This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.
Concise International Chemical Assessment Document 3
1,1,2,2-TETRACHLOROETHANE
First draft prepared by Ms K. Hughes and Ms M.E. Meek, Environmental Health Directorate, Health Canada
Please note that the layout and pagination of this pdf filea re not identical to the printed CICAD
Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization Geneva, 1998 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.
WHO Library Cataloguing in Publication Data
1,1,2,2-Tetrachloroethane.
(Concise international chemical assessment document ; 3)
1.Tetrachloroethylene – toxicity 2.Environmental exposure I.International Programme on Chemical Safety II.Series
ISBN 92 4 153003 0 (NLM Classification: QV 253) ISSN 1020-6167
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Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10 TABLE OF CONTENTS
FOREWORD ...... 1
1. EXECUTIVE SUMMARY ...... 4
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES ...... 5
3. ANALYTICAL METHODS ...... 5
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE ...... 5
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION ...... 5
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE ...... 6
6.1 Environmental levels ...... 6 6.2 Human exposure ...... 6
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS ...... 7
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS ...... 7
8.1 Single exposure ...... 7 8.2 Irritation and sensitization ...... 8 8.3 Short-term exposure ...... 8 8.4 Long-term exposure ...... 8 8.4.1 Subchronic exposure ...... 8 8.4.2 Chronic exposure and carcinogenicity ...... 8 8.5 Genotoxicity and related end-points ...... 10 8.6 Reproductive and developmental toxicity ...... 12 8.7 Immunological and neurological effects ...... 12
9. EFFECTS ON HUMANS ...... 12
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD ...... 13
10.1 Aquatic environment ...... 13 10.2 Terrestrial environment ...... 13
11. EFFECTS EVALUATION ...... 13
11.1 Evaluation of health effects ...... 13 11.1.1 Hazard identification and dose–response assessment ...... 13 11.1.2 Criteria for setting guidance values for 1,1,2,2-tetrachloroethane ...... 14 11.1.3 Sample risk characterization ...... 14 11.2 Evaluation of environmental effects ...... 15
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES ...... 15
iii Concise International Chemical Assessment Document 3
13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION ...... 15
13.1 Advice to physicians ...... 15 13.2 Health surveillance advice ...... 15 13.3 Prevention ...... 15 13.4 Spillage ...... 15
14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS ...... 16
INTERNATIONAL CHEMICAL SAFETY CARD ...... 17
REFERENCES ...... 19
APPENDIX 1 — SOURCE DOCUMENTS ...... 23
APPENDIX 2 — CICAD PEER REVIEW ...... 23
APPENDIX 3 — CICAD FINAL REVIEW BOARD ...... 24
RÉSUMÉ D’ORIENTATION ...... 25
RESUMEN DE ORIENTACIÓN ...... 27
iv 1,1,2,2-Tetrachloroethane
FOREWORD While every effort is made to ensure that CICADs represent the current status of knowledge, new informa- Concise International Chemical Assessment tion is being developed constantly. Unless otherwise Documents (CICADs) are the latest in a family of stated, CICADs are based on a search of the scientific publications from the International Programme on literature to the date shown in the executive summary. In Chemical Safety (IPCS) — a cooperative programme of the event that a reader becomes aware of new infor- the World Health Organization (WHO), the International mation that would change the conclusions drawn in a Labour Organisation (ILO), and the United Nations CICAD, the reader is requested to contact the IPCS to Environment Programme (UNEP). CICADs join the inform it of the new information. Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of Procedures chemicals. The flow chart shows the procedures followed to CICADs are concise documents that provide produce a CICAD. These procedures are designed to summaries of the relevant scientific information take advantage of the expertise that exists around the concerning the potential effects of chemicals upon world — expertise that is required to produce the high- human health and/or the environment. They are based quality evaluations of toxicological, exposure, and other on selected national or regional evaluation documents or data that are necessary for assessing risks to human on existing EHCs. Before acceptance for publication as health and/or the environment. CICADs by IPCS, these documents have undergone extensive peer review by internationally selected experts The first draft is based on an existing national, to ensure their completeness, accuracy in the way in regional, or international review. Authors of the first which the original data are represented, and the validity draft are usually, but not necessarily, from the institution of the conclusions drawn. that developed the original review. A standard outline has been developed to encourage consistency in form. The primary objective of CICADs is character- The first draft undergoes primary review by IPCS and ization of hazard and dose–response from exposure to a one or more experienced authors of criteria documents to chemical. CICADs are not a summary of all available ensure that it meets the specified criteria for CICADs. data on a particular chemical; rather, they include only that information considered critical for characterization The second stage involves international peer of the risk posed by the chemical. The critical studies review by scientists known for their particular expertise are, however, presented in sufficient detail to support and by scientists selected from an international roster the conclusions drawn. For additional information, the compiled by IPCS through recommendations from IPCS reader should consult the identified source documents national Contact Points and from IPCS Participating upon which the CICAD has been based. Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are Risks to human health and the environment will required to take reviewers’ comments into account and vary considerably depending upon the type and extent revise their draft, if necessary. The resulting second of exposure. Responsible authorities are strongly draft is submitted to a Final Review Board together with encouraged to characterize risk on the basis of locally the reviewers’ comments. measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk The CICAD Final Review Board has several characterization are provided in CICADs, whenever important functions: possible. These examples cannot be considered as representing all possible exposure situations, but are – to ensure that each CICAD has been subjected to provided as guidance only. The reader is referred to an appropriate and thorough peer review; EHC 1701 for advice on the derivation of health-based – to verify that the peer reviewers’ comments have guidance values. been addressed appropriately; – to provide guidance to those responsible for the preparation of CICADs on how to resolve any 1 International Programme on Chemical Safety (1994) remaining issues if, in the opinion of the Board, Assessing human health risks of chemicals: derivation the author has not adequately addressed all of guidance values for health-based exposure limits. comments of the reviewers; and Geneva, World Health Organization (Environmental – to approve CICADs as international assessments. Health Criteria 170).
1 Concise International Chemical Assessment Document 3
CICAD PREPARATION FLOW CHART
SELECTION OF PRIORITY CHEMICAL
SELECTION OF HIGH QUALITY NATIONAL/REGIONAL ASSESSMENT DOCUMENT(S)
FIRST DRAFT PREPARED
PRIMARY REVIEW AT PRODUCER LEVEL (1-2 OTHER DOCUMENT PRODUCERS) 1
RESPONSIBLE PRODUCER OFFICER (RO)
REVIEW BY IPCS CONTACT POINTS
REVIEW OF COMMENTS (PRODUCER/RO), PREPARATION OF SECOND DRAFT 2
FINAL REVIEW BOARD 3
FINAL DRAFT 4
EDITING
APPROVAL BY DIRECTOR, IPCS
PUBLICATION
1 Revision as necessary. 2 Taking into account the comments from reviewers. 3 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments (6-10 CICADs are usually reviewed at the Final Review Board). In the case of pesticides the role of the Final Review Board is fulfilled by a joint meeting on pesticides. 4 Includes any revisions requested by the Final Review Board.
2 1,1,2,2-Tetrachloroethane
Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.
Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.
