Appendix N: Chlorinated ethers

REGULATORY TOXICOLOGY AND PHARMACOLOGY 20, S 1 0 4 9 - S 1 0 5 6 (1994)

Appendix N: Chlorinated Ethers

N.1. INTRODUCTION This appendix focuses on bis(2-chloroethyl)ether (Table N-1).

TABLE N- 1 CHLORINATED ETHERS SELECTED FOR ASSESSMENTa

Chemical

Drinking/Waste Water

B/s(2-ehloroethyl)ether

Solvents

Incineration

Pulp & Paper

•

Aquatic assessment focused on the chlorinated ethers as a group, with emphasis on the above chemical.

N.2. SOURCES, PHYSICAL/CHEMICAL PROPERTIES, AND ENVIRONMENTAL FATE

N.2.1. Sources N.2.1.1. Anthropogenic Sources Bis(2-chloroethyl)ether is used in the processing of fats, waxes, greases, and cellulose esters and in the manufacturing of insecticides, scour textiles, butadiene, medicinals, and pharmaceuticals. It is also used as a solvent and as a constituent in paints, lacquers, and varnishes (Verschueren, 1983). Bis(2-chloroethyl)ether may be formed during the chlorination of drinking water when in the presence of ethyl ether (Verschueren, 1983). Some bis(2-chloroethyl)ether would be expected to be released into the environment during its manufacture or use, although these quantities can be controlled by the adoption of good manufacturing practices.

N.2.1.2. Natural Sources No known natural sources of bis(2-chloroethyl)ether were identified in the literature reviewed.

N.2.2. Physical~Chemical Properties The physical/chemical properties of the chlorinated ethers have been measured by several investigators. Table N-2 summarizes the values for molecular weight, vapor pressure, solubility, and log octanol/water partition coefficient (Kow) that have been selected for bis(2-chloroethyl)ether. Unless otherwise indicated, all properties were measured at 25 °C. S1049

0273-2300/94 $6.00 Copyright © 1994 by AcademicPress, Inc. All rights of reproduction in any form reserved.

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APPENDIX N

N.2.3. Environmental Fate

N.2.3.1. Air Based on its vapor pressure (Table N-2), bis(2-chloroethyl)ether would be expected to readily volatilize (EPA, 1979). Based on its water solubility (Table N-2), bis(2-chloroethyl)ether would also readily distribute into water in the environment and would be readily removed from the atmosphere by precipitation (EPA, 1979). Direct photolysis ofbis(2-chloroethyl)ether in the atmosphere is not expected to occur since the chemical does not contain any chromophores that absorb radiation in the visible or near ultraviolet regions of the spectrum (Jaffe and Orchin, 1962). For the same reasons, photolysis would not occur in surface waters. It is expected that bis(2-chloroethyl)ether would probably be transformed in the troposphere by photooxidation. A photooxidation half-life of 4.02 days was estimated for bis(2-chloroethyl)ether based on an estimated rate constant for reaction with hydroxyl radicals in air (Atkinson, 1987).

N.2.3.2. Water/Sediment Since bis(2-chloroethyl)ether is soluble with a relatively low log Kow value (1.58), sorption of the chemical to suspended particles, sediment, or soils and bioaccumulation would be insignificant (EPA, 1979). The half-life for volatilization of bis(2-chloroethyl) from water is 5.78 days (Durkin et al., 1975). Although a very slow process, hydrolysis may be important in the transformation of bis(2-chloroethyl)ether in aquatic environments (EPA, 1979). Based on a neutral hydrolysis rate constant at 20°C and data for hydrolysis in aqueous dioxane at 100°C, a first-order hydrolysis half-life of 22 years for bis(2-chloroethyl)ether was extrapolated (Mabey et aL, 1981). Biotransformation data for bis(2-chloroethyl)ether are limited. Based on data from a loss study in a river, the biotransformation half-life for bis(2-chloroethyl)ether, under aerobic conditionsl was estimated to range from 4 weeks to 6 months (Ludzack and Ettinger, 1963; Dojlido, 1979). For anaerobic conditions, the biotransformation half-lives ranged from 16 weeks to 24 months, calculated based on estimated unacclimated aerobic aqueous biotransformation half-lives (Howard et al., 1991).

