carcinogen Assessment Group (CAG) recently has recalculated its
excess carcinogenic risk estimates resulting from lifetime exposure
to vinyl chloride through the drinking water (U.S. EPA, 1985a). CAG
based its preliminary revised estimates on the Feron et al. (1981)
study. The total number of tumors, considering tumors of the lung
and liver, in rats exposed through the diet was used to calculate the
excess cancer risk. Using the 95% upper limit [qj* = 2.3 (mgAg/day)~
with the linearized multistage model, they calculated that consuming
2 liters of water per day with vinyl chloride concentration of 1.5 uc/_,
0.15 ug/L and 0,015 ug/L would increase the risk of one excess cancer
per 10,000 (10-4), 100,000 (10-5) Dr 1,000,000 (10-6) people exposed,
respectively, per lifetime. The CAG is presently reassessing the
cancer risk estimate based on the Feron et al. (1981) study by takina
into account the more recent data by Til et al. (1983) which, as
375
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Vinyl Chlorir.e
Marc-
3", 19[-
1 0
described previously, is an extension of the earlier Feron et al.
(1981) work to include lower doses.
0 Maximum likelihood estimates as well as 95% upper limits of cancer
risks by the multistage model are presented. Expressing risk as
cases/lifetime/person, examples would be 0.01 mg/kg/day or 0.35 mg/L
exposure associated with risks of 1.6 x 10~2 (MLE) and 1_.9 x 10-2
(UL) and OoOOl mg/kg/day exposure associated with risks of 1 .6 x 10-3
(MLE) and 1.9 x 10-3 (UL).
0 Cancer risk estimates (95% upper limit) with other models are presented
for comparison with that derived with the multistage. For example,
one excess cancer per 1(000,000 (10—6) is associated with exposure
to vinyl chloride in drinking water at levels of 50 ug/L (probit),
0.5 ug/L (logit), and 0.02 ug/L (Weibull). While recognized as
statistically alternative approaches, the range of risks described by
using any of these modeling approaches has little biological signifi-
cance unless data can be used to support the selection of one model
over another.. In the interest of consistency of approach and in
providing an upper bound on the potential cancer risk, the EPA has
recommended use of the linearized multistage approach.
VI. OTHER CRITERIA, GUIDANCE, AND STANDARDS
° The National Academy of Sciences (NAS, 1977) estimated a 10-6 risk
(95% upper bound estimate) from lifetime exposure to 1 ug vinyl
chloride/L drinking water with the multistage model and the lifetime
ingestion study in rats by Maltoni et al. (1981).
° The final RMCL by the U.S. EPA Office of Drinking Water is zero, the
proposed MCL is 1 ug/L", and the practical quantitation level is 1 ug/!
(U.S. EPA, 1985b).
0 Ambient water quality critera (U.S. EPA, 1980b) are 20, 2 and 0.2 ug/!
for risks of 10"5, 10"6, and 10"7, respectively, assuming consumption
of 2 liters of water and 6.5 grams of contaminated fish per day by a
70 kg_adult.
0 A workplace standard of 1 ppm (time-weighted average) was set by OSHA
in 1974 based on the demonstration of angiosarcoma of the liver in
vinyl chloride workers (Federal Register. 39:35890).
0 The ACGIH (1982) has recommended a TLV of 5 ppm (10 mg/m3).
VII. ANALYTICAL METHODS
0 Analysis of vinyl chloride is by a purge and trap gas chromatographic
procedure used for the determination of volatile organohalides in
drinking water (U.S. EPA, 1985c). This method calls for the bubbling
of an inert gas through a sample of water and trapping the purged
vinyl chloride on an adsorbent material. The adsorbent material is
376
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-11-
heated to drive off the vinyl chloride onto a gas chromatographic
column. This method is applicable to the measurement of vinyl chloride
over a concentration range of 0.06 to 1500 ug/L. Confirmatory analysis
for vinyl chloride is by mass spectrometry (U.S. EPA, 1985d). The
detection limit for confirmation by mass spectrometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
° The value of the Henry's Law Constant for vinyl chloride (6.4
atm-m3/mole) suggests aeration as a potential removal technique
for vinyl chloride in water (ESE,1984). Removals of up to 99,27%
were achieved at 9°C using a pilot packed tower aerator. In similar
studies, vinyl chloride was removed from ground water using a
spray aeration system with total VOC concentration was 100 to
200 ug/L (ESE, 1984). Greater than 99.9% VOC removal was obtained
using a four-stage aeration system; each stage employed 20 shower
heads .with a pressure drop of approximately 10 pounds per square
inch. In-well aeration has also demonstrated up to 97% removal of
vinyl chloride using an air-lift pump. However, practical considera-
tions are likely to limit the application of this (Miltner, 1984).
