------- DISCLAIMER This report Is an external draft for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. 11 ------- PREFACE Health and Environmental Effects Documents (HEEDs) are prepared for «the Office of Solid Waste and Emergency Response (OSWER). This document series 1s Intended to support listings under the Resource Conservation and Recovery Act (RCRA) as well as to provide health-related limits and goals for emer- gency and remedial actions under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Both published literature and Information obtained for Agency Program Office files are evaluated as they pertain to potential human health, aquatic life and environmental effects of hazardous waste constituents. The literature searched for 1n this document and the dates searched are Included 1n "Appendix: Literature Searched." Literature search material 1s current up to 8 months previous to the final draft date listed on the front cover. Final draft document dates (front cover) reflect the date the document 1s sent to the Program Officer (OSWER). Several quantitative estimates are presented provided sufficient data are available. For systemic toxicants, these Include Reference doses (RfDs) for chronic and subchronlc exposures for both the Inhalation and oral exposures. The subchronlc or partial lifetime RfD, 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval I.e., for an Interval that does not constitute a significant portion of the llfespan. This type of exposure estimate has not been extensively used, or rigorously defined as previous risk assessment efforts have focused primarily on lifetime exposure scenarios. Animal data used for subchronlc .estimates generally reflect exposure durations of 30-90 days. The general methodology for estimating subchronlc RfDs 1s the.same as traditionally employed for chronic estimates, except that subchronlc data are utilized when available. In the case of suspected carcinogens, RfDs are not estimated. Instead, a carcinogenic potency factor, or q-|* (U.S. EPA, 1980) 1s provided. These potency estimates are derived for both oral and Inhalation exposures where possible. In addition, unit risk estimates for air and drinking water are presented based on Inhalation and oral data, respectively. Reportable quantities (RQs) based on both chronic toxldty and cardno- genldty are derived. The RQ Is used to determine the quantity of a hazardous substance for which notification 1s required In the event of a release as specified under the Comprehensive Environmental Response, Compen- sation and Liability Act (CERCLA). These two RQs (chronic toxldty and cardnogenldty) represent two of six scores developed (the remaining four reflect 1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian toxldty). Chemfcal-spedflc RQs reflect the lowest of these six primary criteria. The methodology for chronic toxldty and cancer based RQs are defined In U.S. EPA, 1984 and 1986a, respectively. 111 ------- EXECUTIVE SUMMARY Chloroacetaldehyde (107-20-0) 1s a colorless liquid with an acrid, penetrating odor (Hawley, 1981; Wlndholz, 1983). This compound Is prepared Industrially by carefully controlled chlorlnatlon of acetaldehyde (Wlndholz, 1983). Chloroacetaldehyde 1s no longer manufactured 1n the United States (HSOB, 1987), although H Is probably Imported. Chloroacetaldehyde 1s used as a fungicide, 1n the manufacture of 2-am1noth1azole, 1n facilitating the removal of bark from trees and 1n dentistry (Lawrence and Autlan, 1972; U.S. EPA/NIH, 1987; Wlndholz, 1983). In the atmosphere, Chloroacetaldehyde Is expected to exist almost entirely In the vapor phase. Reaction with photochemlcally generated hydroxyl radicals (t,,- = 1«7 days) and physical removal by wet deposition would probably be the dominant fate processes. Chloroacetaldehyde removed from the atmosphere by wet deposition, however, may reenter the atmosphere by volatilization. In water, volatilization Is expected to be a signifi- cant, If not the dominant, removal mechanism. The volatilization half-life from a river 1 m deep, flowing 1 m/sec with a wind velocity of 3 m/sec has been estimated to be -2 days. Chloroacetaldehyde Is not expected to undergo chemical oxidation, bloaccumulate significantly In aquatic organisms or adsorb significantly to suspended solid or sediments In water. In moist soil, Chloroacetaldehyde 1s expected to be highly mobile and susceptible to significant leaching. The relatively high vapor pressure of chloroacetalde- \ hyde suggests that H would volatilize fairly rapidly from dry soil surfaces. No monitoring data are available to Indicate ambient air or water levels, drinking water or food contamination or dermal exposure. Potential sources of Chloroacetaldehyde entering the environment are losses at 1v ------- processing sites, losses during transport, disposal processes and use as a fungicide. Ando and Sayato (1984) suggested that VCM can migrate Into drinking water from water pipes made of polyvlnyl chloride and subsequently react with chlorine present In the drinking water, forming chloroacetalde- hyde. The detection of chloroacetaldehyde as a result of chlorlnatlon of VCM 1n drinking water, however, required the presence of much higher concentrations of both VCM and chlorine than are expected to be present under typical conditions. Therefore, the formation of chloroacetaldehyde 1n potable water by this process Is questionable. Another possible source of chloroacetaldehyde 1n the atmosphere 1s - formation from reaction of 1,3-d1chloropropene with ozone and OH radicals (Tuazon et al., 1984). 1,3-D1chloropropene 1s a highly volatile component of widely used Insectlddal fumlgants (Tuazon et al., 1984). Little Information 1s available regarding the toxlclty of chloroacet- aldehyde to aquatic organisms. A 96-hour LC_n of 1.5 mg chloroacetalde- hyde/B. was reported for the copepod, Nltocra splnlpes (Bengtsson and Tarkpea, 1983). Sea lampreys, however, were unaffected by exposure to 5 mg chloroacetaldehyde/a, for 24 hours (Applegate et al., 1957). No pertinent data regarding the absorption and distribution of chloro- acetaldehyde were located 1n the literature. Metabolism and excretion ^ata were limited to one study (Green and Hathway, 1977), In which three urinary metabolites [N-acetyl-S-(2-hydroxyethyl) cystelne, S-(carboxymethyl) cystelne and th1;od1glycol1c add] were found following oral administration of chloroacetaldehyde to rats. Few studies regarding the systemic toxldty of chloroacetaldehyde following administration of the compound by relevant routes (I.e., oral and Inhalation) were located In the available literature. Exposure of rats, ------- guinea pigs, rabbits and mice to chloroacetaldehyde (5.1 mg/m3) by Inhala- tion 7 hours/day, 5 days/week for 6 months had no adverse health effects on any of the animal species tested (Dow Chemical Company, 1962). Weekly oral administration of chloroacetaldehyde to mice (0.25 mg chloroacetaldehyde/ mouse/week) over an entire lifetime was without effect on the mortality rate (Van Duuren et al., 1979). The oral LD5Q of chloroacetaldehyde was reported to be between -82 mg/kg 1n mice and 89-103 mg/kg In rats (Lawrence et al., 1972). Intraperltoneal doses of chloroacetaldehyde of 0.0016 and 0.0032 ml/kg given to rats were associated with the production of a focal, chronic, bronchopneumonla, Increases 1n segmented neutrophlls and decreases 1n both erythrocytes and lymphocytes (Lawrence et al., 1972). No hematologlcal or pulmonary effects were associated with a dose of 0.0008 mi chloroacetalde- hyde/kg. Chloroacetaldehyde Injected IntraperHoneally In rats (0.0016 or 0.0032 ml/kg) 3 times/week for 12 weeks was reported to produce changes. 