820K87128 *"* 31* 1987
p-DIOXANE
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.
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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 1981 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
- /~\
°°
v_y
Synonyms
c 1,4-Dioxane; 1 , 4-Diethylene dioxide
Uses
0 Solvent for cellulose acetate, resins, oils and waxes.
Properties (Windholtz, 1983, Verschueren, 1977)
Chemical formula C4Hg02
Molecular weight 88.10
Physical state Colorless liquid
Boiling point 101. 1CC
Melting point 11.8°C
Vapor pressure 30 mm (20°C)
Density 1.033 g/ml (20°C)
Solubility miscible in water at all concentrations
Taste/odor threshold
Occurrence
0 1,4-Dioxane is a synthetic organic compound with no known natural
sources. Production of dioxane in 1979 was 6 million Ibs.
0 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 bi ode gradation of dioxane has been
identified.
0 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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III. PHARMACOKINETICS
Absorption
0 Oioxane 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
0 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 the whole homogenate. The binding of dioxane to the macromolecules
in the cytosol 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.
Metabolism/Excretion
0 Oioxane has been reported to be metabolized in animals to 2-hydroxy-
ethoxyacetic acid and 1,4-dioxan-2-one. After a single oral dose of
1,000 mgAg t>w of 1,4-(14C)dioxane to rats, Braun and Young (1977)
recovered from the urine 85% of the dose as -hydroxyethoxyacetic
acid (HEAA) and 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 body
weight; the amount of p-dioxane-2-one excreted increased with the
dose level administered.
0 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
The lowest oral lethal dose for humans has been recorded as 500 mg/kg
(NIOSH, 1978).
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Johnstone (1959) described a fatal case of dioxane poisoning. The
estimated exposure by inhalation in this case was 470 ppm (1,690 mg/m3)
for one week; the extent of dermal exposure was not known. Postmortem
examination revealed hepatic and renal lesions as well as demyelination
and edema of the brain.
Animals
Short-term Exposure
Oral LD50 values for experimental animals are 4200 mg/kg (rat), 5700
mg/kg (mouse), 2000 mg/kg (cat), 2000 mgAg (rabbit) and 3150 mg/kg
(guinea pig) (NIOSH, 1978).
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 TO mL of saline. The 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-term 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
nistopathological examination. There was no evidence of toxicity with
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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Developmental Effects
e 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
0 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 (105), 50% tumor dose (TDso),
and maximum effective dose (1095) 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
neoplasms 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 the 0.5 and 1% groups of both sexes (NCI, 1978). The average
daily low dose (0.5% v/v) was 720 (530 to 990) mg/kg/day for males
and 380 (180 to 620) mg/kg/day for females; at the 1% level, the
doses were 830 (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) mgAg
body weight; for females, the doses were 350 (200 to 580) and 640
(500 to 940) mg/kg body weight.
Effects on Inununolqgic 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
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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 enhancement
of phytohemagglutinin stimulation of human lymphocytes was seen, indi-
cating 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-dioxane.
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:
where:
HA = (NOAEL or LOAEL) x (BW) = _ „ ( _ /L)
( UF ) x ( _ L/day )
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Ef feet-Level
in mg/kg bw/day .
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 1 00 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 dose levels, the degenerative change extended into the medulla
and the liver also showed extensive and gross cellular degeneration.
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p-Dioxane
March 31, 1987
A One-day HA for a 10 kg child is calculated as follows:
LOAEL (mg/kg/day)
Where:
(1 ml/day) (1.03 g/ml) (0.80) (1000 mg/g)
(2~Jcg)
412 mg/kg/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 grains to milligrams
2 kg • Assumed body weight of rabbit
One-day HA = (412 mg/kg/day) (10 kg) = 4.12 mg/L (4,120 ug/L)
(1 L/day) (1,000)
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
1,000 = uncertainity factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
Ten-day Health Advisory^
In the absence of an acceptable study for the calculation of a Ten-day
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-year
drinking water study in rats. This study, although scientifically sound,
should not be used for estimating a Longer-term HA because of the carcinogenic
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.
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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). 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.
Because of its suspected carcinogenicity, a Lifetime Health Advisory for
p-dioxane is not recommended.
Evaluation of Carcinogenic Potential
0 A number 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 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), p-dioxane 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 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, 7; Logit, 10~7; and Weibull,
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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.
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 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
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. ANALYTICAL METHODS
0 There is no standardized method for the determination of p-dioxane
in drinking water. However, p-dioxane can be determined by 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 isotopically
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 they 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. The method detection limit is dependent upon the nature
of interferences.
VIII. TREATMENT TECHNOLOGIES
0 Treatment technologies which are capable of removing p-dioxane from
drinking water include adsorption by granular activated carbon (GAC) or
powdered activated carbon (PAC). The only data available demonstrating
removal of p-dioxane are for carbon adsorption. Further studies are
required to determine the effectiveness of 03 or 03-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
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p-Dioxane March 31, 1987
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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. The results showed poor removal efficiency. However, it was
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. The resins showed poor performance with respect
to p-dioxane removal.
A batch laboratory study to demonstrate oxidation of p-dioxane by 100
mg/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).
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
would be candidates for further investigation: adsorbtion by activated
carbon and oxidation by O2one 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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IX. 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. 35:949-958.
Argus, M.F., R.S. Sohal, G.M. Bryant, C. Hoch-Ligestx and J.C. Arcos. 1973.
Dose-response and ultrastructural alterations in dioxane carcinogenesis.
Influence of methylcholanthrene on acute toxicity. Eur. J. Cancer.
9(4):237-243.
Braun, W.H. and J.D. Young. 1977. Identification of -hydroxyethoxyacetic
acid as the major urinary metabolite of 1,4-dioxane in the rat. Toxicol.
Appl. Pharmacol. 39:33-38.
Fairley, A., E.G. Linton and A.H. Ford-Moore. 1934. The 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 chenicals 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, Education
and Welfare, National Institute of Health. DHEW Pub. No. (NIH) 78-1330.
NIOSH. 1977. National Institute of Occupational Safety and Health. Criteria
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.
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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., E.G. Simms, A.L. Goldstein and D.J. Kilian. 1978. The
effects of organic compounds used in the manufacture of plastics on the
responsivity of murine and human lymphocytes. 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 by Isotope Dilution GC/MS. Federal Register.
49(209):433407-433415.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Fed. Reg. 51(185):33992-34003.
September 24.
Verschueren, K. 1977. Handbook of environmental data on organic chemicals.
1st ed. Van Nostrand Reinhold Company, N.Y. p. 377.
Windholz, M., ed. 1983. Merck Index, 10th ed. Merck and Company, Inc.
Rahway, NJ. pp. 481-482.
Woo, Y-T, J.C. Arcos and M.F. Argus. 1977a. Metabolism in vivo of dioxane:
Identification of p-dioxane-2-one as the major urinary metabolite.
Biochem. Pharmacol. 26:1535-1538.
Woo, Y-T, M.F. Argus and J.C. Arcos. 1977b. Tissue and subcellular distri-
bution of 3n-dioxane in the rat and apparent lack of microsome-catalyzed
covalent binding in the target tissue. Life Sci. 21(10):1447-1456.
Woo, Y-T, B.J. Neuburger, J.C. Arcos, M.F. Argus, K. Nishiyama and G.W. Griffin.
1980. Enhancement of toxicity and enzyme-repressing activity of p-dioxane
by chlorination: Stereo-selective effects. Toxicol. Letts. 5:69-75.
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. Health.
3(3):507-520.
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