0 The concentration of vinyl chloride in southern Florida ground water
declined by 25% to 52% following passage through lime softening basins
and filters (Wood and OeMarco, 1980). Since vinyl chloride is a
highly volatile compound, it is probably volatilized during treatment
(ESE, 190-;).
0 Adsorption techniques have been less successful than aeration in
removing vinyl chloride from water. In a pilot study, water from a
ground water treatment plant was passed through a series of four
30-inch granular activated carbon (Filtrasorb 400) columns (Wood-anJ
DeMarco, 1980; Symons, 1978); the empty bed contact time was approxi-
mately su; minutes per column. Influent vinyl chloride concentrations
ranged from below detection to 19 ug/1; erratic removal was reported.
To maintain effluent concentrations below 0.5 ug/1, the estimated
column capacity to breakthrough was 810, 1,250, 2,760 and 2,050 bed
volumes for empty bed contact times of 6, 12, 19 and 25 minutes,
respectively. In addition, the estimated service life of the acti-
vated carbon was low. Similarly, poor removal of vinyl chloride was
achieved using an experimental synthetic resin, Ambersorb XE-340,
(Symons, 1978).
0 Treatment technologies for the removal of vinyl chloride from water
have not been extensively evaluated except on an experimental level.
Available information suggests aeration merits further investigation.
Selection of individual or combinations of technologies to achieve
vinyl chloride removal must be based on a case-by-case technical
evaluation, a:io an assessment of the economics involved.
377
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Vinyl C-iorii-
•viarcn
1 9:
-1 2-
IX. REFERENCES
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Anderson, D„, M.C.E. Hodge and I.F.H. Purchase. 1976. Vinyl chloride:
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Bartsch, H., C. Malaveille and R. Montesano. 1975. Human, rat and mouse
liver-mediated mutagencity of vinyl chloride in S. typhimurium strains.
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Bartsch, H., and R. Montesano. 1975, Mutagenic and carcinogenic effects of
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Bolt, H.M., H. Kappus, A. Buchter and W. Bolt. 1976. Disposition of
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Creech, J.L., and M.N. Johnson. 1974. Angiosarcoma of the liver in the
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sure and human chromosome aberrations. Mutat. Res. 31:163-168.
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(Kbn) 41 (1 ):142—143.
Edmonds, L.D., H. Falk and J.E. Nissim. 1975. Congenital malformations and
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ESE. 1984. Environmental Science and Engineering. Technologies and costs for
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Feron, V.J., A.7. S-3E31:, M.I. Williams, D. van Battum and A.F. de Groot.
1975. Observations on the oral administration and toxicity of vinyl
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Ma r c'n 31, 1 9 £ ¦
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Feron, V.J., C.F.M. Hendrikson, A.J. Speek, H.P. Til and B.J. Spit. 1981.
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reproductive effects of vinyl chloride and some structural analogs.
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Huberraan, E., H. Bartsch and L, Sachs. 1975. Mutation induction in Chinese