1n the respiratory epithelium, suggestive of a premallgnant condition (Lawrence et al., 1972). Chloroacetaldehyde has been shown to Increase the pentobarb1tal-1nduced sleeping time of mice (Lawrence et al., 1972) and to cause J_n vitro hemoly- s1s 1n rabbit erythrocyte preparations and cytotoxldty 1n murlne L-cell preparations. Oral weekly administration of chloroacetaldehyde to mice (0.25 mg/mouse/ week) for the Hfespan did not Increase the Incidence of forestomach tumors over that observed In untreated controls (Van Duuren et al., 1979). Chloroacetaldehyde was negative as a whole carcinogen or as a tumor Initiator when tested on the skin of mice (Van Duuren et al., 1979; Zajdela et al., 1980). vl ------- Cardnogenldty data resulting from human occupational exposure were not located 1n the available literature; also there were no ep1dem1olog1cal studies regarding possible carcinogenic effects associated with exposure to chloroacetaldehyde. Chloroacetaldehyde has been demonstrated to be mutagenlc 1n a variety of assays using both prokaryotes and eukaryotes with and without metabolic activation (B1gnam1 et al., 1980; Rannug et al., 1976; McCann et al., 1975; Malavellle et al., 1975; Phillips et al., 1980; Garro and Phillips, 1980; Hussaln and Osterman-Golkar, 1984; Perrard, 1985; lorprleno et al., 1977; Huberman et al., 1975; Rosenkranz, 1977). Pertinent data regarding the teratogenldty or other reproductive effects associated with exposure to chloroacetaldehyde were not located In the available literature dted 1n Appendix A. RfDs for chloroacetaldehyde are not presented as the available date were regarded as Inadequate. Data are Insufficient for determining an RQ based on chronic toxldty or on carc1nogen1dty. Since data regarding the carcinogenic potential of chloroacetaldehyde are Inadequate, this chemical Is placed 1n EPA Group D -- not classifiable as to human carclnogenldty. ------- TABLE OF CONTENTS Page 1. INTRODUCTION , 1 1.1. STRUCTURE AND CAS NUMBER 1 1.2. PHYSICAL AND CHEMICAL PROPERTIES .... 1 1.3. PRODUCTION DATA 2 1.4. USE DATA 2 1.5. SUMMARY 2 2. ENVIRONMENTAL FATE AND TRANSPORT 4 2.1. AIR 4 2.1.1. Reaction with Hydroxyl Radicals 4 2.1.2. Reaction with Ozone 4 2.1.3. Physical Removal Processes 4 2.2. WATER. . " ........ 4 2.2.1. Oxidation 4 2.2.2. Photolysis 5 2.2.3. Mlcroblal Degradation 5 2.2.4. Volatilization 5 2.2.5. Adsorption 5 2.2.6. B1oaccumulat1on . .... 5 2.3. SOIL . 6 2.3.1. Mlcroblal Degradation ...'.' 6 2.3.2. Adsorption 6 2.3.3. Volatilization 6 2.4. SUMMARY 6 3. EXPOSURE 8 4. AQUATIC TOXICITY 9 4.1. ACUTE TOXICITY 9 4.2. CHRONIC EFFECTS 9 4.3. PLANT EFFECTS . . 9 4.4. SUMMARY 9 5. PHARMACOKINETCS 10 5.1. ABSORPTION 10 5.2. DISTRIBUTION 10 5.3, METABOLISM . 10 5.4. EXCRETION 11 5.5. SUMMARY . 13 ------- TABLE OF CONTENTS (cont.) Page 6. EFFECTS 14 6.1. SYSTEMIC TOXICITY 14 6.1.1. Inhalation Exposures 14 6.1.2. Oral Exposures 14 6.1.3. Other Relevant Information 14 6.2. CARCINOGENICITY. . . 16 6.2.1. Inhalation 4 • 16 6.2.2. Oral. 16 6.2.3. Other Relevant Information. ... 17 6.3. MUTAGENICITY 20 6.4. TERATOGENICITY . 23 6.5. OTHER REPRODUCTIVE EFFECTS 23 6.6. SUMMARY 23 7. EXISTING GUIDELINES AND STANDARDS 25 7.1. HUMAN 25 7.2. AQUATIC 25 8. RISK ASSESSMENT ..;......... 26 8.1. CARCINOGENICITY 26 8.1.1. Inhalation 26 8.1.2. Oral 26 8.1.3. Other Routes 26 8.1.4. Weight of Evidence 26 8.1.5. Quantitative Risk Estimates . . 27 8.2. SYSTEMIC TOXICITY 27 8.2.1. Inhalation Exposures 27 8.2.2. Oral Exposures 28 9. REPORTABLE QUANTITIES 29 9.1. BASER ON SYSTEMIC TOXICITY 29 9.2. BASED ON CARCINOGENICITY 29 10. REFERENCES 32 APPENDIX A: LITERATURE SEARCHED 40 APPENDIX B: SUMMARY TABLE FOR CHLOROACETALDEHYDE 43 1x ------- LIST OF TABLES No. Title Page 6-1 Weekly Intragastrlc Administration of an Aqueous Solution of Chloroacetaldehyde to Ha:ICR Mice: Incidence of Fore- stomach Tumors 18 6-2 Mutagenldty Testing of Chloroacetaldehyde 21 9-1 Chloroacetaldehyde: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 30 ------- LIST OF ABBREVIATIONS BCF B1oconcentrat1on factor CAS Chemical Abstract Service DNA Oeoxyr1bonude1c acid GC Gas chromatography Koc Soil sorptlon coefficient Kow Octanol/water partition coefficient LCso Concentration lethal to 50% of recipients 1050 Dose lethal to 50% of recipients MED Minimum effective dose MS Mass spectrometry NOEL No-observed-effect level ppm Parts per million ppth Parts per thousand RfD Reference dose RQ Reportable quantity VCM Vinyl chloride monomer x1 ------- 1. INTRODUCTION 1.1. STRUCTURE AND CAS NUMBER Chloroacetaldehyde Is also known as 2-chloro-l-ethanal and 2-chloro- acetaldehyde (HSDB, 1987). The structure, CAS number, empirical formula and molecular weight are as follows: H 0 I // Cl-C-C I \ H H Molecular weight: 78.50 Empirical formula: C.H.CIO CAS Registry number: 107-20-0 1.2. PHYSICAL AND CHEMICAL PROPERTIES At room temperature, Chloroacetaldehyde 1s a clear, colorless liquid possessing an acrid, penetrating odor (Hawley, 1981; Wlndholz, 1983). It 1s soluble 1n water at concentrations <50%, but It .forms Insoluble hemlhydrate at concentrations >50% (U.S. EPA/NIH, 1987). Selected physical and chemical properties are as follows: Melting point (40% aqueous d1l.): Boiling point: (40% aqueous d1l.): Vapor pressure at 20°C: Log Kow: ; Water solubility at 20°C Flashpoint: Density (40% aqueous d1l,): Refractive. Index (40% aqueous dll., 25°C) -16.3°C 85°C 100 mm Hg 0.39 ~5xl O5 mg/9. 87.7°C 1 '• 25 1.397 Hawley, 1981 Hawley, 1981 ACGIH, 1981 U.S. EPA, 1987a U.S. EPA/NIH, 1987 Hawley, 1981 Hawley, 1981 Hawley, 1981 0086cl -1- 01/21/88 ------- 1.3. PRODUCTION DATA Chloroacetaldehyde 1s prepared Industrially by carefully controlled chlorlnatlon of acetaldehyde (Wlndholz, 1983). The following Information on chlororoacetaldehyde was obtained from the U.S. EPA TSCA Production File (U.S. EPA, 1977): Company/Location Production/Import Volume Texas Eastman Co. 1-10 million pounds Longvlew, TX International Flavors & Fragrances Inc. <1000 pounds Union Beach, NO (Importer) Henley and Co., Inc. confidential New York, NY (Importer) According to HSDB (1987), Chloroacetaldehyde 1s no longer produced commer- cially In the United States; however, CMR (1986) lists five domestic suppliers for this compound, which suggests that Chloroacetaldehyde 1s probably Imported Into the United States. Import data for recent years were not located 1n the available literature cited 1n Appendix A. 1.4. USE DATA Chloroacetaldehyde 1s used as a fungicide, In the manufacture of 2-am1noth1azole, 1n facilitating the removal of bark from trees and 1n dentistry (Lawrence and Autlan, 1972; U.S. EPA/NIH, 1987; Wlndholz, 1983). 1.5. SUMMARY Chloroacetaldehyde (107-20-0) 1s a colorless liquid with an acrid, penetrating odor\(Hawley, 1981; Wlndholz, 1983). This compound 1s prepared Industrially by carefully controlled chlorlnatlon of acetaldehyde (Wlndholz, 1983). Chloroacetaldehyde 1s no longer manufactured 1n the United States 0086d -2- 01/21/88 ------- (HSDB, 1987), although It 1s probably Imported. Chloroacetaldehyde 1s used as a fungicide, 1n the manufacture of 2-am1noth1azole, 1n facilitating the removal of bark from trees and 1n dentistry (Lawrence and Autlan, 1972; U.S. EPA/MIH, 1987; Wlndholz, 1983). 0086d -3- 01/21/88 ------- 2. ENVIRONMENTAL FATE AND TRANSPORT Limited data regarding the environmental fate and transport of chloro- acetaldehyde were located In the available literature. When possible, predictions regarding environmental fate and transport were derived from physical properties or molecular structure. <:" 2.1. AIR > Based on a vapor pressure of 100 mm Hg at 20°C, chloroacetaldehyde 1s expected to exist almost entirely 1n the vapor phase 1n the atmosphere (ACGIH, 1981; Elsenrelch et al., 1981). . 2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson (1985), the rate constant for the reaction of chloroacetaldehyde with photo- chemlcally generated hydroxyl radicals In the atmosphere has been estimated to be 9.4xlO~12 cm3/molecule-sec at 25°C. Assuming an average hydroxyl radical concentration of 5xl05 molecules/cm3 (Atkinson, 1985), the hydroxyl reaction half-life was estimated to be 1.7 days. 2.1.2. Reaction with Ozone. Reaction of chloroacetaldehyde with ozone 1n the atmosphere 1s not expected to be an Important fate process (U.S. EPA, 1987b). 2.1.3. Physical Removal Processes. Based on Its relatively high water solubility 1t appears that chloroacetaldehyde would be highly susceptible to removal from the atmosphere by wet deposition; however, any chloroacetalde- hyde removed from the atmosphere by this mechanism has the potential to reenter the atmosphere by volatilization. 2.2. WATER 2.2.1. Oxidation. Chloroacetaldehyde Is expected to be Inert to chemical @» ' oxidation In aqueous solution (Jaber et al., 1984). 