3 Concise International Chemical Assessment Document 3
1. EXECUTIVE SUMMARY lowest-observed-(adverse)-effect level [NO(A)EL or LO(A)EL] for hepatotoxicity to be determined with confidence, minimal effects on the liver (reversible This CICAD on 1,1,2,2-tetrachloroethane was increase in lipid content) and other end-points (an prepared by the Environmental Health Directorate of increase in levels of adrenocorticotropic hormone and Health Canada and was based principally on a review reversible alterations in haematological parameters) have prepared by the Government of Canada (1993) to assess been observed in rats exposed to 13.3 mg/m3 for up to 9 the potential effects on human health of indirect expo- months. Based on limited, primarily range-finding sure to 1,1,2,2-tetrachloroethane in the general environ- studies and early investigations, reproductive and devel- ment and the chemical’s environmental effects, as well as opmental effects have been observed in experimental a review prepared by the Agency for Toxic Substances animals only at doses that caused reductions in body and Disease Registry (ATSDR, 1994) intended to weight. characterize information on adverse health effects and public exposure. Data identified as of September 1992 Long-term ingestion of 1,1,2,2-tetrachloroethane were considered in the Government of Canada (1993) resulted in an increased incidence of liver tumours in review. A comprehensive literature search of several on- both male and female B6C3F1 mice. However, similar line databases was conducted in August 1995 to identify exposure was not associated with a significant increase any references published subsequent to those incorpo- in tumours at any site in Osborne-Mendel rats, although rated in this review. Information on the nature of the both species were exposed only for up to 78 weeks. peer review and the availability of the source documents Based on the results of available in vivo and in vitro is presented in Appendix 1. Information on the peer assays, 1,1,2,2-tetrachloroethane has, at most, weak review of this CICAD is presented in Appendix 2. This genotoxic potential. 1,1,2,2-Tetrachloroethane was a CICAD was approved for publication at a meeting of the potent promoter, but not an initiator, of (-glutamyltrans- Final Review Board, held in Brussels, Belgium, on 18–20 peptidase-positive foci in the liver of rats. The profile for November 1996. Participants at the Final Review Board tumour induction by 1,1,2,2-tetrachloroethane is similar meeting are listed in Appendix 3. The International to that of dichloroacetic acid, its primary metabolite. Chemical Safety Card (ICSC 0332) for 1,1,2,2- Information on the mechanism of tumour induction by tetrachloroethane, produced by the International 1,1,2,2-tetrachloroethane is incomplete; for several of its Programme on Chemical Safety (IPCS, 1993), has also metabolites, it has been suggested that tumours are been reproduced in this document. likely induced by mechanisms for which there is a threshold. 1,1,2,2-Tetrachloroethane (CAS no. 79-34-5) is a volatile synthetic chemical that is used principally as an Exposure to 1,1,2,2-tetrachloroethane has been intermediate in the synthesis of other chlorinated hydro- demonstrated to inhibit the activities of environmental carbons, although use of this substance has declined bacteria (the lowest reported IC50 was 1.4 mg/litre) and significantly. Releases to the environment are primarily cause immobilization in Daphnia magna (48-hour EC50 in emissions to ambient air, where the chemical is likely values of 23 mg/litre and above). In freshwater fish to remain for several weeks. 1,1,2,2-Tetrachloroethane is species, the lowest reported LC50 (96 hours) was 18.5 not expected to contribute to the depletion of strato- mg/litre in flagfish (Jordanella floridae), whereas the spheric ozone or to global warming. It is rapidly lowest-observed-effect concentration (LOEC) for longer- removed from aquatic systems and is unlikely to term exposure was 7.2 mg/litre, which resulted in reduced bioaccumulate. Human exposure to 1,1,2,2-tetra- larval survival in the same species. No data were chloroethane is principally via inhalation. identified on the effects of this substance on terrestrial organisms. Very few data are available on the effects of exposure to 1,1,2,2-tetrachloroethane in humans. The In order to provide guidance to relevant authori- toxicological profile of 1,1,2,2-tetrachloroethane has also ties, sample guidance values have been determined on not been well characterized; because of the chemical’s the basis of the potency of 1,1,2,2-tetrachloroethane to declining use, available data are confined primarily to induce liver tumours in mice, as this is the toxicological early limited studies. The acute toxicity of 1,1,2,2- end-point for which the dose–response relationship is tetrachloroethane in experimental animals is slight to best characterized. It is noted, however, that observed moderate. Based on the results of principally limited increases in tumour incidence are currently restricted to short-term and subchronic studies, the liver appears to one species and that there are suggestive but incomplete be the most sensitive target organ. Although most of data indicating that tumours may be induced by a non- the available studies are inadequate to allow a no- or genotoxic mechanism. The potency, expressed as the
4 1,1,2,2-Tetrachloroethane
dose associated with a 5% increase in tumours, ranged (flame ionization or electron capture detection). from 5.8 to 28 mg/kg body weight per day. Sample Detection limits range from 0.7 ng/m3 to 0.3 mg/m3 guidance values for air (the principal source of human (ATSDR, 1994). Purge and trap methods followed by exposure), calculated on the basis of division of this gas chromatography (flame ionization, electron capture potency range by 5000 or 50 000, are 3.4–16 :g/m3 and electrolytic conductivity, or microcoulometric detection) 0.34–1.6 :g/m3. These values correspond to those are generally used for water as well as sediment, soil, or considered by some agencies to represent “essentially other solid samples. Reported detection limits range negligible” risk (i.e. 10–5 to 10–6) for a genotoxic carci- from 0.001 to 5 :g/litre for water and from 1 to 5 :g/kg nogen; it should be noted, however, that a smaller for soil and sediment samples (ATSDR, 1994). Detection margin may also be appropriate in view of the suggestive limits of 0.01 :g/litre and 0.06 ppbv (0.4 :g/m3) have but incomplete evidence for an epigenetic mechanism of been reported for solid-phase microextraction coupled tumour induction. Corresponding values for ingestion with gas chromatography/ion trap mass spectrometry are 1.2–5.6 :g/kg body weight per day and 0.12–0.56 analysis for water and air samples, respectively (Arthur :g/kg body weight per day. Based on a sample estimate et al., 1992; Chai & Pawliszyn, 1995). Gas of exposure, indirect exposure in the general environ- chromatography, often in combination with mass ment is less than these values, which are considered to spectrometry, is commonly used for quantifying 1,1,2,2- be conservative in view of the suggestive but tetrachloroethane in biological samples, with detection incomplete evidence that 1,1,2,2-tetrachloroethane may limits of 400 :g/kg in tissues and 5–500 ng/litre in blood induce tumours through a threshold mechanism. (ATSDR, 1994).