N.2.3.3. Soil The vapor pressure ofbis(2-chloroethyl)ether suggests that volatilization of the chemical from surface soil may occur, and based on its water solubility, leaching would also be expected to occur (EPA, 1979). No information was available concerning the biotransformation of bis(2-chloroethyl)ether in soils; however, Howard et al. (1991) reasoned that the half-life estimated for aqueous biotransformation of bis(2-chloroethyl)ether under aerobic conditions would be representative of soil systems.

TABLE N-2 SUMMARY OF SELECTED PHYSICAL/CHEMICAL PROPERTIES OF CHLORINATED ETHERS

Chemical Name B/s(2-ehloroethyl)ether Sources: b

Verschueren, 1983. Leo et al., 1971.

Molecular Weight (g/mol)

Vapor Pressure (Pa)

Solubility (g/m3)

Log K~

143.02"

186.65 ~

10,200 ~

1.58 b

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POTENTIAL ADVERSE EFFECTS OF CHLORINATED CHEMICALS

N.2.3.4. Fugacity Modeling Fugacity modeling of chemicals in the environment is used to describe the partitioning, movement, and behavior of chemicals within different environmental media based on the specific physical properties of chemicals. Fugacity Level I model describes what percentages of a particular chemical would distribute to air, water, soil, bottom sediment, fish, and suspended sediment given a steady-state situation in which no removal of the chemical occurs by any chemical or physical processes. Fugacity Level II describes the rates at which the various compartments lose the specific chemical by reactive or advective means, again, under steady-state conditions in which the rate of loss from all the media compartments combined equals the rate of input of the chemical to the system. Fugacity Level III attempts to describe the rates at which a particular chemical would move between the various environmental compartments.

Bis(2-chloroethyl) ether Level I fugacity modeling was performed for bis(2-chloroethyl)ether using physical/chemical properties (Table N-3). The results of the fugacity modeling indicate that bis(2-chloroethyl)ether would be expected to partition approximately equally between air (47%) and water (52%), with only small percentages appearing in either soil or sediment and very small amounts in fish and suspended sediment. This partitioning is consistent with the water solubility, vapor pressure, and low octanol/water partition coefficient of bis(2-chloroethyl)ether (Fig. N-l). No Level II or Level III fugacity modeling was performed for bis(2-chloroethyl)ether.

N.3. H A Z A R D ASSESSMENT

N.3.1. Human Health Hazard Assessment

N.3.1.1. Bioavailability, Metabolic Conversion, Pharmacokinetics, and Bioaccumulation Bioavailability Although no studies designed to quantify the bioavailability of bis(2-chloroethyl)ether via ingestion, inhalation, and dermal routes of exposure were identified in the scientific literature reviewed, one phar-

TABLE N-3 PHYSICAL/CHEMICALPROPERTIESOF BIS(2-CHLOROETHYL)ETHER

Temperature °C

25 143.02

Fish-water partition coefficient Air-water partition coefficient

1.82491

Molecular mass g/mol

Vapor pressure Pa

186.65

Soil-water partition coefficient

0.4676331

Solubility g/m3

10,200

Sedt-water partition coefficient

0.9352661

Solubility mol/m3

71.3187

Susp sedt-water partition coefficient

0.9352661

Henry's Law constant pam3/mol

2.617126

1.055795E-3

Log oetanol-water partition coefficient

1.58

Oetanol-water partition coefficient

38.01895 Fugacity Pa

1.956656E-4

Orgauie C-water partition coefficient

15.58777 Total of V Z products

5,110,760

Amount of chemical moles

1,000

APPENDIX N

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Level I Fugacity Modeling B/s(2-chloroethyl)ether Water 52.33% \

Other Compartments 0,31%

Air' 47.3

FIG. N-I. Level I fugacity modeling--Bis(2-chloroethyl)ether.

macokinetic study in rhesus monkeys indicated that bis(2-chloroethyl)ether is readily absorbed from the gastrointestinal tract following ingestion (Smith et al., 1985). When two rhesus monkeys were administered a single dose of 10 mg/kg body vet by gavage, Smith et al. (1985) observed that 24, 48, and 72 hr after dosing, 43 to 61, 51 to 61, and 53 to 63%, respectively, of the dose of bis(2-chloroethyl)ether were recovered in the urine. Seventy-two hours after dosing, fecal elimination was less than 1%. Oral absorption was also demonstrated based on oral administration of 14C-labeled bis(2-chloroethyl)ether and the detection of the majority of the radiolabel appeared in the urine of rats (Lingg et al., 1978). Little of the ~4C radioactivity was excreted in the feces.