0086d -4- 01/21/88 ------- 2.2.2. Photolysis.' Data regarding the photolysis of chloroacetaldehyde 1n water were not located 1n the available literature cited 1n Appendix A. 2.2.3. Mlcroblal Degradation. Stuckl and Le1s1nger et al. (1983) deter- mined that Pseudomonas CElr degraded 2-chloroethanol to glycollc add through chloroacetaldehyde and 2-chloroacetate (Intermediary compounds). This Information Indicates that biological degradation of chloroacetaldehyde Is likely to occur; however, the significance of this Information with regard to the blodegradatlon of chloroacetaldehyde under environmental conditions 1s uncertain. 2.2.4. Volatilization. Henry's Law constant for chloroacetaldehyde was estimated to be 2xlO~s m3-atm/mol at 25°C using the bond contribution method of H1ne and Mookerjee (1975). This value suggests that volatiliza- tion of chloroacetaldehyde from all bodies of water would be a significant fate process (Lyman et al., 1982). Based on this value of Henry's Law constant, the volatilization half-life of chloroacetaldehyde from a river 1 m deep., flowing 1 m/sec with a wind speed of 3 m/sec was estimated to be ~2 days using the method of Lyman et al. (1982). 2.2.5. Adsorption. Experimental data regarding the adsorption of chloro- acetaldehyde to suspended solids and sediments In water were not located In the available literature cited 1n Appendix A; however, the relatively high water solubility and low K suggest that adsorption to suspended solids and sediments 1n water Is probably not a significant fate process. 2.2.6. B1oaccumalat1on. A BCF of 1 was estimated for chloroacetaldehyde using a linear regression equation based on a log K of 0.39 (Lyman et al., 1982; U.S. EPA, 1987a). This BCF value and the relatively high water solubility of this compound suggest that chloroacetaldehyde would not bloaccumulate significantly 1n aquatic organisms. 0086d -5- 01/21/88 ------- 2.3. SOIL 2.3.1. Mlcroblal Degradation. As has been discussed In Section 2.2.3., blodegradatlon of chloroacetaldehyde 1s likely to occur, but no experimental data are available that would allow estimations of blodegradatlon rates In soil under environmental conditions. 2.3.2. Adsorption. A K of 39 was estimated for chloroacetaldehyde using a linear regression equation based on a log K of 0.39 (U.S. EPA, 1987a; Lyman et al., 1982). This KQC value and the relatively high water solubility of chloroacetaldehyde suggest that this compound would be very highly mobile In soil and susceptible to significant leaching (Swann et al., 1983). . 2.3.3. Volatilization. Based on a vapor pressure of 100 mm Hg at 20°C (ACGIH, 1981) chloroacetaldehyde 1s expected to volatilize fairly rapidly from dry soil surfaces. 2.4. SUMMARY In the atmosphere, chloroacetaldehyde 1s expected to exist almost entirely 1n the vapor phase. Reaction with photochemically generated hydroxyl radicals (t,/? = 1.7 days) and physical removal by wet deposition would probably be the dominant fate processes. Chloroacetaldehyde removed from the atmosphere by wet deposition, however, may reenter the atmosphere by volatilization. In water, volatilization Is-expected to be a signifi- cant, 1f not the dominant, removal mechanism. The volatilization half-life from a river 1 m'deep, flowing 1 m/sec with a wind velocity of 3 m/sec has been estimated to be ~2 days. Chloroacetaldehyde 1s not expected to undergo chemical oxidation, bloaccumulate significantly In aquatic organisms or adsorb significantly to suspended solid or sediments 1n water. In moist 0086d -6- 01/21/88 ------- soil, chloroacetaldehyde 1s expected to be highly mobile and susceptible to significant leaching. The relatively high vapor pressure of chloroacetalde- hyde suggests that It would volatilize fairly rapidly from dry soil surfaces. 0086d _7_ 01/21/88 ------- 3. EXPOSURE No monitoring data are available to Indicate ambient air or water levels, drinking water or food contamination or dermal exposure. Potential sources of chloroacetaldehyde entering the environment are losses at processing sites, losses .during transport, disposal processes and use as a fungicide. Ando and Sayato (1984) suggested that VCH can migrate Into drinking water from water pipes made of polyvlnyl chloride and subsequently. react with chlorine present 1n the drinking water, forming chloroacetalde- hyde:. The detection of chloroacetalde as a result of chlorlnatlon of VCM In -drinking water, however, required the presence of much higher concentrations of both VCM and chlorine than are expected to be present under typical conditions. Therefore, the formation of chloroacetaldehyde 1n potable water by this process 1s questionable. Another possible source of chloroacetalde- hyde 1n the atmosphere 1s formation from reaction of 1,3-d1chloropropene with ozone and OH radicals (Tuazon et al., 1984).. 1,3-D1chloropropene Is a highly volatile component of widely used Insectlddal fumlgants (Tuazon et al., 1984). 0086d -8- 01/21/88 ------- 4. AQUATIC TOXICITY 4.1. ACUTE TOXICITY Only two studies were found In the literature concerning the acute aquatic toxlclty of chloroacetaldehyde. The 96-hour 1C for the harpaetlcold copepod, NUocra splnlpes. was reported to be 1.5 mg/8. (Bengtsson and Tarkpea, 1983). Exposure took place In brackish water with a salinity of 7 ppth. No signs of distress were observed In the sea lamprey, Petromyzon marlnus. exposed to 5 mg chloroacetaldehyde/a for 24 hours (Applegate et al.f 1957). 4.2. CHRONIC EFFECTS Pertinent data regarding the effects of chronic exposure of aquatic biota to chloroacetaldehyde were not located 1n the available literature cited 1n Appendix A. 4.3. PLANT EFFECTS Pertinent' data regarding the effects resulting from exposure of plants to chlorbacetaldehyde were not located 1n the available literature cited 1n Appendix A. 4.4. SUMHARY Little Information 1s available regarding the toxldty of chloroacet- aldehyde to aquatic organisms. A 96-hour LC,Q of 1.5 mg chloroacetalde- hyde/si was reported for the copepod, NUocra splnlpes (Bengtsson and Tarkpea, 1983). Sea lampreys, however, were unaffected by exposure to 5 mg chloroacetaldehyd«/l for 24 hours (Applegate et al., 1957). 0086d -9- 01/21/88 ------- 5. PHARMACOKINETICS 5.1. ABSORPTION Pertinent data regarding the absorption of chloroacetaldehyde following either oral or Inhalation exposure were not located 1n the available litera- ture cited 1n Appendix A. 5.2. DISTRIBUTION Pertinent data regarding the distribution of chloroacetaldehyde were not located 1n the available literature dted 1n Appendix A. 5.3. METABOLISM The metabolism of chloroacetaldehyde has not been studied extensively. Chloroacetaldehyde has been found to be a metabolite of a variety of halo- genated organic compounds (GuengeMch et al., 1980; Gwlnner et al., 1983), but only one study (Green and Hathway, 1977) was found regarding the metabo- lism of chloroacetaldehyde Itself. An aqueous solution of chloroacetalde- hyde was administered, by gavage to four adult AlderTy-Park male rats at a dose level of 50 mg/kg (Green and Hathway, 1977). An unspecified number of control animals was also used. Urine was collected and separated Into fractions by anlon-exchange chromatography. The 3N acetic add fraction was analyzed by GC-MS and mass fragmentography for N-acetyl-S-(2-hydroxyethyl) cystelne. The 3N HC1 fraction was analyzed by GC-MS for thlodlglycoUc and chloroacetlc acids. N-acetyl-S-(2-hydroxyethyl) cystelne and S-(carboxy- methyl) cystelne were found 1n the urine of chloroacetaldehyde-treated rats and presumably not 1n the urine of control animals. ThlodlglycoUc add, a derivative of S-(carboxymethyl) cystelne, was the major urinary metabolite and accounted for 9.2X of the administered chloroacetaldehyde dose. A metabolic scheme proposed by Green and Hathaway (1977) Indicates that the first step In the metabolism of chloroacetaldehyde 1s conjugation with 0086d -10- 01/21/88 ------- glutathlone to yield S-formylmethylglutath1one (Figure 5-1). Metabolism of S-formylmethylglutath1one can then proceed along two alternate pathways. One pathway Involving further degradation and cleavage of the glutamate and glyclne residues from glutathlone results 1n the appearance'of N-acetyl-S- (2-hydroxy-ethyl) cystelne. The other pathway Involving dehydrogenatlon of S-formyl-methylglutath1one and further glutathlone cleavage results 1n the formation of S-(carboxymethyl) cystelne. Transam1nat1on followed by oxlda- tlve decarboxylatlon of S-(carboxymethyl) cystelne leads to formation of the major urinary metabolite, thlodlglycoUc add. Evidence for the existence of two separate pathways of S-formylmethyl- glutathlone metabolism comes from an experiment In which S-(2-hydroxyethyl) cystelne was administered orally to a separate group of rats (Green and Hathway, 1977). In this group of rats, the urinary yield of thlodlglycoUc acid was 0.5% of the administered dose, whereas the urinary yield of thlodl- glycoUc acid was 9.2% of the administered dose 1n chloroacetaldehyde- treated rats. This Indicates that, following chloroacetaldehyde administration, the formation of S-(carboxymethyl) cystelne (and the subsequent formation of th1od1glyco!1c acid) proceeds by a route that 1s Independent of the formation of N-acetyl-S-(2-hydroxyethyl) cystelne. 