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O.lcnds
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¦1 4-
Loprieno, N., R. Barale, S. Baroncelli, H. Bartsch, G. Bronzetti, A. Cammelli
C. Corsi, D. Frezza, R. Nieri, C. Leporini, D. Rosellini and A.M. Rossi.
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Vinyl Chloride
March 3*, 19-IT
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382
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March 31, 1987
XYLENES
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides inforration on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be antic:pated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed us; legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, cr 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions far
lifetime exposure and the consumption of drinking water. The cancer unit
risk -is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
383
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Xylenes
March 31, 1987
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This Health Advisory is based on information presented in the Office of
Drinking Water's Health Effects Criteria Document (CD) for Xylenes (U.S. EPA,
1985a). The HA and CD formats are similar for easy reference. Individuals
desiring further information on the toxicological data base or rationale for
risk characterization should consult the CD. The CD is available for .review
at each EPA Regional Office of Drinking Water counterpart (e.g., Water Supply
Branch or Drinking Water Branch), or £er a fee from the National Technical
Information Service, U.S° Department of Commerce, 5285 Port Royal Rd.,
Springfield, VA 22161, PB « 86-117942/AS. The toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
GENERAL INFORMATION AND PROPERTIES
CAS No.
Structural Formula
Xylene
1330-20-7
Meta-
108-38-3
CH3
o
CHi
Para-
106-42-3
CH3
o
CH-j
Synonyms
0 Xylols; dimethylbenzene
Uses
0 As solvents for paints, inks and adhesives, and as components of
detergents and other industrial and household products.
Properties (Verschueren, 1983) ¦
Xylene
Ortho-
Meta-
Para-
Chemical Formula
C8H10
CbHtO
c8h1 0
Molecular Weight
106.16
106.16
106.16
Boiling Point
144.4"C
139.0°C
138.4°C
Melting Point
-25#C
-48 °C
-1 3°C
Density
—
—
—
Vapor Pressure, mm Hg, 20° C
5
6
6.5
Water Solubility, mg/1, 20° C
175
160
—
25° C
—
—
198
Log Octanol/Water Partition
3.12
3.20
3.15
Coefficients
Taste Thresholdb
Odor Threshold
Conversion Factor
0.3-1.0 mg/L
1 ppm = 4.3 mg/m3
a Leo et al. (1971)
b National Inst, for Water Supply (1977]
384
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Xylenes
March 31, 19S7
-3-
Occurrence
0 Xylene occurs naturally as a component of petroleum oil.
0 Xylenes are produced in large amountsf 5 billion lbs in 1982 (U.S. ITC,
1984). Xylenes are also produced indirectly in large volumes during
gasoline refining and other operations. Xylene content of gasoline
can be as high as several percent.
0 Releases of xylenes to the environment are largely to air due to their
volatile nature, wijth smaller amounts to water and soil. Releases of
xylenes to water are due to spills and leaks of gasoline and other
petroleum products and, to a lesser extent, from the disposal of waste
from paints, inks and other industrial products. Because of the wide-
spread use of petroleum products, releases of xylene occur nationwide.
8 Xylenes degrade rapidly in air with a half life of a few days. Xylenes
released to surface water rapidly volatilize to the air. Xylenes
released to the ground bind somewhat to soil and slowly migrate with
ground water. Xylenes are biodegraded readily in soils and surface
waters. In the absence of biodegradation, xylenes are expected to be
stable in ground water.
° Xylenes occur at low levels in drinking water, food, and air. Xylene
occurs in both ground and surface public water supplies, with higher
levels occurring jn surface water supplies. TOie EPA's Community
Water Supply Survey, found 3% of all ground water derived'public
drinking water systems sampled had levels greater than 0.5 ug/L. The
highest level reported in ground water was 2.5 ug/L. The survey
reported that 6% of all surface water derived drinking water system
are contaminated at levels higher than 0.5 ug/L. None of the syster.s
were reported to contain levels higher than 5.2 ug/L. Mo information
on the occurrence of xylene in foods has been identified. Xylenes
are found in the air of urban and suburban areas at levels of approxi-
mately 2 ug/L. Because of the widely dispersed low levels of xylenes
reported in water, air is likely to be* the major source of exposure.
III. PHARMACOKINETICS
Absorption
° Xylenes are absorbed readily after inhalation. Data on absorption
after ingestion are not available. Sedivec and Flek (1976) exposed
human volunteers to 0.2 mg/L (200 mg/m^) o-, m- and p-xylene vapors
and also to their mixture at a ratio of 1:1:1 for an 8-hour period.
The amrur.t absorbed or retained was 63.6% * 4.2% for all-isomers.