Metabolic

Conversion

Metabolism studies have demonstrated that bis(2-chloroethyt)ether is metabolized via two distinct pathways (Smith and Lingg, 1985). The first pathway involves direct reaction of the chemical with glutathione transferase, reductive dechlorination, and terminal oxidation, followed by degradation of the conjugate to thiodiglycolic acid. The second pathway involves the hydrolysis of the C - O - C bond(s), with the formation of 2-chloroethanol which is then conjugated with glucuronide (Smith and Lingg, 1985). Most of the metabolism appeared to proceed through glutathione conjugation of the parent chemicals (Smith and Lingg, 1985). A small percentage (about 10%) of an oral dose of bis(2-chloroethyl)ether was converted to CO2 and excreted in the exhaled air (Lingg et al., 1978), likely from further oxidative metabolism of the chloroethanol and diglycolic acid metabolites.

Tissue Distribution No studies have been identified that examine the tissue distribution pattern of bis(2-ehloroethyl)ether after oral or any other route of exposure.

Excretion In rats and rhesus monkeys, bis(2-chloroethyl)ether and its metabolites were excreted primarily in the urine (Lirlgg et al., 1978; Smith et al., 1985). Studies in rhesus monkeys demonstrated that slightly more than 60% of an oral dose of bis(2-chloroethyl)ether was excreted in the urine over a 72-hr period (Smith et al., 1985). Over the same time period, fecal elimination accounted for less than 1% of the administered dose. A small amount (about 10%) of an oral dose of bis(2-chloroethyl)ether was also reported to be excreted as CO2 in the exhaled air (Lingg et al., 1978). The major metabolite isolated in the acidic fraction of urine has been identified as thiodiglycolic acid (Lingg et al., 1978; Smith and Lingg, 1985). A conjugated derivative of 2-chloroethanol has also been

POTENTIAL ADVERSE EFFECTS OF CHLORINATED CHEMICALS

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identified as a minor urinary metabolite in rats and rhesus monkeys (Lingg et al., 1978; Smith and Lingg, 1985).

N.3.1.2. Mammalian Toxicology (Laboratory Animal and Biochemical Studies) L e t h a l Effects Acute lethality studies of bis(2-chloroethyl)ether in rats and mice through the inhalation route of exposure (Kosyan, 1967; NIOSH, 1988) showed LCs0 values of 650 mg/m 3 for 2 hr and 330 mg/m 3 for 4 hr, respectively. Earlier, Carpenter et aL (1949) reported a 4-hr LCs0 value for bis(2-chloroethyl)ether in rats of 250 ppm (about 1500 mg/m3). Exposures of guinea pigs to air concentrations of bis(2-chloroethyl)ether of 500 ppm (3000 mg/m 3) immediately caused severe eye irritation followed by respiratory distress and death after exposures of 1.5 to 8 hr (Schrenk et al., 1933). Continuous exposure of the guinea pigs over a 10-hr period to bis(2-chloroethyl)ethcr at a concentration of 105 ppm (600 mg/m 3) resulted in death. However, no systemic toxicity occurred following 1-hr exposure to this air concentration. Severe lung damage and effects in the liver, kidney, and brain were noted in the animals which died as a result of inhalation exposure to bis(2-chloroethyl)ether (Schrenk et al., 1933). Exposure to bis(2-chloroethyl)ether by dermal application resulted in lethality in hamsters at doses of 300 mg/kg body wt (Smyth and Carpenter, 1948).

N o n l e t h a l Effects Exposures of rats and guinea pigs on 93 occasions during a 130-day period to concentrations of bis(2chloroethyl)ether in the air of 69 ppm (Kirwin and Sandmeyer, 1981) resulted in alterations to organ weights and slight growth depression. These effects were considered to be part of the physiological response to stress rather than a toxic response to bis(2-chloroethyl)ether(ACG1H, 1992). The potential for bis(2-chloroethyl)ether to induce damage to the lung, liver, kidney, and/or brain at nonlethal exposure concentrations has not been investigated.

O t h e r Effects No information on reproductive, teratogenic, developmental, or immune system effects was identified in the literature reviewed. No data were identified in the scientific literature concerning the potential of bis(2chloroethyl)ether to induce teratogenicity in experimental animals.