5.4. EXCRETION The only Information located regarding excretion of chloroacetaldehyde and Its metabolites was that of Green and Hathway (1977). The three urinary metabolites observed following oral administration of chloroacetaldehyde were thlodlglycoUc add, S-(carboxymethyl) cystelne and N-acetyl-S-(2- hydroxyethyl) cystelne. Information regarding other routes of elimination was not located 1n the available literature. 0086d -11- 03/30/88 ------- C1CHZ - C - H Ch1 oro*cetaldehyde •» Glutathione C = 0 I CHCHjS NH C = 0 I CH - CHpSCHpCHO I NH I S-foriy)« OH C = 0 I CHCHZ S CH2 C02H NH COeH CHCH, SCH,CH, I I NH(Qc) OH C0H C0H S-Ccarbo>y«*thyl> cyctaiiw COeH - CH2SCH2C02H C II 0 S(CHeC02H)2 Thiodislycolic acid FIGURE 5-1 Proposed Scheme for the Metabolism of Chloroacetaldehyde Source: Green and Hathway, 1977 0086d •-12- 01/21/88 ------- 5.5. SUMMARY No pertinent data regarding the absorption and distribution of chloro- acetaldehyde were located In the literature. Metabolism and excretion data were limited to one study (Green and Hathway, 1977), 1n which three urinary metabolites (N-acetyl-S-(2-hydroxyethyl) cystelne, S-(carboxymethyl) cystelne and th1od1glyco!1c add) were found following oral administration of chloroacetaldehyde to rats. 0086d -13- 01/21/88 ------- 6. EFFECTS 6.1. SYSTEMIC TOXICITY 6.1.1. Inhalation Exposures. 6.1.1.1. SUBCHRONIC — Rats (20/sex), guinea pigs (8/sex), rabbits (2/sex) and mice (10 females) were exposed to chloroacetaldehyde at 1.6 ppm (5.1 mg/m3) 7 hours/day, 5 days/week for 6 months (Dow Chemical Company, 1962). There was a similar number of air-exposed and unexposed control animals for each species. Gross and microscopic examination and observa- tions of growth,- mortality, hematology and organ weights Indicated that chloroacetaldehyde exposure produced no adverse effects on the health ,of any of the species tested. 6.1.1.2. CHRONIC ~ Pertinent data regarding the toxldty of chloro- acetaldehyde following chronic Inhalation exposure were not located 1n the available literature cited In Appendix A. 6.1.2. Oral Exposures. 6.1.2.1, SUBCHRONIC — Pertinent data regarding the toxldty of chloroacetaldehyde following subchronlc oral exposure were not located 1n the available literature dted 1n Appendix A. 6.1.2.2. CHRONIC — One study of the toxldty of chloroacetaldehyde following chronic oral administration was found 1n the available literature. In this study (Van Duuren et al., 1979), HarlCR Swiss mice were given chloroacetaldehyde In water by gavage at a dose of 0.25 mg chloroacetalde- hyde/mouse/week. •" The study was conducted over the lifetime of the mice '. (<636 days). The mortality rate of the chloroacetaldehyde-treated mice did not differ from that of untreated controls. No other details were provided. 6.1.3. Other Relevant Information. Rats (5/sex), guinea pigs (5/sex), 5 female mice and 1 female rabbit were exposed by Inhalation to 5 ppm of 0086d -14- 01/21/88 ------- chloroacetaldehyde 7 hours/day, 5 days/week, for a total of 8 exposures 1n 10 days (Dow Chemical Company, 1962). There were similar numbers of unexposed controls. Exposed animals exhibited slight eye and nasal Irrita- tion. The growth of the male rats was slightly depressed and the female rabbit exhibited central lobular fatty degeneration of the liver. No other adverse effects related to chloroacetaldehyde exposure were observed. The growth of the other exposed animal groups was the same as controls, organ weight and gross pathology data were negative, and there was no microscopic evidence of adverse effects In tissues. A subchronlc toxldty study of chloroacetaldehyde was conducted In male Sprague-Dawley rats by administering a 0.5% aqueous solution of the compound Intraperltoneally 3 times/week for 12 weeks (Lawrence et a!., 1972). The dose levels used (calculated as pure chloroacetaldehyde) were 0, 0.00032, 0.0008, 0.0016 and 0.0032 mi chloroacetaldehyde/kg. There were 12 rats In all groups except for the highest dose group, which had 8. Liver function tests (I.e., sulfobromophthaleln excretion), organ weight determinations, and hlstologlcal and hematologlcal examinations were performed. .The highest dose level (0.0032 ml/kg) caused death In 5/8 rats during the course of the study. The two highest dose levels (0.0016 and 0.0032 ml chloroacet- aldehyde/kg) were associated with the production of a focal, chronic bronchopneumonla, Increases In segmented neutrophlls and decreases 1n both erythrocytes and lymphocytes. There was also a significant decrease 1n hemoglobin at the 0.0032 ml/kg dose level. No hematologlcal or pulmonary '. effects were associated with a dose of 0.0008 ml chloroacetaldehyde/kg. The results of liver function tests were unremarkable. The acute toxldty of chloroacetaldehyde was also Investigated following oral administration of the compound to rats and mice (Lawrence et al., 0086d -15- 01/21/88 ------- 1972). The oral LD50 value 1n mice was 0.0692 mi chloroacetaldehyde/kg (or 82.3 mg/kg, assuming a specific gravity of 1.19 for chloroacetaldehyde) and 1n rats, the oral L05Q was 0.0751 ml/kg (or 89.3 mg/kg). Chloroacetaldehyde administration, either by Intraperlto'neal Injection or by Inhalation exposure, Increased the pentobarbltal sleeping time In mice (Lawrence et al., 1972). Inhalation of chloroacetaldehyde at a concentra- tion of 0.042 mg/m3 for 31 seconds on 3 consecutive days before pento- .barbUal administration resulted 1n a significant Increase 1n sleeping time as measured by the duration of loss of the righting reflex. Similarly, an Increase In pentobarbltal-lnduced sleeping time was noted 1n mlee Injected IntrapeMtoneally with 0.00061 ml chloroacetaldehyde/kg for 3 days before pentobarbltal administration. These results were subsequently shown not to be an artifact of chloroacetaldehyde-lnduced hepatic necrosis. In in vitro experimentation, chloroacetaldehyde was found to cause hemolysls 1n rabbit erythrocyte preparations and cytotoxldty In murlne L-cell preparations (Lawrence et al., 1972). 6.2. CARCINOGENICITY 6.2.1. Inhalation. Pertinent data regarding the cardnogenlcHy of chloroacetaldehyde following Inhalation exposure were not located 1n it he available literature cited 1n Appendix A. 6.2.2. Oral. One study was located 1n the literature regarding the carclnogenlclty of chloroacetaldehyde following oral administration of the compound with ml.ce. Ha:ICR Swiss mice (30 males and 30 females) received weekly oral doses of chloroacetaldehyde (0.25 mg chloroacetaldehyde/mouse/ week) in water (Van Duuren et al., 1979). The mice were treated with chloroacetaldehyde until they were moribund or found dead. The time of 0086d -16- 03/30/88 ------- death of the last mouse was 636 days. Control animals (100 females and 60 males) received no chloroacetaldehyde. In addition, a positive control group received B-prop1olactone. Following treatment, the stomach, liver and kidneys were analyzed for tumors. The results Indicated that the Incidence of forestomach tumors 1n chloroacetaldehyde-treated mice were not significantly different from untreated controls (Table 6-1). In addition, none of the tumors found In the chloroacetaldehyde-treated mice were squamous carcinomas. Mice treated with 3-prop1olactone, however, had significantly (p<0.0005) Increased Incidences of both total forestomach tumors and squamous carcinomas. B-Prop1olactone-treated mice also experienced decreased longevity, whereas the rate of mortality was not adversely affected by chloroacetaldehyde treatment. 