Distribution
° Using whole-body autoradiography to detect radiolabeled xylene and
metabolites, Bergman (1978) reported distribution of the compound in
many tissues and organs of exposed mice. 14C-m-Xylene was administered
385
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Xylenes
March 31, 19S7
-4-
to mice by inhalation for 10 minutes. Whole mice were frozen and
sectioned before exposure to X-ray film. In mice sacrificed immediate!
after xylene exposure, radiolabel was detected in the lungs, liver
and kidneys. Rapid distribution to the brain and adipose tissue also
was evident. Two hours after exposure, radiolabel in the lungs was
restricted to the bronchi. In addition to the previously noted
organs, radiolabel was detected in the intestine after two hours.
The last traces of xylene were detected in the adipose tissue of mice
sacrificed four hours after exposure*
• In rats exposed to 14C-p-xylene for 1-8 hours by inhalation at 208
ng/m3 (48 ppm), radiolabel was detected (in decreasing concentration)
in the kidneys, subcutaneous fat, sciatic nerve, blood, liver, lungs,
spleen, muscles, cerebrum and cerebellum (Carlson, 1981). Distribution
to all tissues was rapid, allowing near maximal levels in tissues
(except in kidneys and subcutaneous fat) within one hour.
Metabolism
° Metabolism of xylenes varies somewhat according to the isomer but, in
general, proceeds by oxidation of methyl groups and ring hydroxylation.
The resulting metabolites include methyl hippuric acid (95%) and
xylenols (1-2%) (Harper et ,al. 1975).
Excretion
0 Elimination of xylenes is primarily through urinary excretion of
metabolites, representing nearly 95% of the absorbed dose, and the
remaining 5% by pulmonary exhalation of unchanged solvent (Sedivec
and Flek, 1976; Astrand et al., 1978).
HEALTH EFFECTS
Humans
0 The Towest oral lethal dose (LDLo) for humans has been-reported as
50 mg/kg (NIOSH, 1978).
° Xylenes produce central nervous system disturbances as reflected in
changes in numerative ability, short-term memory and electroencephalo-
graphic patterns.
0 Gamberale et al. (1978) observed no adverse health effects in fifteen
male subjects at rest following.70 minutes of inhalational exposure
to xylene at 435 and 1300 mg/n>3. However, in another experiment,
eight male subjects were exposed to xylene at 1300 mg/m3 with 30
minutes cC ex-rcis>a on a bicycle ergometer which was continued during
behavior tests. The authors concluded that there was evidence of
reduction in the performance level on three of the four tests. The
tests conducted were: simple addition and choice reaction time,
short-term memory and critical Hicker fusion frequency.
386
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Xylenes March—-31, 1 9£"
-5-
0 Savolainen et al. (1980) observed adverse effects on the psycho-
physiological functions in eight male students following inhalational
exposure to m-xylene at 391 mg/m3 for five consecutive days and one
day after the weekend. Body balance, reach on time and manual coordi-
nation were impaired. However, tolerance against the observed effects
developed during one working week.
Animals
Short-term exposure
° In rats, oral LD5g values range from 4,300 to 5,000 mg/kg(NIOSH. 1978),
whereas inhalation LCsq5 (four hours) are 20,600 to 29,000 mg/m
(Carpenter et al., 1975; Harper et al., 1975).
Lonq-tenr. Exposure
° Carpenter et al. (1975) exposed rats to mixed xylenes at 770, 2000 or
3500 mg/m3 for six hours/day, five days/week for 13 weeks duration.
No effects on body weight gain, hematology, blood chemistry, kidney,
or liver weights or tissue histology were reported at two lower dose
levels. At the highest dose level, one rat treated at 3500 mg/m3 for
seven weeks showed slight renal tubular regeneration and, at 13 weeks,
the response was noted in rats in a non-dose-related manner.
0 Jenkins et al. (1970) reported the results of repeated (30 exposures)
or continuous inhalation exposure (90 days) to o-xylene by rats,,
guinea pigs, monkeys and dogs. The exposure levels were 337 or
3,358 mg/m3 in rats and monkeys. One of the dogs exhibited tremors
of varying severity throughout exposure. No significant effects were
observed with respect to body weight, hematology, and histopathologicai
exarination at the lower dose of 337 mg/m3 xylene.