Genotoxicity Bis(2-chloroethyt)ether has been demonstrated to be a direct-acting, base-pair mutagen without exogenous metabolic activation in the Salmonella typhimurium, Escherichia coli, and Bacillus subtilis bacterial mutagenicity assays (Shirasu et al., 1975). In frameshift mutation tests using S. typhimurium strains TA98 and TA 1538, bis(2-chloroethyl)ether in the vapor phase was reported to be weakly mutagenic without the presence of exogenous metabolic activation (Fishbein, 1977). Fishbein (1977) also indicated that bis(2-chloroethyl)ether was mutagenic toward Saccharomyces cerevisiae. Bis(2-chloroethyl)ether did not induce heritable translocations in mice (Jorgenson et al., 1977).

Carcinogenicity Bis(2-chloroethyt)ether has been demonstrated to be carcinogenic to two different strains of mice when administered via the oral route of exposure (Innes et al., 1969). However, no carcinogenic effects were observed in an 18-month rat study in which bis(2-chloroethyl)ether was administered in the diet at the maximum tolerable dose (Ulland et al., 1973; Weisburger et aL, 1981). Similarly, no tumorigenic effects

S 1054

APPENDIX N

were noted in a 2-year subcutaneous injection study also in rats (Norpoth et al., 1986). In another subcutaneous injection study, Van Duuren et al. (1972) reported bis(2-chloroethyl)ether to be marginally carcinogenic based on the induction of injection-site sarcomas in female ICR/Ha mice. Groups of male and female (C57BL/6 X C3H/Anf)FI and (C57BL/6 X AKR)FI mice were treated by daily gavage with 300 ppm of bis(2-chloroethyl)ether in water until 28 days old, then were fed bis(2-chloroethyl)ether in the diet thereafter for 80 weeks [approximate dose of 100 mg bis(2-chloroethyl)ether/kg body wt/day (Calabrese and Kenyon, 1991)]. This treatment resulted in an increased incidence ofhepatomas [14/16 and 9/17 in the (C57BL/6 × C3H/Anf)FI and (C57BL/6 X AKR)F~ mice, respectively (Innes et al., 1969)]. There were only 8 hepatomas in 79 control mice. Although bis(2-ehloroethyl)ether was found to be noncarcinogenic to rats through oral or subcutaneous injection exposure, EPA (1992) has classified bis(2-chloroethyl)etheras a probable human carcinogen (group B2) based primarily on responses in mice.

N.3.1.3. Mechanisms of Toxicity Given that bis(2-chloroethyl)ether is a direct-acting mutagen and given that the structural analogue bis(chloromethyl)ether is an alkylating agent in vivo (Calabrese and Kenyon, 1991), it is likely that bis(2chloroethyl)ether acts by direct interaction with DNA.

N.3.1.4. Epidemiology Studies Brief exposures of human volunteers to bis(2-chloroethyl)etherat concentrations of greater than 550 ppm caused intolerable, extreme irritation of the eyes and nasal passages (Schrenk et al., 1933). Brief exposure of the volunteers to bis(2-chloroethyl)ether at concentrations of between 100 and 260 ppm caused irritation but was tolerable. At concentrations of 35 ppm, the volunteers could still detect the odor of bis(2-chtoroethyl)ether but felt no irritation effects. No studies of tong-term exposures of humans to bis(2-chloroethyl)ether were identified in the literature reviewed.

N.3.1.5. Exposure

Limits

The carcinogenic potency, or q* value, for bis(2-chloroethyl)ether is 1.1 (mg/kg body wt/day) -l (EPA, 1992) based on dose-response extrapolation of the liver tumor data reported in the mouse bioassay (Innes et al., 1969) using a linearized multistage model. The q~ value reported for bis(2-chloroethyl)ether by the EPA (1992) would result in an RsD of 9.1 X 10-3 #g/kg body wt/day based on a risk level of 1 per 100,000. Other exposure limits that have been set for bis(2-chloroethyl)ether by various agencies include a TWATLV of 5 ppm (29 mg/m 3) set for occupational exposure (ACGIH, 1992; OSHA, 1989), and an ambient water quality guideline of 0.030 #g]liter based on a 1 in 1 million risk of cancer from the consumption of 2 liters of water and 6.5 g offish/shellfish per day by a 70-kg human (EPA, 1980). It should be emphasized that the above exposure limit is based on a carcinogenicity study in mice. Based on species-dependent metabolic differences, it is possible that the use of q* values calculated by EPA overestimate the human risks by several orders of magnitude, although an exact estimate of the difference in target tissue exposure is not available. It must also be emphasized that the current EPA q* values are 95th percentile upper estimates of risks and that the risks may range anywhere between 0 and the upper bound risk estimate (EPA, 1986; NRC, 1994) (i.e., 95% of the time, the risk is between 0 and 1.1 (mg/kg body wt/day)-1.