6.2.3. Other Relevant Information. Several studies have been performed to determine whether chloroacetaldehyde produces tumors 1n the skin follow- ing topical or subcutaneous application; Chloroacetaldehyde (T.O mg/mouse) dissolved 1n 0.1 ma acetone was applied to the shaved dorsal surface of 30 female Ha:ICR Swiss mice 3 times/week for 83 weeks (Van Duuren et al., 1979). Control groups consisted of untreated and acetone-treated mice. Following treatment, skin, liver, stomach and kidney tissue were observed for pathology. No skin paplllomas were observed 1n the chloroacetaldehyde- treated mice and the Incidence of remote tumors was not significantly different from controls. Van Duuren et al. (1979) also studied the possible skin tumor1gen1dty of chloroacetaldehyde by administering the compound 1n water subcutaneously and subchronlcally to 30 female Ha:ICR Swiss mice (0.25 mg chloroacetalde- hyde/mouse/week for 90 weeks). As a positive control, 30 mice received 0.30 0086d -17- 01/21/88 ------- TABLE 6-1 Weekly Intragastrlc Administration of an Aqueous Solution of Chloroacetaldehyde to Ha:ICR Swiss Mice: Incidence of Forestomach Tumors3 Sex M F M F H F M F Ooseb (mg/mouse) 0 0 0.25 0.25 0 0 0.25 0.25 Duration of Treatment0**1 (days) 636 649 636 630 636 649 636 630 Tumor Type all all all all squamous cell carcinoma squamous cell carcinoma squamous cell carcinoma . squamous cell • Tumor Incidence 8/60 5/100 1/30, 3/30 1/60 0/100 0/30 0/30 Strengths of Study: Weakness of Study: carcinoma QUALITY OF EVIDENCE Lifetime exposure by relevant route; large numbers of control animals; positive controls used. Only one, nontoxlc dose given; weekly administration; limited number of endpolnts explored. Overall Adequacy: Inadequate aSource: Van Duuren et al., 1979 ^Compound administered once a week cM1ce treated until moribund or found dead ^Duration of study equal to duration of treatment 0086d -18- 01/21/88 ------- mg B-proplolactone on the same treatment schedule. Other (negative) control groups received nothing (100 mice), water (30 mice) or trloctanoln (30 mice). There were no observed differences between chloroacetaldehyde- treated mice and negative control groups with respect to local sarcoma Incidence. The positive control, B-proplolactone-treated mice, had a statistically significant (p<0.0005) Increase In tumor Incidence. Several studies also Indicate that chloroacetaldehyde 1s unable to function as an Initiator of skin paplllomas 1n Initiation-promotion tumorl- genesls experiments. Chloroacetaldehyde (1.0 ml/mouse) was applied 1n 0.1 ml acetone to the shaved backs of 30 female Swiss mice (Van Duuren et al., 1979). Chloroacetaldehyde Initiation was followed 14 days later by applica- tion of 2.5 yg of the tumor promoter PMA In 0.1 ml acetone. Promotion with PMA was continued 3 times/week for ~60 weeks. Positive controls were given 0.020 mg DMBA as an Initiator, whereas negative controls received repeated exposure to the promoter at dose levels of 0.0025 (120 mice) or 0.0050 (90 mice) mg PMA/mouse. Paplllomas were found .1n 3/30 chloroacet- aldehyde-lnltlated mice, which was not significantly different from the papHloma Incidence observed In the PMA-treated controls (9/120 and 6/90 for the respective PMA doses). The papllloma Incidence 1n DMBA-1n1t1ated mice (29/30) was significantly higher (p<0.0005) than the tumor Incidence In PMA controls. Initiation of skin tumoMgenesIs 1n mice using chloroacetaldehyde was also studied by Zajdela et al. (1980). Male XVIInc/Z mice (groups of 20-28) received single applications of chloroacetaldehyde dissolved In 80 yl acetone on their shaved backs at dose levels of 0.05, 0.1, 1.0 or 2.5 mg chloroacetaldehyde/mouse. Chloroacetaldehyde Initiation was followed by promotion with TPA 3 times/week for 42 weeks. The occurrence of paplllomas 0086d -19- 03/30/88 ------- and carcinomas was observed 1n the mice for ~84 weeks. The positive control group consisted of 45 mice Initiated with 50 yg DMBA, followed by promo- tion with croton oil 3 times/week for 12 weeks. Negative controls consisted of 28 mice receiving TPA (3 times/week for 42 weeks) without chloroacetalde- hyde Initiation. Survival was not affected by chloroacetaldehyde treatment and was similar to the survival rate of TPA-treated negative controls (22/28 TPA controls lived for 84 weeks). In contrast, only 7/45 positive control (DMBA-treated) mice survived the average observation period of 50 weeks. The Incidence of paplllomas 1n the chloroacetaldehyde-1n1t1ated mice was neither dose-related nor statistically different from the negative controls, and none of the chloroacetaldehyde-1n1t1ated mice had skin carcinomas. Persistent paplllomas and skin carcinomas were observed, however, 1n 37/45 mice treated with DHBA-croton oil. Lawrence et al. (1972) Injected chloroacetaldehyde IntraperUoneally In Sprague-Dawley rats (0.0016 or 0.0032 ma chloroacetaldehyde/kg) 3 times/ week for 12 weeks. The authors reported "These changes Included focal chronic bronchopneumonla and certain changes of respiratory epithelium suggesslve of a premallgnant condition", but this 1s not supported by any data. No carclnogenldty data from human occupational exposure were located 1n the available literature nor were ep1dem1olog1cal studies located regarding possible carcinogenic effects related to chloroacetaldehyde exposure. 6.3. MUTAGENICJTY Chloroacetaldehyde has been tested for mutagenlclty In both prokaryotes and eukaryotes using a variety of assays (Table 6-2). Forward and reverse mutation assays 1n prokaryotes have been positive both with and without metabolic activation of chloroacetaldehyde (B1gnam1 et al., 1980; Rannug et al.. 1976; McCann et al., 1975; Malavellle et al., 1975; Phillips et al., 0086d -20- 07/05/88 ------- Hutagentclty Testing of Chloracetaldehyde o CO IV I o C* Assay Reverse nutation Reverse nutation Reverse nutation Reverse •utatton Reverse mutation Reverse nutation Forward mutation DMA repair Indicator/ Organism Salmonella typhlmurlum TA98. TA100 TA1535. TA1537. . TA1S38 S. typhlimirlum TA98. TA100 TA1S3S. TA1S37, TA1538 S. tvphlmurlum TA100. TA1535 S. typhlnurlum TA1S35 S. typhlnurlum TA1530 Bacillus subtllts llv 82. lev A169 markers B. subtllls $105 strains G68 Gb7075 Escherlchla coll pol A* pol A* Compound and/or Purity NR 45X aqueous solution 45X aqueous solution aqueous solution SOX aqueous solution SOX aqueous solution SOX aqueous solution NR Application Concentration Activating or Dose System plate -2-28 yg/plate -S-9 Incorporation plate 3-60xlO~» ±S-9 Incorporation pi/plate spot test 3-30 rag/plate »S-9 plate 0.1-1. 5, nN -S-9 Incorporation plate 0.4-40 *S-9 Incorporation iinol/njt plate Incorpo- 0.2S-S oH NR ration (DNA transformation mixture) plate 1-4 a* NR Incorporation NR 10 »t NR Response Comment <• Highly mutagenlc to TA100, weakly muta- genlc to TA1S3S »A Positive In TA100; addition of S-9 decreased response. */» Positive In TA100; addition of S-9 decreased response. *• Dose-dependent In- creases In revertants at doses which were originally cytotoxlc f/f Highly cytotoxlc at the highest concen- tration * Dose -dependent In- crease In mutation activity with base pair, but not with frameshlft, mutation strain t Mutagenlc to both normal and repair- deficient host cell reactivation strains t Preferential Inhibi- tion of pol A* growth Reference HcCann et al. . 1975 Blgnaml et al.. 1980 Blgnaml et al.. 1980 Rannug et al.. 1976 Nalavetlle et al.. 197S Phillips et al.. 1980 Garro and Phillips. 1980 Rosenkranz. 