2. IDENTITY AND PHYSICAL/CHEMICAL 4. SOURCES OF HUMAN AND PROPERTIES ENVIRONMENTAL EXPOSURE
1,1,2,2-Tetrachloroethane (CAS no. 79-34-5; There are no known natural sources of 1,1,2,2-
Cl2CHCHCl2; acetylene tetrachloride, sym-tetrachlor- tetrachloroethane. The principal use of 1,1,2,2-tetra- ethane; see structural diagram below) is a synthetic chloroethane is as an intermediate in the manufacture of chemical that is a colourless, non-flammable liquid at other chlorinated hydrocarbons, such as vinyl chloride, room temperature. It is highly volatile, with a vapour 1,2-dichloroethane, trichloroethylene, and tetrachloro- pressure of 0.65 kPa at 20°C and water solubility of 2900 ethylene; in the past, it was also used as an industrial mg/litre at 20°C. The log octanol/water partition solvent and as a pesticide. Use, and hence production, coefficient for 1,1,2,2-tetrachloroethane is about 2.5, of 1,1,2,2-tetrachloroethane has declined significantly; whereas its Henry’s law constant was determined to no recent data on production were identified. Releases range from 0.0003 to 0.0009 m3•atm/mol (Tse et al., 1992; to the atmosphere through its use as a chemical interme- Government of Canada, 1993; Nichols et al., 1993). diate in Canada in 1990 were estimated to be approxi- Additional physical/chemical properties are presented in mately 246 kg (Government of Canada, 1993), whereas the International Chemical Safety Card (ICSC 0332) 64 251 pounds (29 144 kg) were estimated to be emitted reproduced in this document. to air from reporting industries in the USA in 1991 (ATSDR, 1994). In 1991, 953 kg of 1,1,2,2-tetrachloro- Cl Cl ethane were discharged to water from reporting facilities * * in the USA (ATSDR, 1994). Cl ) C ) C ) Cl * * H H 5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
3. ANALYTICAL METHODS 1,1,2,2-Tetrachloroethane is released to the environment primarily in emissions to ambient air. Based Analysis of 1,1,2,2-tetrachloroethane in air usually on its vapour pressure, it is not likely to be transferred to involves preconcentration on a sorbent tube followed by other compartments. The atmospheric lifetime for 1,1,2,2- thermal or solvent desorption or collection in a cryogen- tetrachloroethane reacting with hydroxyl radicals from ically cooled trap followed by gas chromatography moderately polluted areas is estimated to be between 43
5 Concise International Chemical Assessment Document 3
and 100 days, based on estimated and measured reaction :g/m3. Maximum concentrations of up to 79 :g/m3 have rates, respectively (Government of Canada, 1993). The been detected in the vicinity of waste sites in the USA half-life in the troposphere is estimated to be in excess of (ATSDR, 1994). 800 days, and diffusion into the stratosphere is expected to be slow.1 Based on these estimates, there is Although data are limited, levels of 1,1,2,2-tetra- significant potential for long-range transport of 1,1,2,2- chloroethane in surface waters in Canada, the USA, and tetrachloroethane. In the stratosphere, 1,1,2,2- Germany generally range from <0.005 to 4 :g/litre, from tetrachloroethane undergoes photolysis to produce <10 :g/litre to a maximum reported value of 180 :g/litre, chlorine radicals, which may subsequently react with and from <0.03 to 10 :g/litre, respectively; the chemical ozone; however, the ozone depletion potential for was not detected (detection limits 0.001–0.05 :g/litre) in 1,1,2,2-tetrachloroethane is very much less than 0.001 surface waters in Japan. relative to the standard CFC-11 (trichlorofluoromethane), based on the method developed by Nimitz & Skaggs 1,1,2,2-Tetrachloroethane was not detected in (1992). sediment in Japan in 1976 (detection limits ranged from 0.05 to 1 :g/g dry weight). 1,1,2,2-Tetrachloroethane released to the aquatic environment is rapidly removed via volatilization, with an 6.2 Human exposure estimated half-life of 6.2 hours from running water and 3.5 days from still water.1 Hydrolysis and biodegra- Exposure of the general population to 1,1,2,2- dation are the principal routes of removal from tetrachloroethane in environmental media may be groundwater. The hydrolysis half-life in subsurface estimated based on concentrations determined in various sediment at 25°C was determined to be 29 days (Haag & media and reference values for body weight and con- Mill, 1988). Neutral and base-catalysed hydrolyses of sumption patterns. Owing to the paucity of relevant 1,1,2,2-tetrachloroethane in pure water yielded tri- data from other countries, particularly for recent years, chloroethylene as essentially the sole degradation exposure has been estimated here based primarily on product (Haag & Mill, 1988). The products of anaerobic data from North America, as an example. However, biodegradation of 1,1,2,2-tetrachloroethane were deter- countries are encouraged to estimate total exposure on mined in a 6-week study to be (in decreasing order) cis- the basis of local data, possibly in a manner similar to 1,2-dichloroethylene, trans-1,2-dichloroethylene, that outlined here. trichloroethylene, 1,1,2-trichloroethane, 1,1- dichloroethylene, and vinyl chloride (Hallen et al., 1986). Mean levels in residential indoor air in Canada and the USA are generally below the limits of detection (i.e. 1,1,2,2-Tetrachloroethane is not expected to bio- <0.1 :g/m3; see Table 1). Based on a daily inhalation accumulate in aquatic species, based on low measured volume for adults of 22 m3, a mean body weight for males and calculated bioconcentration factors in fish (Govern- and females of 64 kg, the assumption that 4 of 24 hours ment of Canada, 1993). are spent outdoors (IPCS, 1994), and the range of mean levels of 1,1,2,2-tetrachloroethane in ambient air in recent surveys in Canada of <0.1–0.25 :g/m3, the mean intake of 1,1,2,2-tetrachloroethane from ambient air for the 6. ENVIRONMENTAL LEVELS AND general population is estimated to range from <0.006 to HUMAN EXPOSURE 0.01 :g/kg body weight per day. Average intake of 1,1,2,2-tetrachloroethane from indoor air, based on the assumption that 20 of 24 hours are spent indoors (IPCS, 6.1 Environmental levels 1994) and the mean concentration in residential indoor air in Canada and the USA of <0.1 :g/m3, is estimated to Data considered to be most representative of be <0.03 :g/kg body weight per day. current levels of 1,1,2,2-tetrachloroethane in environ- mental media are presented in Table 1. Mean concen- In a survey of 1159 household products in the trations of 1,1,2,2-tetrachloroethane in recent surveys of USA, 1,1,2,2-tetrachloroethane was not detected above ambient air in cities in Canada ranged from <0.1 to 0.25 the limit of detection of 0.1% (see Table 1).
1,1,2,2-Tetrachloroethane has not been detected in 1 Source: Hazardous Substances Data Bank, National recent surveys of drinking-water in Canada and has been Library of Medicine, Bethesda, MD, 1996. only extremely rarely detected (<0.03%) in recent surveys in the USA (detection limits 0.05–1.0 :g/litre; see Table 1 Source: Hazardous Substances Data Bank, National 1), although it was detected in groundwater near landfill Library of Medicine, Bethesda, MD, 1996. sites in Finland at levels ranging from <0.1 to 2.5 :g/litre
6 1,1,2,2-Tetrachloroethane
Table 1: Levels of 1,1,2,2-tetrachloroethane in various media.
Medium Location Year Concentrations Reference Ambient air Canada 1989–1990 <0.1–0.25 :g/m3 (means) Environment Canada, unpublished data, 1992 Ambient air USA pre-1987 0.7 :g/m3 (mean) Shah & Heyerdahl, 1988 Indoor air Canada 1991 <0.1 :g/m3 (mean) Fellin et al., 1992 Indoor air USA pre-1987 0.098 :g/m3 (mean) Shah & Heyerdahl, 1988 Drinking-water Canada 1988–1991 <0.05 :g/litre P. Lachmaniuk, personal communication, 1991 1990 <1.0 :g/litre Ecobichon & Allen, 1990 Drinking-water USA pre-1986 <0.5 :g/litre ATSDR, 1994 1984–1992 NDa–5.8 :g/litre Storm, 1994 Surface water Canada 1985 <1.0–4.0 :g/litre COARGLWQ, 1986 1981 <0.005–0.06 :g/litre Kaiser & Comba, 1983 Surface water USA 1980–1988 <10–180 :g/litre ATSDR, 1994 Surface water Japan 1976 <0.001, <0.002, <0.05 :g/litre Environment Agency Japan, 1976 Surface water Germany 1989–1990 <0.03–10 :g/litre Wittsiepe, 1990 Food (34 groups) Canada 1991 <50 :g/kg (solids), <1 :g/litre Enviro-Test Laboratories, 1991 (liquids) 1992 <5 :g/kg (solids), <1 :g/litre Enviro-Test Laboratories, 1992 (liquids) Food (231 items) USA <13 :g/kg, <20 :g/kg Daft, 1988 Consumer products USA <0.1% Sack et al., 1992 (1159 items) Sediment Japan 1976 <0.05 :g/g, <1 :g/g Environment Agency Japan, 1976 a Detection limit not specified.