N.3.2. A q u a t i c a n d T e r r e s t r i a l W i l d l i f e No data were identified on the potential effects ofbis(2-chloroethyl)etheron aquatic or terrestrial wildlife.

N.3.3. Other Environmental Effects No data were identified on the potential effects of bis(2-chloroethyl)ether on ozone depletion, acid rain, or forest decline.

POTENTIAL ADVERSE EFFECTS OF CHLORINATED CHEMICALS

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REFERENCES

American Conference of Governmental Industrial Hygienists (ACGIH) (1992). Dichloroethyl Ether. ACGIH, Cincinnati, OH. ATKINSON, R. (1987). Structure-activity relationship for the estimation of rate constants for the gas-phase reactions of OH radicals with organic compounds. Int. J. Chem. Kinetics 19, 799-828. Cited in Howard et aL, 1991. CAL~d~RESE,E. J., AND KENYON, E. M. (1991). Air Toxics and Risk Assessment. Lewis Publisher, Chelsea, MI. Canadian Council of Resource and Environment Ministers (CCREM) (1987). Canadian Water Quality Guidelines. Task Force on Water Quality Guidelines, CCREM. CARPENTER,C. P., SMYTH, H. F., AND POSSANI,U. C. (1949). The assay of acute vapor toxicity, and the grading and interpretation of results on 96 chemical compounds. J. lnd. Hyg. Toxicol. 31,343-35 l. Cited in ACGIH, 1992. DOJLIDO, J. R. (1979). Investigations of Biodegradability and Toxicity of Organic Compounds. Final Report 1975-79. EPA, Municipal Environmental Research Lab., Cincinnati, OH. EPA 600/2-79-163. Cited in Howard et aL, 1991. DURKIN, P. R., HOWARD,P. H., AND SAXENA,J. (1975). Investigation of Selected Potential Environmental Contaminants: Haloethers. (U.S.) EPA, Office of Toxic Substances, Washington, DC. EPA 560/2-75-006. Cited in EPA, 1979. Environmental Protection Agency (EPA) (1979). Water-Related Environmental Fate of 129 Priority Pollutants, Vol. II. EPA, Washington, DC. PB80-204381. Environmental Protection Agency (EPA) (1980). Ambient Water Quality Criteria for Chlorinated Benzenes. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-028. NTIS PB81-117392. Environmental Protection Agency (EPA) (1986). Superfund Public Health. Evaluation Manual Washington, DC. EPA 1540/1-86-060. Environmental Protection Agency (EPA) (1992). Integrated Risk Information System (1RIS). On-line database, 7/13/92. FISHBEIN,L. (1977). Potential Industrial Carcinogens and Mutagens. (U.S.) EPA, Office of Toxic Substances, Washington, DC. EPA 560/5-77-005. Cited in EPA, 1992. HOWARD, P. H., BOETHLING,R. S,, JARVIS, W. F., MEYLAN, W. M., AND MICHALENKO,E. M. (1991). Handbook of Environmental Degradation Rates, pp. 428-429. Lewis Publishers, Chelsea, MI. INNES,J. R. M., ULLAND,B. M., VALERIO,M. G., PETRUCELLI,L., FISHEBEIN,t., HART, E. R., PALLOTTA, A. J., BATES,R. R., FALK, H. L., GART, J. J., KLEIN, M., MITCHELL,I., AND PETERS, J. (1969). Bioassay of pesticides and industrial chemicals for tumorigenicity in mice. A preliminary note. J. Natl. Cancer Inst. 42, 1101-1114. Cited in Calabrese and Kenyon, 1991. JAFFE, H. H., AND ORCHrN, M. (1962). Theory and Application of Ultraviolet Spectroscopy. Wiley, New York. Cited in EPA, 1979. JORGENSON, T. A., RUSHBROOK,C. J., NEWELL,G. W., AND TARDIFF, R. G. (1977). Study of mutagenic potential of bis(2-chloroethyl) and bis(2-chloroisopropyl)ethers in mice by the heritable translocation test. Toxicol. AppL PharmacoL 41, 196. Cited in EPA, 1992. KIRWIN, C. J., AND SANDMEYER,E. E. (1981). Ethers. In Patty's Industrial Hygiene and Toxicology (G. D. Clayton and F. E. Clayton, Eds.), pp. 2491-2566. Wiley, New York. KOSYAN, S. A. (1967). Tr. Erevan. Gos. Inst. Usoversh. Vrachel. 3, 617. Cited in Calabrese and Kenyon, 1991. LEO, A., HANSCH, C., AND ELKINS, D. (1971). Partition coefficients and their uses. Chem. Rev. 71, 525616. Cited in CCREM, 1987. LINGG, R. D., et aL (1978). Society of Toxicology--17th Annual Meeting. San Francisco, California, March 12. Abstract 69 on page 59. Cited in Smith and Lingg, 1985. LUDZACK, F. J., AND ETTINGER, M. B. (1963). Biodegradability of organic chemicals isolated from rivers. Purdue Univ. Eng. Bull. Ext. Set. No. 115, 278-282. Cited in Howard et aL, 1991. MABEY,W, R., SMITH,J. H., PODOLL,R. T., JOHNSON,H. L., MILL, T., CHOU, T. W., GATES,J., PARTRIDGE, I. W., AND VANDEN BERG, D. (1981). Aquatic Fate Process Data for Organic Priority Pollutants, p. 434. (U.S.) EPA, Washington, DC. EPA-440/4-81-014. Cited in Howard et aL, 1991. National Institute for Occupational Safety and Health (NIOSH) (1988). KN0875000. Ether, Bis(2-chloroethyl). RTECS, on line. Cited in Calabrese and Kenyon, 1991.