* Ultrastructural hepatic effects have been reported in rats following
subchronic oral exposure (200 mg/kg diet for up to 6 months) (Bowers
et al., 1982). Two types of intracellular vesicles in rats treated
with o-xylene were observed. One type appeared to be an extension of
the endoplasmic reticulum and the second vesicle type was associated
with the hepatocyte plasmalemma.
Tatrai et al. (1981) reported hepatomegally and ultrastructurally
evident proliferation of the smooth endoplasmic reticulum following
chronic inhalation exposure of 4750 mg/m3, eight hours/day, seven
days/week for one year in rats.
Reproductive _Effects_
No information was found in the available literature on the repro-
ductive effects of xylene.
Developmental Effects
Twenty CFY rats, 240 to 280 g, were exposed to 1,000 mg/m3 of mixed
xylenes 24 hoars/day during days 9 to 14 of pregnancy, and although
387
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Xylenes
March 31, 1967
-6-
there were increased incidences of fused sternebrae and extra ribs in
the offspring, the authors interpreted these as. signs of embryotoxicity
rather than teratogenicity (Hudak and Ungvary, 1978). No signs of
maternal toxicity were noted. In another study, Charles River rats
aged 12 weeks were exposed to 0, 100 or 400 ppm of xylenes (0, 434 or
1,730 asg/m3) during days 6 to 15 of pregnancy (25 rats per group); the
authors reported no signs of teratogenicity whether on the per-fetus
or the per-litter basis (Litton Bionetics, 1978)•
Mutagenicity
0 Xylene was not mutagenic in the Anes test with or without activation
or in other short-term in vitro assays (Litton Bionetics, 1978).
Carcinoqeni ci ty
° A long-term carcinogenicity bioassay in rats and mice has been
conducted by the NTP; however, the final report is not yet released
by the NTP (1986).
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula.:
HA = (NOAEL or LOAEL) x (BW) . Bg/L < uq/L)
-------
Xylenes
March 31, 19S7
-7-
Step 1: Determination of the Total Absorbed Dose (TAD)
Total absorbed dose = (1300 mg/m3) (1 m3) (0.64) = 11o9 mg/kg/day
(70 kg)
where:
I,300 mg/m3 » NOAEL based on absence of redaction in the performance
level on tests in humans.
1 m3 ¦ assumed amount of air inhaled during one hour by a human.
0.64 = 64% absorption factor in humans (Sedivek and Flek, 1976).
70 kg * assumed body weight of an adult.
Step 2: Determination of a One-day HA
One-day HA « (11 ,9 ">g/kg/day) (10 kg) „ 1U9 mg/L « 12 mg/L (12,000 ug/L")
(10) (1 L/day)
where:
II.9 mg/kg/day = TAD.
10 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from a human study.
10 kg = assumed body weight of a child.
1 L/day - assumed daily water consumption of a child.
Ten-day Health Acviscry
Insufficient data using oral exposure to calculate a Ten-day Health
Advisory are available currently. The Longer-term HA for the 10 kg child
(7800 ug/L) is recommended for a ten-day exposure.
Longer-term Health Advisory
The study by Carpenter et al. (1975) is the most appropriate basis for
calculating a Longer-term HA. A group of male rats were exposed by inhalation to
mixed xylenes at 770, 2000, or 3500 mg/m3 for six hours/day on five days/week
for up to thirteen weeks. No effects on body weight, hematology, blood
chemistry, kidney or liver weight, or tissue histology were observed at 770
or 2000 mg/m^ exposure levels of xylene. Based on the 2000 mg/m3 exposure
level as a N0i\ET., a Longer-term HA may be derived for a 10 kg child as follows:
Step 1: Deterr.:nation of the Total Absorbed Dose (TAD)
tad - <2>00C mg/r,3) (6 hours/day) (1 m3/hour) (5/7) (0.64) = 7S mq/kq/day
(70 kg)
389
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Xylenes March 31, 19S7
-8-
where:
2,000 mg/m3 = NOAEL based on the absence of various toxicological
parameters in rats.
6 hr/day » duration of exposure.
1 m3/hr ¦ assumed respiratory volume for a rat.