(Assmuth & Strandberg, 1993). Similarly, it has not been 7. COMPARATIVE KINETICS AND detected in three surveys of foodstuffs in Canada and METABOLISM IN LABORATORY ANIMALS the USA (detection limits were 1 :g/litre for liquids and AND HUMANS 5–50 :g/kg for solids; see Table 1). No data were identified on levels of 1,1,2,2-tetrachloroethane in human breast milk. Drinking-water and food probably do not 1,1,2,2-Tetrachloroethane is readily absorbed represent significant sources of exposure to 1,1,2,2- following inhalation, ingestion, and dermal exposure and tetrachloroethane, based on its volatility and low is likely distributed throughout the body, although potential for bioaccumulation. relevant data are limited. Based on data on the metabo- (Assmuth & Strandberg, 1993). Similarly, it has not been lism of 1,1,2,2-tetrachloroethane in mice, Yllner (1971) detected in three surveys of foodstuffs in Canada and suggested that the principal pathway of degradation : the USA (detection limits were 1 g/litre for liquids and involves stagewise hydrolytic cleavage of the carbon– : 5–50 g/kg for solids; see Table 1). No data were chlorine bonds and oxidation to dichloroacetaldehyde identified on levels of 1,1,2,2-tetrachloroethane in human hydrate, dichloroacetic acid (the major metabolite), and breast milk. Drinking-water and food probably do not eventually glyoxylic acid. The glyoxylic acid is then represent significant sources of exposure to 1,1,2,2- metabolized to oxalic acid, glycine, formic acid, and tetrachloroethane, based on its volatility and low carbon dioxide. A small proportion of the parent potential for bioaccumulation. compound is probably non-enzymatically dehydro- Therefore, the principal media of exposure to chlorinated to trichloroethylene, which is further 1,1,2,2-tetrachloroethane for the general population are converted to trichloroacetic acid and trichloroethanol. In likely indoor and outdoor air, with negligible amounts addition, a minor amount of 1,1,2,2-tetrachloroethane being contributed by food and drinking-water. may be oxidized to tetrachloroethylene, which, in turn, is metabolized to trichloroacetic acid and oxalic acid. It has Although data on levels of 1,1,2,2-tetrachloro- also been proposed that 1,1,2,2-tetrachloroethane may be ethane in the workplace were not identified, workers may metabolized via cytochrome P-450 to dichloroacetyl be exposed to the substance via inhalation or dermal chloride, which is hydrolysed to dichloroacetic acid contact in “business services” (not further specified) as (Halpert, 1982). In addition to the liver, metabolism may well as the chemical and allied products industries also occur in the epithelia of the respiratory tract and (ATSDR, 1994). upper alimentary tract (Eriksson & Brittebo, 1991). The
7 Concise International Chemical Assessment Document 3 metabolites of 1,1,2,2-tetrachloroethane are eliminated in 8.4 Long-term exposure the urine, faeces, skin, and expired air. 8.4.1 Subchronic exposure
Only a few limited studies have been identified on 8. EFFECTS ON LABORATORY MAMMALS the effects in experimental animals following subchronic 1 AND IN VITRO TEST SYSTEMS exposure to 1,1,2,2-tetrachloroethane (see Table 2). Ingestion of up to 316 mg/kg body weight per day had no effects on body weight gain or mortality in groups of 8.1 Single exposure five male or female B6C3F1 mice, whereas doses of 100 (females) or 178 (males) mg/kg body weight per day and The acute toxicity of 1,1,2,2-tetrachloroethane in above resulted in decreased body weight gain in groups experimental animals is slight to moderate. Exposure to of five male or female Osborne-Mendel rats in sub- concentrations of around 1000 ppm (6980 mg/m3) for 4 or chronic studies preliminary to longer-term bioassays (no 6 hours or about 5000–6000 ppm (34 900–41 880 mg/m3) other end-points appear to have been examined) (NCI, (duration not specified) caused deaths in rats and mice, 1978). Histopathological damage (including chronic inflammation, necrosis, or atrophy) was observed in the respectively. Oral LD50s of 250–330 and 1000 mg/kg body weight for 1,1,2,2-tetrachloroethane in rats have liver, kidney, testicles, and thyroid gland of rats (n = 10 per group) administered oral 1,1,2,2-tetrachloroethane been reported. The dermal LD50 (24 hours) in rabbits was 6360 mg/kg body weight (Kennedy & Graepel, 1991; doses of 3.2–50 mg/kg body weight per day for periods ATSDR, 1994). ranging from 2 to 150 days (Gohlke et al., 1977), although the limited documentation of results in this study 8.2 Irritation and sensitization precludes validation of an effect level.
3 Epidermal and dermal changes were reported in Exposure to 1,1,2,2-tetrachloroethane at 50 mg/m rabbits following cutaneous exposure to 1,1,2,2-tetra- for approximately 5 weeks resulted in alterations in bio- chloroethane (Smyth et al., 1969). Exposure to 580 ppm chemical parameters and organ weights in male rats (4050 mg/m3) 1,1,2,2-tetrachloroethane caused ocular (strain and number not specified), although no “morpho- irritation in guinea-pigs (Price et al., 1978). No infor- logical changes” were noted upon examination (the mation on the sensitization potential of this substance nature and extent of the histopathological examination was identified. were unspecified) (Schmidt et al., 1975). Depressed agglutinin formation was observed in rabbits exposed to 3 8.3 Short-term exposure 100 mg/m , 3–4 hours/day, for 4–6 weeks (Navrotskiy et al., 1971) (no other effects were noted in this study, for In general, dose–response relationships have not which only secondary accounts were available). Hepatic been well characterized in available short-term studies in effects, including a transient increase in DNA synthesis, experimental animals owing to limitations of the studies, reversible histopathological changes (cytoplasmic including use of only one level of exposure or inade- vacuolization and hyperplasia), and an increase in relative liver weight, were observed in female Sprague- quate description of protocol or results. Hepatic effects, 3 including increased organ weight, congestion, fatty Dawley rats (n = 55) exposed for 15 weeks to 560 ml/m (reported by ATSDR [1994] to be equivalent to 130 ppm degeneration, histological changes, alterations in levels 3 of enzymes, and elevated DNA synthesis (the degree of [907 mg/m ], although information on the exposure level which increased with dose), have been observed in presented in the original paper was unclear) (Truffert et rodents following short-term inhalation of 1,1,2,2-tetra- al., 1977). chloroethane at concentrations as low as 13.3 mg/m3 (for 2–10 days) and ingestion of the chemical at doses as low as 75 mg/kg body weight per day (for 4 days) in the few 1 available, principally limited, studies (Horiuchi et al., Subchronic studies have been completed for the 1962; Gohlke & Schmidt, 1972; Schmidt et al., 1972; National Toxicology Program (NTP) in which groups of 10 male or female F344 rats and B6C3F mice were Hanley et al., 1988; NTP, 1996). In a limited account of a 1 study in rats, Ulanova et al. (1984) reported effects on administered microencapsulated 1,1,2,2- tetrachloroethane in feed at doses equivalent to 18–300 the nervous system and kidneys to be similar following continuous or intermittent exposure for 4–27 days to mg/kg body weight per day and 88–1400 mg/kg body comparable time-weighted-average concentrations of weight per day, respectively, for 13 weeks. The results 1,1,2,2-tetrachloroethane (235 and 250 mg/m3). of these studies are currently being reviewed by the NTP’s Pathology Working Group.