1977 CO 00 ------- o 0 CO c* a. Assay Forward mutation Reverse mutation Reverse mutation £J Forward i mutation Forward mutation Gene conversion Polycls- tronlc mutation Single point mutation ON Forward J^ mutation Indicator/ Organism E. coll Sd-4 E. coll K12 All K12 A23 K12 A46 Streptomyces coellcolor A3(2) strain his Al S. coellcolor A3(2) strain his Al Schlzosac- charomyccs pombe PI Saccharomyces cerevlslae D4 Asperqlllus nldulans 35 A. nldulans 35 CHO V79 cells Compound and/or Purity dissolved " In '0.2 M EtOH aqueous solution 45X aqueous solution 45X aqueous solution SOX aqueous solution SOX aqueous solution 45X aqueous solution 45X aqueous solution SOX aqueous solution TABLE 6-2 (cont Application Concentration or Dose liquid -0.1-4 mM suspension liquid 10-200 mM suspension plate Incorpo- 0.25-1.0 wt ration and spot test plate Incorpo- 0.25-10 ut ration and spot test liquid 0.78-6.25 mM suspension liquid 3.1-12.5 mM suspension plate 20-40 pt Incorporation spot test 5-20 pt liquid 1.6-12.8 pM cultures '' Activating Response Comment System NR * Dose-dependent muta- tion to streptomycin nondependence none * Dose-response; Reversion frequency greatest near 100X cytotoxlclty none «• Strongly mutagenlc only In spot test none * Mutagenlc only In spot test ^S-9 *A Dose-response ±S-9 i Weak Increase In mutation frequency at cytolethal con- centrations none <• Nutagenlclty not replicated In spot test none «• ' Stronger Induction of 8-azoguanlne resis- tance In liquid test NR * Reference Hussaln and Osterraan- Golkar. 1984 Perrard. 1985 Blgnaml et al.. 1980 Blgnaml et al.. 1980 Lorprleno et al.. 1977 Lorprleno et al.. 1977 Blgnaml et al.. 1980 Blgnaml et al.. 1980 Huberman et al.. 1975 GO 00 NR = Not reported ------- 1980; Garro and Phillips, 1980; Hussaln and Osterman-Golkar, 1984; Perrard, 1985). In eukaryotes (yeast), chloroacetaldehyde has been demonstrated overall to be mutagenlc 1n a number of mutation assays (LorpMeno et al., 1977; B1gnam1 et al., 1980). Chloroacetaldehyde has also proven to be mutagenlc In mammalian cells (Huberman et al., 1975). 6.4. TERATOGENICITY Pertinent data regarding the teratogenldty of chloroacetaldehyde were not located 1n the available literature dted 1n Appendix A. 6.5. OTHER REPRODUCTIVE EFFECTS Pertinent data regarding other reproductive effects of chloroacetalde- hyde were not located 1n the available literature dted 1n Appendix A. 6.6. SUMMARY Few studies regarding the systemic toxldty of chloroacetaldehyde following administration of the compound by relevant routes (I.e., oral and Inhalation) were located In the available literature. Exposure of rats, guinea pigs, rabbits and mice to chloroacetaldehyde (5.1 mg/m3) by Inhala- tion 7 hours/day, 5 days/week for 6 months had no adverse health effects on any of the animal species tested (Dow Chemical Company, 1962). Weekly oral administration of chloroacetaldehyde to mice (0.25 mg chloroacetaldehyde/ mouse/week) over an entire lifetime was without effect on the mortality rate (Van Duuren et al., 1979). The oral LD5Q of chloroacetaldehyde was reported to be -82 mg/kg In mice and 89-103 mg/kg 1n rats (Lawrence et al., 1972). f Intraperltoneal doses of chloroacetaldehyde of 0.0016 and 0.0032 ma/kg given to rats were associated with the production of a focal, chronic, bronchopneumonla, Increases In segmented neutrophlls and decreases 1n both erythrocytes and lymphocytes (Lawrence et al., 1972). No hematologlcal or 0086d -23- 06/24/88 ------- pulmonary effects were associated with a dose of 0.0008 ml chloroacetalde- hyde/kg. Chloroacetaldehyde Injected IntraperHoneally 1n rats (0.0016 or 0.0032 ml/kg) 3 times/week for 12 weeks was reported to produce changes In the respiratory epithelium, suggestive of a premallgnant condition (Lawrence et al.. 1972). Chloroacetaldehyde has been shown to Increase the pentobarbHal-lnduced sleeping time of mice (Lawrence et al., 1972) and to cause In vitro hemoly- s1s In rabbit erythrocyte preparations and cytotoxlclty 1n murlne L-cell preparations. Oral weekly administration of Chloroacetaldehyde to mice (0.25 mg/mouse/ week) for the llfespan did not Increase the Incidence of forestomach tumors over that observed In untreated controls (Van Duuren et al., 1979). Chloroacetaldehyde was negative as a whole carcinogen or as a tumor Initiator when tested on the skin of mice (Van Duuren et al., 1979; Zajdela et al., 1980). Cardnogenldty data resulting from human occupational exposure were not located 1n the available literature; also there were no ep1dem1olog1cal studies regarding possible carcinogenic effects associated with exposure to Chloroacetaldehyde. Chloroacetaldehyde has been demonstrated to be mutagenlc 1n a variety of assays using both prokaryotes and eukaryotes with and without metabolic activation (B1gnam1 et al., 1980; Rannug et al., 1976; McCann et al., 1975; Malavellle et al.., 1975; Phillips et al., 1980; Garro and Phillips, 1980; Hussaln and Osterman-Golkar, 1984; Perrard, 1985; LorpMeno et al., 1977; Huberman et al., 1975; Rosenkranz, 1977). Pertinent data regarding the teratogenlcHy or other reproductive effects associated with exposure to Chloroacetaldehyde were not located 1n the available literature dted In Appendix A. 0086d -24- 06/24/88 ------- 7. EXISTING GUIDELINES AND STANDARDS 7.1. HUMAN Because of chloroacetaldehyde's severely Irritating nature, a celling limit of 1 ppm (~3 mg/m3) has been recommended for human occupational exposure (ACGIH, 1986). Continuous exposure to this level of chloroacet- aldehyde was discouraged, however, because of the compound's demonstrated mutagenlc activity (ACGIH, 1986). The celling limit of 1 ppm was adopted by the ACGIH (1987). The OSHA (1985) permissible exposure limit 1s also 1 ppm for chloroacetaldehyde. 7.2. AQUATIC Guidelines and standards for the protection of aquatic biota from chloroacetaldehyde were not located 1n the available literature cited 1n Appendix A. 0086d -25- 06/24/88 ------- 8. RISK ASSESSMENT 8.1. CARCINOGENICITY 8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of chloroacetaldehyde following Inhalation exposure were not located 1n the available literature cited 1n Appendix A. 8.1.2. Oral.. The only study found In the available literature concerning the carclnogenldty of chloroacetaldehyde following oral administration was that of Van Duuren et al. (1979), 1n which 30 male and 30 female Ha:ICR Swiss mice receiving 0.25 mg chloroacetaldehyde/mouse once a week for up to 636 days did not exhibit an Increased Incidence of forestomach total tumors or squamous carcinomas compared with that of negative controls. Thirty mice of each sex receiving a positive control substance, B-prop1olactone, on a weekly basis had statistically significant (p<0.0005) Increases In both total forestomach tumors and squamous carcinomas. Because of an Inadequate number of mice 1n each group and the use of only one dose level, this study was judged Inadequate for assessment of the carcinogenic potential of chloroacetaldehyde. ; 8.1.3. Other Routes. Several studies (Van Duuren et al., 1979; Zajdela et al., 1980) have demonstrated that chloroacetaldehyde 1s not tumorlgenlc to the skin following repeated exposure either by the topical or subcuta- neous routes. These same studies also demonstrated that chloroacetaldehyde does not function as an Initiator when used 1n Initiation-promotion skin tumor1genes1s experiments. 8.1.4. Weight of Evidence. Because there are no data regarding the carclnogenldty of chloroacetaldehyde 1n humans and because the only study on the carclnogenldty of chloroacetaldehyde 1n mice following oral exposure 0086d -26- 06/24/88 ------- (Van Duuren et al., 1979) was judged Inadequate for assessment of chloro- acetaldehyde carcinogenic potential, this compound 1s placed 1n EPA Group 0 (U.S. EPA, 1986b) - not classifiable as to human carclnogenlcHy. 8.1.5. Quantitative Risk Estimates. The lack of adequate studies on the carclnogenlcHy of chloroacetaldehyde following exposure either by the oral or Inhalation route precludes the derivation of quantitative risk estimates. 8.2. SYSTEMIC TOXICITY 8.2.1. Inhalation Exposures. 