5/7 ¦ Conversion of 5 day/week dosing regimen to daily dosinc
regimen.
0.64 s absorption efficiency in humans.
70 kg ¦ assumed body weight of an adult.
Step 2: Determination of the Longer-term HAs
For a 10 kg child:
Longer-tera HA = <78 mg/kg/day) (10 kg) „ 7<8 Bg/L (7 800 ug/L)
(100) (1 L/day)
where:
78 mg/kg/day » TAD.
10 kg = assumed body weight of a child.
10C = uncertainty factor, chosen in accordance with NAS/0DW
guidelines for use with a NOAEL from an animal study..
1 L/day = assumed daily water consumption of a child.
For a 70 kg adult:
Longer-term HA - (78 mg/kg/day) (70 kg) « 27.3 mg/L (27,300 ug/L)
(100) (2 L/day)
where:
78 mg/kg/day ¦ TAD.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
390
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Xylenes
March 21, 19S7
-9-
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADD. The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects_over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chromic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2)» A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classifed as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should.be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Compound-specific, chronic ingestion data for xylenes do not exist at
this time. In the absence of appropriate ingestion studies, the Lifetime
Health Advisory for xylenes will be derived from the inhalation studies of
Jenkins et al. (1970) instead of the Bowers et al. (1982) study, even
though the route and duration of exposure used in the Jenkins study are not
ideal for development of a Lifetime HA.
Tne study by Bowers et al. (1982) was designed primarily to investigate
the first hepatocyte changes following long-term exposure to low levels of
o-xylene or other methylbenzenes administered to aged male rats, weighing 800
to 900 g, in the diet at 200 mg/kg food for up to six months prior to electron
microscopic examination of their livers, but not other tissues. Certain
major weaknesses of this study rule out its consideration in the development
of a Lifetime HA. These weaknesses are: (1) the use of aged animals weighing
800 to 900 g in the experiment; (2) the stability of o-xylene was not monitored
(i.e., any loss due to evaporation not mentioned); (3) the use of a single
exposure level; (4) the lack of histological examination of tissues other
than liver of animals on test diet; and (5) ultrastructural changes in the
hepatocytes of rats ingesting o-xylene was not stated specifically for o-xylene.
The inhalation study by Jenkins et al. (1970) was selected as the basis
for the Lifetime HA. In sthis study, o-xylene was administered by inhalation
to rats, guinea pigs, monkeys and dogs for 30 repeated exposures at 3,358
mg/m3, eight hours/day, five days/week or 90 days continuous exposure at
337 mg/m3. At 3, 358 m3/ir3, two rats died on the third day of exposure and
another rat and one monkey died on day seven; one of the dogs exhibited
tremors of varying severity throughout the exposure. Besides the above
mentioned observations, no significant effects were observed with respect tc
body weight, hematology, and histopathological examination at either dose.
391
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Xylenes March 31, 196"
-10-
Using 337 mg/m^ as a NOAEL, the Lifetime HA for a 70 kg adult is calcu-
lated as follows:
Step 1: Determination of the Total Absorbed Dose (TAD):
TAD « (337 mg/m3) (20 a3/day) (0.64) „ 6u62 mg/kg/day
70 kg
where:
337 mg/m 3 ¦ nvnu oaaea on uie aosence of toxicologic&l effects in rats>
20 m3/day » assumed respiratory volume per day of a rat.
0o64 = assumed absorption factor for xylenes (64%).
70 kg = assumed body veight of an adult.
Step 2: Determination of the Reference Dose (RfD)
RfD » 61.62 mg/kg/day . 0.06162 mgAg/day
(1,000)
where:
61.62 mg/kg/day « TAD.
1,000 - uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 3: Determination of the Drinking Hater Equivalent Level (DWEL)
DWEL = (0'06162 mgAg/day) (70 kg) .2.16 mg/L (2,200 ug/L)
(2 L/dayL
where:
0.06162 mg/kg/day - RfD.
70 kg *¦ assumed body weight of an adult.
2 L/day ¦ assumed daily water consumption of an adult.
Step 4: Determination of Lifetime HA:
Lifetime HA = 2 mg/L x 0.20 = 0.4 mg/L (400 ug/L)
where:
2 mg/L = DWEL.