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National Research Council (NRC) (1994). Science and Judgement in Risk Assessment. National Academy Press, Washington, DC. NORPOTH, K., HEGER, M., MULLER, G., MOHTASHAMPIAR,E., KEMENA, A., AND WITTING, C. (1986). Investigations on metabolism, genotoxic effects and careinogenicity of 2,2'-dichloroethyl ether. J. Cancer. Res. Clin. Oncol. 112, 125-130. Cited in Calabrese and Kenyon, 1991. Occupational Safety and Health Administration (OSHA) (1989). Air contaminants; final rule. Fed. Regist. 54, 2332-2959. Cited in Calabrese and Kenyon, 1991. SCHRENK, H. H., PATTY, F. A., AND YANT, W. P. (1933). Acute responses of guinea pigs to vapors of some new commercial organic compounds. VII. Dichloroethyl ether. Public Health Rep. 48, 1389-1398. Cited in ACGIH, 1992. SHn~su, Y., MORrCA,M., KATO,K., AND KADA,T. (1975). Mutagenieity screening of pesticides in microbial systems. Mutat. Res. 31, 268. Cited in EPA, 1992. SMITH, C. C., AND LINGG, R. D. (1985). Metabolism of j3-haloethers in rats and monkeys. In Investigation of the Metabolism of Chlorinated Hydrocarbons in Subhuman Species (C. C. Smith, S. T. Cragg, G. F. Wolfe, and W. W. Weigel, Eds.), Univ. of Cincinnati. SMITH, C. C., CP,AGG, S. T., WOLFE, G. F., AND WEIGEL, W. W. (1985). Investigation of the Metabolism of Chlorinated Hydrocarbons in Subhuman Species. Prepared for Health Effects Research Lab, Research Triangle Park, NC. SMYTH, H. F., AND CARPENTER,C. P. (1948). Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30, 63-68. Cited in ACGIH, 1992. ULLAND, B., WEISBURGER,E. K., AND WEISBURGER,J. H. (1973). Chronic toxicity and carcinogenicity of industrial chemicals and pesticides. Toxicol. Appl. Pharmacol. 25, 446. Cited in Calabrese and Kenyon, 1991. VAN DUUREN,B. L., KATZ, C., GOLDSCHMIDT,B. M., FRENKEL,K., ANDSIVAK,A. (1972). Carcinogenicity of halo-ethers. II. Structure-activity relationships of analogs of Bis(chloromethyl)ether. J. NatL Cancer Inst. 48, 1431-1439. VERSCHUEREN,K. (1983). Handbook of Environmental Data on Organic Chemicals. Van Nostrand/Reinhold, New York. WEISBURGER,E. K., ULLAND,B. M., NAM, J. M., el al. (1981). Carcinogenicity tests of certain environmental and industrial chemicals. J. Natl. Cancer Inst. 67, 75-88. Cited in ACGIH, 1992.