8 1,1,2,2-Tetrachloroethane
Table 2: Investigations of non-neoplastic effects of 1,1,2,2-tetrachloroethane.
Study design Effects Effect level Comments Reference INHALATION
Male rats exposed to 50 mg/m3, 4 Neurological effects; alterations in Effects at 50 Strain and number of rats not Schmidt et al., hours/day, 5 days/week, for 5 weeks; biochemical parameters and organ mg/m3 specified; nature and extent of 1975 or to 130 mg/m3 for 15 minutes, 5 weights (although within ranges histopathological examination not times/day, separated by 40-minute observed in controls); no specified intervals, for 5 weeks “morphological changes” Fifty-five female Sprague-Dawley rats Transient increase in hepatic DNA Effects at 560 One exposure group only; Truffert et al., exposed to 560 ml/m3 for 5 or 6 synthesis, reversible histopatho- ml/m3 uncertainty concerning exposure 1977 hours/day, 5 days/week, for 15 weeks; logical changes in the liver; increase (equivalent to level based on unclear liver, kidneys, lungs, ovaries, uterus, in relative liver weight 130 ppm or information in article (note: and adrenal glands histopathologically 907 mg/m3, concentration more than examined based on approximately 10-fold higher than ATSDR [1994] that at which effects were conversion) reported in other studies, no matter how converted) Male rats exposed to 13.3 mg/m3 Increased adrenocorticotropic Minimal Exposure pattern (e.g. number of Schmidt et al., (probably for 4 hours/day) for 110 or hormone activity in the hypophysis effects at exposed days per week) not 1972 265 days; one group exposed for 265 greatest at 4 months and lessened 13.3 mg/m3 clearly specified; histopatho- days and allowed to recover until day towards the end of the study; logical effects not described in 325; seven rats sacrificed after each reversible decrease in body weight; published account of study interval reversible increase in lipid content of liver and reversible alterations in haematological parameters, which were significantly different from controls only at one point in time during the study Rabbits exposed to 100 mg/m3 3–4 Depressed agglutinin formation after Effects at 100 Secondary accounts available Navrotskiy et hours/day for 4–6 weeks or exposed for 4–6 weeks; early signs of liver mg/m3 only; strain, number, and sex not al., 1971 7–11 months (different protocols noted degeneration after 7–11 months specified; may be only one in two secondary accounts) exposure level; no other effects noted Chinchilla rabbits exposed to 0, 2, 10, or Decrease in titres of typhoid Effects at 10 Sex and number of animals per Shmuter, 1977 100 mg/m3, 3 hours/day, 6 days/ week, antibodies, an increase in the mg/m3; no exposed group not specified for 8 months (n = 50 for controls) electrophoretic mobility of antibodies effects at 2 towards $- and "-globulin fractions, mg/m3 and a decrease in the level of “normal” haemolysins to the Forsman’s antigen of sheep erythrocytes Six rabbits were exposed to 10 mg/m3, 3 Decreased levels of acetylcholine Effects at 10 Isomer not specified; no end- Kulinskaya & hours/day, for approximately 8 months; and acetylcholinesterase in the mg/m3 points other than cholinergic Verlinskaya, 15 rabbits were used as controls; blood indices were investigated 1972 animals were immunized at 1.5 and 4.5 months with typhoid vaccine INGESTION Groups of 10 rats administered 3.2, Damage to liver, kidney, Effects at 3.2 Inadequate documentation of Gohlke et 8.0, 20, or 50 mg/kg body weight testicles, and thyroid gland mg/kg body protocol and results; no al., 1977 per day by gavage for 2–150 days (determined by histological, weight per quantitative data; not enzyme histochemical, and day reported in which dose groups histoautoradiographic effects were observed (some techniques) groups were also concomitantly exposed to high temperatures); not possible to verify effect level
Five male or female B6C3F1 mice No effects on body weight gain No effects at No end-points other than NCI, 1978 administered 0, 32, 56, 100, 178, or or mortality highest dose body weight and mortality 316 mg/kg body weight per day by of 316 mg/kg appear to have been gavage, 5 days/week, for 6 weeks, body weight examined followed by 2 weeks of observation per day Five male or female Osborne- Decrease in body weight gain in Effects at No end-points other than NCI, 1978 Mendel rats administered 0, 56, males at 178 mg/kg body weight 100 mg/kg body weight and mortality 100, 178, 316, or 562 mg/kg body per day and in females at 100 body weight appear to have been weight per day by gavage, 5 and 178 mg/kg body weight per per day; no examined; no data presented days/week, for 6 weeks, followed by day; all females exposed to 316 effects at 56 on effects on body weight 2 weeks of observation mg/kg body weight per day died; mg/kg body gain at two highest doses or one male exposed to 100 mg/kg weight per on mortality for other dose body weight per day died day groups
9 Concise International Chemical Assessment Document 3
Table 2: Continued Study design Effects Effect level Comments Reference
Fifty male or female B6C3F1 mice Slight dose-related decreases in Significance of decrease in NCI, 1978 (n = 20 in controls) administered body weight gain; dose-related body weight gain not time-weighted-average doses of 0, increases in mortality; no presented; no end-points 142, or 284 mg/kg body weight per increases in incidences of non- other than body weight, day by gavage, 5 days/week, for 78 neoplastic lesions mortality, or histopathology weeks, followed by 12 weeks of were examined observation Fifty male or female Osborne- Reversible dose-related Significance of decrease in NCI, 1978 Mendel rats (n = 20 in controls) decreases in body weight gain; body weight gain not administered time-weighted- increased mortality at higher presented; no end-points average doses of 0, 62, or 108 dose; no increases in incidences other than body weight, mg/kg body weight per day (male) of non-neoplastic lesions mortality, or histopathology or 0, 43, or 76 mg/kg body weight were examined per day (female) by gavage, 5 days/week, for 78 weeks, followed by 32 weeks of observation
8.4.2 Chronic exposure and carcinogenicity grade 1,1,2,2-tetrachloroethane in corn oil by gavage at time-weighted-average doses of 62 or 108 mg/kg body The chronic toxicity of 1,1,2,2-tetrachloroethane has not weight per day (males) and 43 or 76 mg/kg body weight been extensively investigated; available studies are not per day (females) for 78 weeks, although there were two adequate to allow the confident determination of an males with hepatocellular carcinomas and one with a “effect level” for non-neoplastic effects. A reversible hepatic neoplastic nodule in the high-dose group. There decrease in body weight and a reversible increase in lipid were also reversible dose-related decreases in body content of the liver were observed in male rats exposed weight gain and increased mortality in exposed rats (NCI, to 1,1,2,2-tetrachloroethane by inhalation at 13.3 mg/m3 1978). for 110 or 265 days or for 265 days with a 60-day recovery period (seven rats were killed at each interval); In a limited bioassay designed to investigate the there were also reversible alterations in haematological potential of 1,1,2,2-tetrachloroethane to induce pulmo- parameters, which were statistically significantly nary adenomas in a sensitive strain of mice, there was no different from controls only at one point in time during increase in the number of these tumours in a group of 20 the study, and increased adrenocorticotropic