0.20 = assumed relative source contribution of water.
;92
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Xylenes
March 31, 1937
-11-
It should be noted that an estimated concentration for detection by
taste and odor in surface water was 0.3 to 1.0 mg/L (National Inst, for Water
Supply, 1977) and that the HA nay exceed these thresholds for some individuals.
Evaluation of Carcinogenic Potential
0 The carcinogenic potential of xylene will be assessed when the report
of the NTP animal bioassay for carcinogenicity (1986) is available
for review.
0 IARC has not evaluated the xylenes for their carcinogenic potential.
° Applying the criteria proposed in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), the xylenes may be classified in
Group D: Not Classified. This category is for agents with inadequate
animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
° NAS (198C) calculated SNARLs (Suggested-no-adverse-response-levels)
for xylenes in drinking water. The NAS-SNARL value was 21 mg/L
xylene for a 1-day exposure and 11.2 mg/L for a 7-day exposure (for
a 70 kg adult).
0 U.S. EPA- (1981) also provided draft HAs for a 1-day, 10-day, and
longer-term exposure to xylenes in drinking water. These HAs for a
10 kg child were 12.0 mg/L, 1.2 mg/L, and 0.62 mg/L of xylene,
respectively.
0 ACGIH (19S1) has "recommended a TWA of 100 ppm.
VII. ANALYTICAL METHODS
0 Analysis of xylene(s) is by a purge-and-trap gas chromatographic pro-
cedure used for the determination of volatile aromatic and unsaturated
organic compounds in water (U.S. EPA, 1985b). This method calls for
the bubbling of an inert gas through the sample and trapping benzene
on an adsorbent material. The adsorbant material is heated to drive
off xylene(s) onto a gas chromatographic column. The gas chromatograph
is temperature programmed to separate the method analytes which are
then detected by the photoionization detector. This method is
applicable to the measurement of xylene(s) over a concentration range
of 0.02 to 1500 ug/L. Confirmatory analysis for xylene(s) is by mass
spectrometry (U.S. EPA, 1985c). The detection limit for confirmation
by mass spectroitietry is 0.2 ug/L.
3 S 3
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Xylenes
March 31, 19£7
-1 2-
VIII. TREATMENT TECHNOLOGIES
0 Treatment technologies which will remove xylene from water include
granulated activated carbon (GAC) and aeration. Limited data suggest
that conventional treatment aay be partially effective in xylene
removal«
# Dobbs and Cohen (1980) developed adsorption isotherms for several
organic compounds including p-xylene. It was reported that Filtrasorb®
300 carbon exhibited adsorptive capacities of 130 mg, 85 mg-, 54 mg
and 35 mg p-xylene/g carbon when the initial xylene concentrations
were 10, 1.0, 0.1 and 0.01 sng/L, respectively. These values along
with Freundlich constants of X ¦ 85 and 1/n " 0.19 indicate that
p-xylene and its closely related isomers, o-xylene and m-xylene, should
be amenable to carbon adsorption. Powdered activated carbon (PAC)
added at the well field to xylene-contaminated water containing 0.03
to 0o5 ug/L removed 60 to >99% of the xylene (U.S. EPA, 1985dK The
higher the xylene load the less efficient the adsorptiono GAC was
slightly less effective when used o« water containing 0.05 ug/L in
xylene. In 16 samples tested the average removal efficiency was 50%
(McCarty et al., 1979a). When the m-xylene (0.046 ug/L) and p-xylene
(0.012 ug/L) were measured separately only 20% and 17% removals were
experienced using adsorption on GAC. Each of these studies, however,
were conducted on wastewater containing a number of organic contaminants
and therefore are not completely representative of what might be
expected with potable water treatment.
0 Xylene is amenable to aeration on the basis of its Henry's Law Constant
of 255 atoms at 20°C (U.S. EPA, 1985d). Although only 19% of the
xylene in wastewater could be removed by aeration, the process was
much more successful in the treatment of potable well water contaminated
by a gasoline spill (McCarty et al., 1979b). At air-to-water ratios
of 17 to 1 or greater, 80 to 100% removal of all three xylene isomers
was accomplished. At low air to water ratios (8:1), poor removal per-
formance was experienced. Average influent concentrations for the
o, m and p isomers were 10, 2.9 and 6.9 ug/L, respectively.
