Document 0LjjxJRbgy9M92r1594yO4GQn

March 31, 1957 p-DXOXANE Health Advisory Office of Drinking Water U.S. Environmental Protection Agency I* INTRODUCTION f The Health Advisory {HA? Program, sponsored Jy 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 nonearcinegenic end points of toxicity. Health Advisories do not quantitatively incorporate ary 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 provideslow-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. 16 S NGC36552 -2- rwrcn j i, i yfc7 Fhis 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 -- /-\ W Synonyms * 1,4-Dioxane? 1,4-Diethylene dioxide Uses. 9 Solvent for cellulose acetate, resins, oils and waxes. Properties (Windholts, 1983, Verschueren, 1977) Chemical formula Molecular weight Physical state Boiling point Melting point Vapor pressure Density Solubility _ Taste/odor threshold . Occurrence C4hB2 88.10 Colorless liquid 101.1*C 11.8*C 30 bus. (20C) ' 1.033 g/ml (20*9C* ) .miscible in water at all concentrations 9 1,4-Dioxane is a synthetic organic coiqpound 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'aobile in soil. .Ho 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. 166 NGC36553 p-Oioxane March 31# 1 987. -3- III. PHARMACOKINETICS Absorption * Dioxane has been reported to be absorbed readily through the lungs# shin and gastrointestinal tracts of mammals. 6 There is evidence that dioxane is absorbed after ingestion. Several investigators administered dioxane in vater to rats and observed X 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-Davley rats, weighing 95 to 130 g, were administered a single intraperitoneal dose of H3-dixane at 500 uCi/100 g, body weight# and sacrificed after 1, 2, 6 or 16 hours, cystolie, microsomal# mitochondrial and nuclear fractions were examined. ` Ohe 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 tats with Inducers of microsomal enzymes had 'no significant effect on the covalent binding of dioxane to the.various subcellular fractions of the liver. Metabolisr/Sxcreticn 0 Dioxane has been reported to be metabolized in animals to 2-hydrexyethoxyacetic acid and ` 1 # 4-dioxan-2-one. After a single oral dose of T,ooo mg/*g bv of 1 #4-( 1 4c)diox*ne to rats# Braun and Young (1 977) recovered from the urine 85% of the dose as -hydrosyethoxyacetie 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 tp 400 mg dioxane/kg body 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 * The lowest oral lethal dose for humans has been recorded as 500 mg/kg - (NIOSK, 19785. 167 NGC36554 -4- 0 Johnstone (1959) described & fatal case of dioxane poisoning. The estimated exposure fcy inhalation in this case was 470 ppra (1,690 mg/m-! for one week; the'extent of dermal exposure was not known. Postmortem, examination-revealed hepatic and renal lesions as well as demyelinaticr. and edema of the brain Animals Short-term Exposure * Oral LD5Q values for esqjerimental animals are 4200 mg/kg (tat), 5700 mg/kg (mouse), 2000 Big/k9 (cat), 2000 mg/kg (rabbit) and 3150 mg/kg (guinea pig) (N10SH, 1978) * * * Fairley et ai. (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* 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 S 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 fcy microscopic examination. In the rabbit administered the -2 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 shoved no microscopic abnormalitiesj areas of cloudy swelling were seen in the liver of the' rabbit given 2 mL of dioxane. Longer-term Exposure 6 Xociba et al, (1974) reported liver and kidney damage in male and 'female Sherman strain rats* The animals were given drinking' water v containing 0, 1.0# 0*1 or 0.01% dioxane for up to 716 d&ys. 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 histopathologieal 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 * No reports were available on the reproductive effects of 1,4-dioxane in humans or other mammalian species. 168 NGC36555 p--Siexane -5- March 31, 19E? Developmental Effects No reports were available on the developmental effects of 1,4-dioxane . in humans or other mammalian species* Mutagenicity 9 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 1,4dioxane in the drinking water were 0.75, 1.0, 1*4 and 1.6% 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* 9 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 ag/kg/day, respectively for males and females) and 0.1% (94*0 and 149.0 stgAg/day, respec tively), there was no significant difference in the'incidence of neoplasms between the control and the experimental groups. In a 90-week study in B6C3F-J 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, 1973). The average daily low dose (0.5% v/v) was 720 (530 to 990) mgAg/day for males and 380 (180 to 620) mgAg/<3sy for females; at the 1% level, the doses were 630 (680 to 1150) and 860 (450 to 1560) mgA9/day , respectively. In the NCI (19.7B) 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 levelsAverage doses for 110 weeks for males were 240 (130 to 380) and 530 (290 to 780) ngAg body weight; for females, the doses were 350 (200 to 580) and 640 (500 to 940) mgA9 bocfc' weight. Effects on Immunologic Status and Competence' 9 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 * ,, 1: 169 NGC36556 p-uioxar.e March 31, -5- lymphocytes as veil as depressing phytohemagglutinin stimulation of lymphocytes.. These results were interpreted to indicate stimulationof 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 huaa'n lymphocytes was seen, indi cating a stimulation'of T-cell responses and an enhancement of the immune response; little or no effect vas 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 noncarcinogenie end" point of toxicity. The HAs for noncarcinogenic toxicants are derived using the following formula: where: HA = jNOAEL or_ L0AEL1 x _<BW) B mg/L ( ug/L) (UF) x (____ L/day) NOAEL or LOAX1 * No- or Lowest-Qbserved-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 Cneday HA. In this study, a single dose of 1, 2, 3 or 5 bL