8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Rats, rabbits, guinea pigs and mice were .exposed to 1.6 ppm chloroacetaldehyde (5.1 mg/m3) by Inhalation 7 hours/day, 5 days/week for 6 months (Dow Chemical Company, 1962). There were no adverse effects on growth, mortality, hematology or organ weights. H1stolog1cal analyses were also unremarkable. The study by Dow Chemical Company (1962) was the only Inhalation toxldty study of chloroacetaldehyde that was of sufficient duration to be classified as either subchronlc or chronic. A number of animal species were used 1n this study but the numbers of animals In each group were low. In addition, there was only one exposure level In this study of chloroacetaldehyde toxldty and this exposure level proved to be a NOEL (I.e., no dose response data are available). Even though RfDs were derived using this study (U.S. EPA, 1986c, 1987c), revaluation of the data base under the present RfD guidelines has determined 1t to be Inadequate for derivation of RfQs. 8.2.1.2. CHRONIC EXPOSURES — Data regarding the toxldty of chloro- acetaldehyde following chronic Inhalation exposure were not located 1n the available literature. 0086d -27- 07/05/88 ------- 8.2.2. Oral Exposures. 8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — There were no data located 1n the literature regarding the toxldty of chloroacetaldehyde following subchronlc oral exposure. 8.2.2.2. CHRONIC EXPOSURES — A chronic oral study of chloroacetalde- hyde toxldty Indicated that the longevity of 30 male and 30 female Ha:ICR Swiss mice was unaffected by exposure to 0.25 mg chloroacetaldehyde/mouse/ week over an entire lifetime (Van Duuren et al., 1979). This dosing schedule (I.e., one dose/week) was suggestive of repeated acute rather than chronic exposure and-thls study was therefore deemed Inadequate for chronic toxldty risk assessment. 0086d -28- 07/05/88 ------- 9. REPORTABLE QUANTITIES 9.1. BASED ON SYSTEMIC TOXICITY The systemic toxldty of chloroacetaldehyde was discussed In Section 6.1. Because the chloroacetaldehyde exposure level used In the subchronlc Inhalation toxldty study by Dow Chemical Company (1962) did not produce observable toxldty, the data are Insufficient for derivation of an RQ (Table 9-1). 9.2. BASED ON CARCINOGENICITY Studies regarding the carclnogenldty of chloroacetaldehyde were reviewed 1n Section 6.2. and summarized In Table 6-1. The only study of the carcinogenic effects of chloroacetaldehyde following exposure by a relevant route (I.e., oral or Inhalation) was that by Van Duuren et al. (1979), 1n which 30 male and 30 female mice given an oral dose of chloroacetaldehyde (0.25 mg chloroacetaldehyde/mouse/week) over the course of a lifetime had an Incidence of forestomach tumors and squamous carcinomas that did not exceed that of negative controls. Because of the small number of mice used and the use of only one chloroacetaldehyde dose level, this study was not considered adequate to assess the carclnogenldty of chloroacetaldehyde. Van Duuren et al. (1979) and Zajdela et al. (1980) also reported that chloroacetaldehyde was unable to function as a skin tumoMgen either follow- ing repeated exposure to the compound Itself or by using chloroacetaldehyde as an Initiator followed by treatment with several promoting agents. Lawrence et al. (1972), however, reported changes suggestive of a premallg- nant condition 1n the respiratory epithelium of rats Injected 1ntraper1to- neally with chloroacetaldehyde (0.0016 or 0.0032 mi/kg) 3 times/week for 12 weeks. 0086d -29- 07/05/88 ------- TABLE 9-1 Chloroacetaldehyde Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Dose: Effect: Reference: RVd: RVe: : ^ Composite Score: RQ: Data are not sufficient for deriving an RQ. 0086d -30- 07/05/88 ------- Structurally related compounds, such as formaldehyde and acetaldehyde, are known to be carcinogenic. Unlike these related compounds, there are no data available to show carcinogenic activity of chloroacetaldehyde. Chloro- acetaldehyde 1s mutagenlc and a presumed Intermediate In* the metabolic pathway of ethylenedlchlorlde. Because Information on the potential cardnogen1c1ty of chloroacetaldehyde 1s Inadequate, there being only positive short term data Indicating potential the overall evidence Indicates that chloroacetaldehyde should be classified 1n we1ght-of-ev1dence Group D because of Inadequate data (U.S. EPA, 1986b). Accordingly, Group D compounds cannot be ranked on the CERCLA hazard ranking scheme. 0086d -31- 07/05/88 ------- 10. REFERENCES ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1981. Documentation of the Threshold Limit Values, 4th ed. Supplemental Documen- tation. Cincinnati, OH. p. 82. ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. p. 120. ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1987. TLVs - Threshold limit values and biological exposure Indices for 1987-1988. Cincinnati, OH. p. 14. Ando, M. and Y. Sayato. 1984. 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OPD Chemical Buyers Directory, 74th annual ed., H. Van, Ed. Schnell Publishing Co., New York, NY. Dow Chemical Company. 1962. Toxldty of chloroacetaldehyde determined on experimental animals (unpublished report). Biochemical Research Laboratory, The Dow Chemical Company, Midland, MI. E1senre1ch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic contaminants of the Gireat; Lakes ecosystem. Environ. Sd. Techno!. 15(1): 30-38. Garro, A.J. and R.A. Phillips. 1980. Detection of mutagen-lnduced lesions 1n Isolated DNA by marker rescue of Bacillus subtnils phase 105. Mutat. Res. 73(1): 1-13. (CUed In U.S. EPA, 1986c) Green, T. and U.E. Hathway. 1977. The chemistry and biogenesis of the S-conta1n1ng metabolites of vinyl chloride In rats. Chem. B1ol. Interact. 17(2): 137-150. 0086d -33- 07/05/88 ------- Guengerlch, P.P., W.M. Crawford, J.Y. Domoradzkl, T.L. MacDonald and P.G. Watanabe. 1980. Iri vitro activation of 1,2-d1chloroethane by mlcrosomal and cytosollc enzymes. Toxlcol. Appl. Pharmacol. 55: 303-317. (CHed In U.S. EPA, 1986c) Gwlnner, L.M., R.J. La1b, J.G. Fllser and H.M. Bolt. 1983. Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride toward DNA: Comparative studies with 2,2-d1chlorod1ethyl ether. Cardnogen1s1s. 4(11): 1483-1486. (CHed 1n U.S. EPA, 1986c) Hawley, G.G. 1981. The Condensed Chemical Dictionary. Van Nostrand Relnhold Co., New York. p. 232. Mine, J. and P.K. Mookerjee. 1975. The Intrinsic hydrophlllc character of organic compounds. Correlations 1n terms of structural contributions. J. Org. Chem. 40(3);: 292-298. HSDB (Hazardous Substance Data). 1987. Report No. 2521. On-Llne October 19, 1987. CAS No. 302-17-0. Huberman, E., H. Bartsch and L. Sachs. 1975. Mutation Induction In Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde. Int. 0. Cancer. 16: 639-644. (CHed 1n U.S. EPA, 1986c) 0086d -34- 07/05/88 ------- Hussaln, S. and S. Osterman-Golkar. 1984. Dose-response relationships for mutations Induced 1n E_. coll by some model compounds. WHh an addendum: Reaction kinetics 1n water of chloroethylene oxide, chloroacetaldehyde, and chloroacetone. HeredHas. 101(1): 57-68. Jaber, H.M., W.R. Mabey, A.T. Lu1, et al. 1984. Data Acquisition for Environmental Transport and Fate Screening. SRI Intl., Menlo Park, CA. EPA 600/6-84/009. NTIS PB84-243906. p. 46. Lawrence, W.H. and J. Autlan. 1972. Possible toxic effects from Inhalation of dental Ingredients by alteration of drug biologic half-life. J. Dent. Res. 51: 878. Lawrence, W.H., E.O. DllUngham, J.E. Turner and J. Autlan. 1972. Toxldty profile of chloroacetaldehyde. J. Pharm. Sd. 61: 19-25. LorpMeno, N., R. Barale, S. BaroncelH, et al. 1977. Induction of gene mutations and gene conversions by vinyl chloride metabolites In yeast. Cancer Res. 3(1): 253-257. Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical Property Estimation Methods. McGraw-Hill Book Co., New York. p. 4-9, 5-5, 15-13 to 15-34. f Malavellle, C., H. Bartsch, A. Barbln et al. 1975. Mutagenldty of vinyl chloride, chloroethyleneoxlde, chloroacetaldehyde, and chloroethanol. Blochem. Blophys. Res. Commun. 63: 363-370. (CHed In U.S. EPA, 1986c) 0086d -35- 07/05/88 ------- McCann, J., V. Simmon, D. Stre1tw1eser and B.N. Ames. 1975. MutagenlcHy of chloroacetaldehyde, a possible metabolic product of 1,2-d1chloroethane (ethylene dlchlorlde), chloroethanol (ethylene chlorohydrln), vinyl chloride and cyclophosphamlde. Proc. Natl. Acad. Sc1. USA 72(8): 3190-3193. (CHed 1n U.S. EPA, 1986c) OSHA (Occupational Safety and Health Administration). 1985. OSHA Safety and Health Standards. Code of Federal Regulations. 