° Air stripping is an effective, simple and relatively inexpensive
process for removing xylene and other organics from water. However,
use of this process then transfers the contaminant directly to the
air stream. When considering use of air stripping as a treatment
process, it is suggested that careful consideration be given to the
overall environmental occurrence, fate, route of exposure, and various
hazards associated with the chemical.
394
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Xylenes
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March 31, 19=7
IX. REFERENCES
ACGIH. 1981. American Conference of Governmental Industrial Hygienists.
TLVs - Threshold limit values for chemical substances in workroom air
adopted by ACGIH for 1981. Cincinnati, OH.
Astrand, I., J. Engstrom and P. Ovrum. 1978. Exposure to xylene and ethyl-
benzene. I. Uptake, distribution and elimination in man. Scand. J.
Work Environ. Health. 4(3):185-194.
Bergman, K. 1978. Application of whole-body autoradiography to distribution
studies of organic solvents. Int. Symp. Control Air Pollut. Work Environ.
(Part 2):128-139.
Bowers, D.E., Jr., M.S. Cannon and D.H. Jones. 1982. Ultrastructural changes
in livers of young and aging rats exposed to methylated benzenes. Am. J.
Vet. Res. 43(4):679-683.
Carlson, A. 1981. Distribution and elimination of carbon C14-labeled
xylene in rats. Scand. J. Work Environ. Health. 7:51-55.
Carpenter, C.P., E.R. Kinkead, D.L. Geary, Jr., L.J. Sullivan and J.M. King.
1975. Petroleum hydrocarbon toxicity studies: V. Animal and human
response to vapors of mixed xylenes. Toxicol. Appl. Pharmacol.
33:543-558.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/8-80-023. MERL, EPA. Cincinnati, Ohio.
Gamberale, F., G. Annwall and M. Hultegren. . 1978. Exposure to xylene and
ethylbenzene. III. Effects on central nervous functions. Scand. J.
Work Environ. Health. 4:204-211.
Harper, C., R.T. Drew and J.R. Fouts. 1975. Benzene and p-xylene: A com-
parison of inhalation toxicities and in vitro hydroxylations. In:
D.J. Jollow, J.J. Kocsis, R. Snyder and H. Vainio, eds. Biologically
reactive intermediates. London, England: Plenum Press, pp. 302-311.
Hudak, A., and G. Ungvary. 1978. Embryotoxic effects of benzene and its
methyl derivatives: toluene, xylene. Toxicology. 11:55-63.
Jenkins, L.J., R.A. Jones and J. Siegel. 1970. Long-term inhalation screening
studies of benzene, toluene, o-xylene and cumene on experimental animals.
Toxicol. Appl. Pharmacol. 16:818-823.
Leo, A., C. Hansch and D. Elkins. 1971. Partition coefficients and their
uses. Chem. Rev. 71:583.
Litton Bionetics, Inc. 1978. Mutagenicity evaluation of xylene: Final
report. LEI Project No. 20847. Submitted to American Petroleum Institute,
Washington, D.C. 150 pp.
395
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Xylenes
March 31, 1967
-1 4-
McCarty, P.L„, D. Argo and M. Reinhard. 1979a. Operational experiences
with activated carbon adsorbers at Water Factory 21. 3* AWWA.
11:683-689.
McCarty, P.L., K.H. Sutherland, J. Graydon and M. Reinhard. 1979b. Volatile
organic contaminants removal by air stripping. Presented at the Seminar
on Controlling Qrganics in Drinking Water, American Water Works Annual
Conference, San Francisco, CA.
Middleton, F.M., A.A. Rosen and RoH. Burttschell. 1956. Taste and odor
research tools for water utilities. J. Am. Water Works Assoc. 50:21-28.
NAS. 1980. National Academy of Sciences. Drinking Water and Health, Volume 3
National Academy Press. Washington, D.C. p. 181.
National Institute for Water Supply. 1977« Compilation of odor threshold
values in air and water.
NIOSHo 1978. Registry of toxic effects of chemical substances. U.S.
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