hormone strain A mice intraperitoneally administered the chemical activity in the hypophysis (Schmidt et al., 1972). for 24 weeks; however, mortality was high in this study However, histopathological effects were not described in (Theiss et al., 1977; Stoner, 1991). the published account of the investigation. In a study for which only secondary accounts were available, early In an initiation/promotion assay, 1,1,2,2-tetra- signs of liver degeneration were observed in rabbits chloroethane did not initiate formation of (-glutamyl- exposed to 100 mg/m3 for 7–11 months (Navrotskiy et al., transpeptidase-positive foci in the liver (a putative 1971) (no further details were provided). preneoplastic indicator) in groups of 10 male Osborne- An increase in the incidence of hepatocellular Mendel rats administered an oral dose of 100 mg/kg carcinomas was observed in groups of 50 (n = 20 in body weight followed by exposure to phenobarbital for 7 controls) male and female B6C3F1 mice administered weeks, although it acted as a potent promoter in rats technical-grade 1,1,2,2-tetrachloroethane in corn oil by initiated with a single dose of diethylnitrosamine gavage at time-weighted-average daily doses of 142 or followed by exposure to 1,1,2,2-tetrachloroethane by 284 mg/kg body weight for 78 weeks (1/18, 13/50, and gavage for 7 weeks at 100 mg/kg body weight per day 44/49 in males, and 0/20, 30/48, and 43/47 in females, in (Story et al., 1986; Milman et al., 1988). the vehicle controls, low-dose group, and high-dose group, respectively). These tumours also appeared Little information on the mechanism(s) of liver earlier in mice administered the higher dose. Slightly tumour induction in mice exposed to 1,1,2,2-tetrachloro- decreased body weight gain and increased mortality ethane has been identified. Several of the metabolites of were also observed in exposed mice; there were no 1,1,2,2-tetrachloroethane, including trichloroethylene, increases in the incidences of non-neoplastic lesions tetrachloroethylene, trichloroacetic acid, and dichloro- (NCI, 1978). acetic acid, have been hepatocarcinogenic in experimen- tal animals (e.g. NCI, 1977; Maltoni et al., 1986, 1988; There were no significant increases in the NTP, 1986, 1990; Herren-Freund et al., 1987; Bull et al., incidence of any type of neoplastic or non-neoplastic 1990; DeAngelo et al., 1991). Indeed, the toxicological lesion in groups of 50 (n = 20 in controls) male or female profile for 1,1,2,2-tetrachloroethane is very similar to that Osborne-Mendel rats similarly administered technical- for dichloroacetic acid, the principal metabolite.
10 1,1,2,2-Tetrachloroethane
8.5 Genotoxicity and related end-points DNA repair, or unscheduled synthesis of DNA in mammalian cells in vitro. Results of identified in vitro studies are summar- Exposure to 1,1,2,2-tetrachloroethane at 349 mg/m3 ized in Table 3. Predominantly negative results have for 5 days did not induce dominant lethal mutations in been reported for the induction of gene mutation in rats, and results for chromosomal aberrations in rat bone prokaryotic systems with and without metabolic marrow cells were equivocal; however, this activation, whereas both positive and negative results concentration did not induce cytotoxicity (McGregor, have been observed for gene conversions in yeast and 1980). 1,1,2,2-Tetrachloroethane did not induce fungi. 1,1,2,2-Tetrachloroethane induced sister unscheduled DNA synthesis in hepatocytes of mice chromatid exchange but not chromosomal aberrations, exposed to doses of up to 1000 mg/kg body weight by
Table 3: Genotoxicity of 1,1,2,2-tetrachloroethane in vitro. Result With Without Species (test system) End-point activation activation Reference
Saccharomyces cerevisiae D7 Mitotic gene conversion nt + Callen et al., 1980 Recombination nt + Saccharomyces cerevisiae D7 Gene conversion and reversion Nestmann and Lee, 1983 XV185-14C nt – nt – Salmonella typhimurium Reverse mutations Brem et al., 1974 TA1530 nt + TA1535 nt + TA1538 nt – Salmonella typhimurium Reverse mutations Nestmann et al., 1980 TA1535 – – TA100 – – TA1537 – – TA1538 – – TA98 – – Salmonella typhimurium Reverse mutations Milman et al., 1988 TA1535 – – TA1537 – – TA98 – – TA100 – – Salmonella typhimurium Reverse mutations Haworth et al., 1983 TA1535 – – TA1537 – – TA98 – – TA100 – – Salmonella typhimurium TA100 Reverse mutations – – Warner et al., 1988 Salmonella typhimurium Reverse mutations Mersch-Sundermann et al., TA97 + – 1989a TA98 + – TA100 – – TA102 – – Salmonella typhimurium Forward mutations – – Roldan-Arjona et al., 1991 BA13/BAL13 Escherichia coli (polymerase DNA damage nt + Brem et al., 1974 deficient pol A+/pol A–) Escherichia coli PQ37 Gene mutation – – Mersch-Sundermann et al., 1989b Escherichia coli Induction of prophage lambda + – DeMarini & Brooks, 1992 Aspergillus nidulans Mitotic malsegregation nt + Crebelli et al., 1988 Chinese hamster ovary cells Chromosomal aberrations – – Galloway et al., 1987 Chinese hamster ovary cells Sister chromatid exchange + + Galloway et al., 1987 BALB/c3T3 cells (mouse) Sister chromatid exchange + + Colacci et al., 1992 Mouse hepatocytes DNA growth, repair, or synthesis nt – Williams, 1983 Mouse hepatocytes DNA repair nt – Milman et al., 1988 Rat hepatocytes DNA growth, repair, or synthesis nt – Williams, 1983 Rat hepatocytes DNA repair nt – Milman et al., 1988 Human embryonic intestinal cells Unscheduled DNA synthesis – – McGregor, 1980 nt = not tested
11 Concise International Chemical Assessment Document 3 gavage, whereas results for the induction of S-phase increased resorptions were observed in range-finding synthesis were negative and equivocal (Mirsalis et al., studies in rats and mice exposed to 1,1,2,2- 1989). tetrachloroethane in the feed during gestation at doses 1,1,2,2-Tetrachloroethane has also been reported greater than those that induced maternal toxicity to bind to cellular macromolecules, including DNA, (increased mortality or decreased body weight gain) RNA, and proteins of several organs in rodents, (NTP, 1991a,b). following in vivo exposure (Mitoma et al., 1985; Colacci et al., 1987; Eriksson & Brittebo, 1991). Results for cell 8.7 Immunological and neurological transformation in mammalian cells have been mixed, with effects positive results being reported by only one of four investigators (Little, 1983; Tu et al., 1985; Milman et al., Immunological effects have been observed in 1988; Colacci et al., 1990, 1992, 1993). limited studies in rabbits exposed to 1,1,2,2-tetrachloro- ethane by inhalation. For example, Shmuter (1977) 1,1,2,2-Tetrachloroethane did not induce sex-linked reported a decrease in the titres of typhoid antibodies, recessive lethal mutations or mitotic recombination in an increase in the electrophoretic mobility of antibodies Drosophila melanogaster in three studies (McGregor, towards $- and "-globulin fractions, and a decrease in 1980; Woodruff et al., 1985; Vogel & Nivard, 1993). the level of “normal” haemolysins to the Forsman’s antigen of sheep erythrocytes in animals exposed to With the possible exception of the equivocal 1,1,2,2-tetrachloroethane at 10 mg/m3 and above for results for chromosomal aberrations observed in female 8 months, whereas alterations in levels of acetylcholine rats following inhalation (McGregor, 1980), the weight of and acetylcholinesterase in the blood have been evidence overall indicates that 1,1,2,2-tetrachloroethane observed at 10 mg/m3 (Kulinskaya & Verlinskaya, 1972). is not genotoxic or that it is only weakly genotoxic, acting through a