29: 1910-1000. (Cited In U.S. EPA, 1986c) Perrard, M.H. 1985. MutagenlcHy and toxlclty of chloroethylene oxide and chloroacetaldehyde. Exper1ent1a. 41: 676-677. Phillips, R.A., S.A. Zahler and A.J. Garro. 1980. Detection of mutagen- Induced lesions 1n Isolated ONA using a new Bacillus subtnis transforma- tion-based assay. Mutat. Res. 74(4): 267-281. (CHed 1n U.S. EPA, 1986c) Rannug, U., R. Goethe and C.A. Wachtmelster. 1976. The mutagenlclty of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetlc add, conceivable metabolites of vinyl chloride. Chem. Blol. Interact. 12: 251-263. (CHed 1n U.S. EPA, 1986c) Rosenkranz, H.S. 1977. MutagenlcHy of halogenated alkanes and their derivatives. Environ. Health Perspect. 21: 79-84. Stuckl, G. and T. Le1s1nger. 1983. Bacterial degradation of 2-chloro- ethanol proceeds via 2-chloroacet1c add. FEMS M1crob1ol. Lett. 16: 123-126. (Taken from CA98:120827v) 0086d -36- 07/05/88 ------- Swann, R.L., D.A. laskowskl, P.J. HeCall, K. Vander Kuy and H.J. Dlshburger. 1983. A rapid method for the estimation of the environmental parameters octanol/water partition coefficient, soil sorptlon constant, water to air ratio and water solubility. Res. Rev. 85: 17-28. Tuazon, E.G., R. Atkinson, A.M. Winer and J.N. Pitts, Jr. 1984. A study of the atmospheric reaction of l,3-d1chloropropene and other selected organo- chlorlne compounds. Arch. Environ. Contain. Toxlcol. 13: 691-700. U.S. EPA. 1977. Computer Print-out of Non-confidential Production Data from TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC. U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of Health Effect Assessment Chapter of the Consent Decree Water Criteria Documents. Federal Register. 45(31): 49347-49357. U.S. EPA 1984. Methodology and Guidelines for Reportable Quantity Deter- minations Based on Chronic Toxlclty Data. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Wash- ington, DC. U.S. EPA. 1986a. Methodology for Evaluating Carclnogenldty 1n Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102. Prepared by the Office of Health and Environmental Assessment, Carcinogen Assessment Group, Washington DC for the Office of Solid Waste and Emergency Response, Washington, DC. 0086d -37- 07/18/88 ------- U.S. EPA. 19865. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. U.S. EPA. 1986c. Health and Environmental Effects Profile for Chloroacet- aldehyde. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). CLOGP3 computer program. PC version. Office of Toxic Substances, Washington, DC. U.S. EPA. 1987b. Graphical Exposure Modeling System (GEMS). Fate of Atmospheric Pollutants (FAP). PC version. Office of Toxic Substances, Washington. DC. U.S. EPA. 1987c. Interim Methods for Development of Inhalation Reference Doses. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of A1r Quality Planning and Standards, Research Triangle Park, NC. U.S. EPA/NIH (National Institute of Health). 1987. OHM-TADS (Oil and Hazardous Materials Technical Assistance Data System). On-Hne computer data base. Van Duuren, B.L., B.M. Goldschmldt, G. Loewengart, et al. 1979. Cardno- genldty of halogenated oleflnlc and aliphatic hydrocarbons 1n mice. J. Natl. Cancer Inst. 63(6): 1433-1439. 0086d -38- 07/18/88 ------- Hlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc., Rahway. NO. p. 296. Zajdela, P., A. Crolsy. A. Barbln, C. Malavellle, L. Tomatlc and H. Bartsch. 1980. Carclnogenlclty of chloroethylene oxide, an ultimate reactive metabo- lite of vinyl chloride, and b1s(chloromethyl)ether after subcutaneous admin- istration and 1n Initiation-promotion experiments 1n mice. Cancer Res. 40(2): 352-356. 0086d -39- 07/18/88 ------- APPENDIX A LITERATURE SEARCHED This HEED 1s based on data Identified by computerized literature searches of the following: CHEMLINE TSCATS CASR online (U.S. EPA Chemical Activities Status Report) TOXLINE TOXLIT TOXLIT 65 RTECS OHM TADS STORET : SRC Environmental Fate Data Bases SANSS AQUIRE TSCAPP NTIS Federal Register CAS ONLINE (Chemistry and Aquatic) HSDB These searches were conducted In October 1987, and the following secondary sources were reviewed: ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1987. TLVs: Threshold Limit Values for Chemical Substances 1n the Work Environment adopted by ACGIH with Intended Changes for 1987-1988. Cincinnati, OH. 114 p. Clayton, G.D^ and F.E. Clayton, Ed. 1981. Patty's Industrial Hygiene and toxicology, 3rd rev. ed., Vol. 2A. John Wiley and Sons, NY. 2ff78 p. Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John WHey and Sons, NY. p. 2879-3816. Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and Sons, NY. p. 3817-5112. 0086d -40- 07/05/88 ------- Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo- pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23 Volumes. Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed. Publishing Sciences Group, Inc., Littleton, MA. 575 p. IARC (International Agency for Research on Cancer). IARC Mono- graphs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC, WHO, Lyons, France. Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson. 1984. Data acquisition for environmental transport and fate screening for compounds of Interest to the Office of Solid Waste. EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo Park, CA. NTP (National Toxicology Program). 1987. Toxicology Research and Testing Program. Chemicals on Standard Protocol. Management Status. Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide Register. McGraw-Hill Book Co., NY. Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van Nostrand Relrihold Co., NY. SRI (Stanford Research Institute). 1987. Directory of Chemical Producers. Menlo Park, CA. U.S. .EPA. 1986. Report on Status Report 1n the Special Review Program, Registration Standards Program and the Data Call 1n Programs. Registration Standards and the Data Call 1n Programs. Office of Pesticide Programs, Washington, DC. USITC (U.S. International Trade Commission). 1986. Synthetic Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ. 1392, Washington, DC. Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY. Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual. British Crop Protection Council. 695 p. Wlndholz, M.;. Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc., Rahway, NJ. 0086d -41- 07/05/88 ------- In addition, approximately 30 compendia of aquatic toxlclty data were reviewed, Including the following: Battelle's Columbus Laboratories. 1971. Water Quality Criteria Data Book. Volume 3. Effects of Chemicals on Aquatic Life. Selected Data from the Literature through 1968. Prepared for the U.S. EPA under Contract No. 68-01-0007. Washington, DC. Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty of Chemicals to F1sh and Aquatic Invertebrates. Summaries of Toxlclty Tests Conducted at Columbia National Fisheries Research Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife Serv. Res. Publ. 137, Washington, DC. McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed. Prepared for the Resources Agency of California, State Water Quality Control Board. Publ. No. 3-A. Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target Species. Prepared for the U.S. EPA, Washington, DC. PB-269605. Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S. EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876. 0086d -42- 07/05/88 ------- o o CD APPENDIX B Sunnary Table for Chloroacetaldehyde Inhalation Exposure Subchronlc Chronic 9 Species ! guinea pig guinea pig Exposure 5.1 mg/m*. 7 hours/day, 5 days/week (0.51 mg/kg/day) 5.1 mg/m*. 7 hours/day. 5 days/week (0.51 mg/kg/day) Effect RfD or qj* NOEL 0.4 rag/day or 0.02 rag/m» NOEL 0.04 rag/day or 0.002 mg/raa Reference Dow Chemical Company. 1962 Dow Chemical Company. 1962 Carclnogenlclty NO Oral Exposure. Subchronlc Chrpnlc CarclnogenlcHy guinea pig 5.1 og/m*. 7 hours/day. 5 days/week (0.51 mg/kg/day) guinea pig 5.1 aq/m*. 7 hours/day. 5 days/week (0.51 mg/kg/day) NOEL 0.003 mg/kg/day ' or 0.2 rog/day .V NOEL 0.0003 mg/kg/day or 0.02 rag/day NO Dow Chemical Company. 1962 Dow Chemical Company. 1962 REPORTABLE QUANTITIES Based on Chronic Toxlclty: NO Based on Carclnogenlclty: NO ND = Not determined O Ifl oo ------- |