of 1,4-dioxane vas 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 flioxane 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 dess levels, the degenerative change extended into the medulla and the liver also showed extensive and gross cellular degeneration. x 170 NGC36557 tr -7- A One-day HA for a 10 kg child is calculated as follows: LOAEL (mgAs/day ) ** ml/dayj (1.03 g/ml) (0*80) (1000 mg/g) (2 kg) 41 2 mgAg/day Where: 1 ml/day * Administered dose of p-dioxane (LOAEL) f 1.03 g/ml * Density of dioxane f 0.80 * Percent composition of dioxane solution 1000 sig/g Conversion factor for grams' to milligrams 2 kg * Assumed body weight of rabbit One-day HA Where: : mg/kg/day) (10 kg) = 4.12 mg/li (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 L/day = Assumed volume of water consumed daily by a child 1,OOC * uncertainity .factor, chosen in accordance with NAS/OO* 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. JCpciba et al. (1974) observed a no effect level of 9*6 ma/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. 171 NGC36558 p-Dioxane -8- March 31, 1967 Lifetiroft 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 noncarcinogenic 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 NOASL (or loaEL), identified from a chronic (or subchronic} study, divided by an uncertainty factor(s). From the.RfD, a Drinking Water Equivalent Level (DVfEL) 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 s 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 * A number of studies show that p-dioxane is carcinogenic in more than one animal species. IAR2 has classified 1,4-dioxane in Group 2B, indicating sufficient evidence_of its carcinogenicity in.animals'(IARC, 1982). * IPA has not classified this chemical. Drinking water concentrations estimated by EPA to increase the risk by one excess cancer per million (10*6} would be 7 aicrograms per liter, assuming consumption of 2 liters of water per day by a 70-kg adult over a 70-year lifetime and using the linearised multistage . model* The drinking water concentrations associated with a risk of 10"4 and 10"5 would be 700 and 70 ug/L, respectively. The linearized multistage model is only one method of estimating car cinogenic risk. Using the 10- risk level, the following comparisons in micrograms/L can be made: Multistage, 7; Logit, 10"7; and weibull, 10~7. Each model is based on differing assumptions* Ho current understanding of-the biological mechanisms of carcinogenesis is able to predict which of these models is more accurate than another. 172 NGC36559 p-Dioxane -9- March 31, 1937 * While recognized as statistically alternative approaches, the range of risks described fcy using ary 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 * NIOSH has recommended an exposure standard of 1 ppm/30 M in air (NIOSH, 1977). TLV 25 ppm,- STEL * 100 ppm {ACGIH, 1980). VII. ANALYSIS There is no standardized method for the determination of p-dioxane in drinking water. However, p-dioxane can be determined fcy the purge and trap gas chromatographic-mass spectrometric (GC-HS) 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 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 ly 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 Treatment technologies which are capable of removing p-dioxane from drinking "water include adsorption by granular activated carbon (GAO 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 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. McGuire et al. 11978) 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 FAC treatment at 50 mg/L with 5-hour contact time. The results showed poor removal efficiency. However, it was 173 NGC36560 p-Dioxane -10- March 31/ 19B7 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 shoved poor performance with respect to p-dioxane removal. A batch laboratory study to demonstrate oxidation of p-dicxane by 1 00 mg/L chlorine and 100 mg/1 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 60:1 air-to-vater ratio over a 2.4-hour period (McGuire et al., 1978). 9 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 carbod and oxidation by ozone or bzone/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. 174 NGC36561 p-Eioxane -1 I- March 31, 1957 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 agentst Hepatocarcinogeaicity of dioxane. J. Nat. Cancer Inst. 35:949-953. Argus, M.F., R.S. Sohal, G.M. Bryant, C. Booh-Ligesti and J.C* Arcos. 1973. Dose-response and ultrastructural alterations in dioxane carcinogenesis. Influence of aethylcholanthrene on acute toxicity. Eur. J* Cancer. 9(4):23^-243 Braun, W.H, and J.D. Young. 1977. Identification of -hydroxyethosyacetic 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. 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" chemicals to humans. Supplement 4. IARC, Lyon, France. Johnstone, JUT. 1959. Death due to dioxane? AMA Arch. Ind. Health. 20:445-447. Kociba,-R.J., S.B. HcCollister, 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 uni-t processes for the removal-of trace, organic compounds from drinking water. JAV7KA. 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. DREW. 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. N 175 NGC36562 Suffet, I.H., 1. 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 O 2) : 1315-1322. Thurman, G.B., B.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 lymphocytesr Toxicol. Appl. Pharmacol. 44t61?-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 Hater. t 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)s 433407-433415. Verschueren, K. 1977. Handbook of environmental data on organic chemicals* 1st ed. Van Nostrand Reinhold Company, N.Y, p. 377. Windholz, M., ed. 1963. Merck Index, 10th ed. Merck and Compary, 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. * 26:1535-1-538. ' Woo, Y-T, K.F. Argus and J.C. Arcos. 1977b. Tissue and subcellular distri bution of 3n-dioxane in the rat and apparent lack of miprosome-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. 176