mechanism that results in gene Neurological effects have been observed in several conversion and induction of sister chromatid exchange. species following acute or short-term exposure to 1,1,2,2- tetrachloroethane (e.g. at concentrations as low as 200 8.6 Reproductive and developmental ppm [1396 mg/m3] for 6 hours [Horvath & Frantik, 1973] toxicity or 50 mg/m3 for approximately 5 weeks [Schmidt et al., 1975]). A single oral dose of 50 mg/kg body weight Although available data are limited, reproductive increased levels of several neurotransmitters in the brain and developmental effects have been observed only in of rats (Kanada et al., 1994). experimental animals exposed orally or by inhalation to levels of 1,1,2,2-tetrachloroethane that are also associ- ated with decreases in body weight. Effects on repro- ductive parameters, including decreases in testicular, 9. EFFECTS ON HUMANS epididymal, and caudal weights, decreased epididymal sperm motility, and altered estrous cycles, were observed in pilot studies in rats and mice orally exposed Death has been reported following suicidal inges- for 90 days to doses that also caused significant tion of doses of 1,1,2,2-tetrachloroethane estimated to decreases in body weight (NTP, 1993). Although range from 285 to 6000 mg/kg body weight (ATSDR, histological changes in the testes have been observed in 1994). Hepatic effects and death have also been reported rats administered 1,1,2,2-tetrachloroethane doses of 8 following accidental poisoning with 1,1,2,2-tetra- mg/kg body weight per day in peanut oil by gavage for chloroethane. Other effects noted in earlier reports of 150 days (Gohlke et al., 1977), no effects on reproductive workers or volunteers exposed to 1,1,2,2-tetrachloro- organs were reported in the long-term studies in which ethane concentrations ranging up to 1800 mg/m3 include rats and mice were administered much higher doses for respiratory failure, mucosal irritation, unconsciousness, 78 weeks (NCI, 1978) (see section 8.4.2) or in inhalation gastrointestinal and neurological distress, jaundice, liver studies in rats (Gohlke & Schmidt, 1972; Schmidt et al., enlargement or degeneration, headache, tremors, dizzi- 1972) or a single monkey (Horiuchi et al., 1962). No ness, numbness, and drowsiness (ATSDR, 1994). effect on male fertility or viability and no macroscopic changes in offspring were observed in male rats exposed No statistically significant increase in mortality to 13.3 mg/m3 for 258 days (Schmidt et al., 1972). Small, due to any specific cause was noted in a limited epidemi- but statistically significant, increases in one type of ological investigation in a population of 1099 men sperm abnormality were observed in rats exposed to 349 exposed to unknown concentrations of “tetrachloro- mg/m3 for 5 days, although the authors considered this ethane” (Norman et al., 1981). The prevalence of effect to be of questionable biological significance nervous symptoms, including tremors, headaches, and (McGregor, 1980). Decreased fetal body weight and/or
12 1,1,2,2-Tetrachloroethane
vertigo, was reported to increase with airborne concen- as the end-point, the 48-hour EC50 values were 23 and 25 tration of 1,1,2,2-tetrachloroethane (up to 98 ppm [684 mg/litre for unfed and fed D. magna, respectively. mg/m3]) in a group of 380 workers in India exposed for LeBlanc (1980) conducted a similar test with D. magna at varying durations, although no information was 22°C and reported nominal 24-hour and 48-hour LC50 presented on the prevalence of these signs in an unex- values of 18 and 9.3 mg/litre, respectively. Pawlisz & posed group. Exposed workers also reported loss of Peters (1995) reported that prior exposure of D. magna to appetite, nausea, vomiting, and abdominal pain (Lobo- sublethal concentrations of 1,1,2,2-tetrachloroethane
Mendonca, 1963). Similar symptoms (i.e. loss of (6.3–50% of the 48-hour LC50 of 0.095 mmol/litre) for 24 appetite, bad taste in the mouth, epigastric pain, sensa- hours did not influence the body burden required to tion of pressure in the liver area, headaches, general narcoticize the animals upon subsequent exposure to the debility, lack of stamina, loss of body weight, and occa- chemical at the LC50. sional painful prurigo) were observed in employees of a penicillin plant exposed to concentrations of 1,1,2,2- The measured 28-day LOEC and no-observed- tetrachloroethane ranging from 10 to 1700 mg/m3. The effect concentration (NOEC) for reproductive impairment prevalence of symptoms decreased with the implemen- in D. magna were 14.4 and 6.9 mg/litre, respectively, tation of improvements in working conditions, and most under flow-through conditions (Richter et al., 1983). workers were reported to be free of symptoms when maximum levels were below 250 mg/m3 (Jeney et al., Numerous acute toxicity studies have been con- 1957). ducted on a variety of freshwater fish species; in gener-
al, 96-hour LC50 values were very similar. Under flow- through conditions, the measured 96-hour LC50s for 30- 10. EFFECTS ON OTHER ORGANISMS IN day-old fathead minnows (Pimephales promelas) were THE LABORATORY AND FIELD 20.3 and 20.4 mg/litre (Veith et al., 1983; Walbridge et al., 1983). In juvenile (2- to 4-month-old) flagfish, the
measured 96-hour LC50 for 1,1,2,2-tetrachloroethane in 10.1 Aquatic environment the flow-through toxicity test was 18.5 mg/litre; the nominal LC50 value in a static-renewal 96-hour toxicity Bioassays were conducted by Blum & Speece test was 26.8 mg/litre (ATRG, 1988; Smith et al., 1991). No (1991) on three groups of bacteria: methanogens adequate acute toxicity studies of marine fish were (anaerobes from an enrichment culture maintained for identified. >10 years), aerobic heterotrophic bacteria, and Nitroso- monas obtained from the mixed liquor of an activated Chronic toxicity studies under flow-through test sludge wastewater treatment plant. Inhibition of gas conditions were conducted on the early life stages of production by methanogens, inhibition of oxygen uptake flagfish by ATRG (1988) and Smith et al. (1991). Egg by aerobic heterotrophic bacteria, and inhibition of hatchability was unaffected at a measured 1,1,2,2-tetra- ammonia oxidation by Nitrosomonas were the end- chloroethane concentration of 22.0 mg/litre, the highest points used in this study to evaluate toxicity. Varying concentration tested in both studies. The measured degrees of sensitivities were exhibited; however, LOECs for reduced 10-day larval survival were 10.6 and 7.2 mg/litre, whereas the LOECs for 28-day juvenile Nitrosomonas, with an IC50 value of 1.4 mg/litre, was survival were 11.7 and 8.5 mg/litre (ATRG, 1988; Smith et more sensitive than methanogens (IC50 value of 4.1 mg/litre) and significantly more sensitive than aerobic al., 1991). There were no statistically significant effects on the growth of 1-week-old fry over a 28-day exposure heterotrophs (IC50 value of 130 mg/litre). period, even at the highest concentration of 1,1,2,2- tetrachloroethane tested (11.7 mg/litre). Based on bioluminescence, the 5-minute LC50 for 1,1,2,2-tetrachloroethane was 5.4 mg/litre in a Microtox test using Photobacterium phosphoreum (Blum & Ninety-day carcinogenicity studies were con- Speece, 1991). ducted under flow-through conditions on 2-day-old guppy (Poecilia reticulata) and 6-day-old Japanese Unfed and fed Daphnia magna (first instar, <24 medaka (Oryzias latipes) exposed continuously to 1,1,2,2-tetrachloroethane at 4 mg/litre, exposed once per hours old) had similar measured 48-hour LC50 values of 62 and 57 mg/litre, respectively, under static test condi- week (24 hours) to 8 mg/litre, or exposed once per week tions (Richter et al., 1983). With complete immobilization (24 hours) to 15 mg/litre. Histopathological examination
13 Concise International Chemical Assessment Document 3 of all exposed groups at 90 days did not reveal any 1,1,2,2-Tetrachloroethane was a potent promoter, but did evidence of carcinogenicity (Hawkins, 1991). not act as an initiator, in an initiation/promotion assay. The weight of evidence of available in vitro and in vivo 10.2 Terrestrial environment assays suggests that this substance is not genotoxic or that it is, at most, weakly genotoxic. Although available No studies were identified on the effects of 1,1,2,2- data are incomplete, it has been proposed that the liver tetrachloroethane on terrestrial organisms. tumours may be induced by mechanisms that may not be relevant to humans, for which humans are less susceptible, or for which there may be a threshold of exposure. In addition, it has been hypothesized that the 11. EFFECTS EVALUATION carcinogenicity of 1,1,2,2-tetrachloroethane may be associated with the formation of free radicals, lipid peroxidation, or hepatic damage (such as focal necrosis 11.1 Evaluation of health effects associated with intense cellular proliferation) (Hanley et al., 1988; Larson & Bull, 1992; Paolini et al., 1992). 11.1.1 Hazard identification and dose–response Therefore, on the basis of data currently available, it is assessment not possible to draw any firm conclusions with respect to the potential carcinogenicity of 1,1,2,2-tetrachloro- Owing to the significant decline in the use of this ethane in humans. substance, the toxicological profile of 1,1,2,2-tetrachloro- ethane has not been well characterized, with the Owing to the limitations of available studies on the available data being confined primarily to early limited potential toxicological effects associated with exposure studies. to 1,1,2,2-tetrachloroethane, it is not possible to confi- dently determine a NO(A)EL or LO(A)EL for non- Based on the results of studies in experimental neoplastic effects. The toxicological end-point for which animals, the acute toxicity of 1,1,2,2-tetrachloroethane is the dose–response relationship is best characterized is slight to moderate. The chemical may induce skin, eye, the increase in hepatocellular carcinomas observed in and mucosal irritation. Owing to the limitations of the the long-term bioassay in mice (NCI, 1978). It is noted, available data in humans on effects associated with however, that the observed increases in tumour longer-term exposure to 1,1,2,2-tetrachloroethane, it is incidence are restricted to one species and that the necessary to rely on information obtained from the weight of available data indicates that 1,1,2,2- limited studies in animals for determination of the critical tetrachloroethane is, at most, weakly genotoxic. effects and associated effect levels. Based on multistage modelling of the incidence of The results of available studies on the non- hepatocellular carcinomas in male or female mice exposed neoplastic effects of 1,1,2,2-tetrachloroethane in experi- to time-weighted-average doses of 0, 142, or 284 mg/kg mental animals exposed by ingestion or inhalation body weight per day for up to 78 weeks, adjusted for indicate that the liver is the principal target organ. continuous exposure for a standard duration of 104 However, the majority of subchronic and chronic studies weeks and corrected for the expected rate of increase in are too limited to allow a confident determination of a tumour formation in rodents in a standard bioassay of NO(A)EL or LO(A)EL for hepatic or other effects, 104 weeks, the doses associated with a 5% increase in because of either the lack of information presented in the tumour incidence (TD0.05) range from 5.8 to 28 mg/kg published accounts or the limitations of the study body weight per day. designs (e.g. small numbers of animals per experimental group, lack of histopathological examination, etc.). 11.1.2 Criteria for setting guidance values for 1,1,2,2-tetrachloroethane Long-term exposure to 1,1,2,2-tetrachloroethane resulted in a significantly increased incidence of As noted in section 11.1.1, the toxicological end- hepatocellular carcinomas in both male and female mice. point for which the dose–response relationship is best However, no significant increases in tumours were characterized, and which might provide the basis for observed in similarly exposed rats, although there was a derivation of limits of exposure or for judgement of the non-statistically significant increase at the highest dose quality of environmental media by relevant authorities, is tested (which was lower, on a time-weighted-average the increase in hepatocellular carcinomas observed in basis, than the lowest dose to which mice were exposed), the long-term bioassay in mice (NCI, 1978). and both species were exposed only for up to 78 weeks.
14 1,1,2,2-Tetrachloroethane
A value, for example, 5000 or 50 000 times less than 11.2 Evaluation of environmental effects the TD0.05s derived above might be considered conservative as a guidance value. This margin (5000– 1,1,2,2-Tetrachloroethane is released to the 50 000) affords protection similar to that associated with environment principally in emissions to ambient air, the range for low-dose risk estimates generally consid- where it is moderately persistent. Because of its ered by various agencies to be “essentially negligible” volatility, rapid photo-oxidation in the atmosphere, and (i.e. 10–5 to 10–6). As, on the basis of available data, an atmospheric ozone-depleting potential of less than 1,1,2,2-tetrachloroethane is, at most, weakly genotoxic, a 0.001 relative to CFC-11, 1,1,2,2-tetrachloroethane is not smaller margin (e.g. 1000) might also be considered expected to contribute significantly either to the appropriate. As available data indicate that air is the depletion of the stratospheric ozone layer or to global principal medium of human exposure, the most conserva- warming. tive of these approaches result in, for example, a range of airborne concentrations of 3.4–16 :g/m3 or 0.34–1.6 Terrestrial organisms have the greatest potential :g/m3, respectively. Corresponding values for ingestion for exposure to 1,1,2,2-tetrachloroethane in ambient air in are 1.2–5.6 :g/kg body weight per day or 0.12–0.56 the environment. However, no data were identified on :g/kg body weight per day. It should be noted, how- the effects of 1,1,2,2-tetrachloroethane in terrestrial ever, that these possible guidance values for air have species. Therefore, it is not possible to characterize the been extrapolated directly from a study in which the risk to these organisms associated with levels of 1,1,2,2- chemical was administered orally to experimental animals. tetrachloroethane present in the environment. Although there may be substantial variations in toxicokinetics following exposure to 1,1,2,2-tetrachloro- Although 1,1,2,2-tetrachloroethane may be ethane by different routes, available data are inadequate released to surface waters in industrial effluents, it is to quantitatively account for these differences in the rapidly removed by volatilization. Based on the results derivation of guidance values. of several studies in aquatic bacteria, invertebrates, and fish, effect levels are generally greater than 1 mg/litre. It is noteworthy that a provisional tolerable con- Although data are limited, concentrations of 1,1,2,2- centration derived on the basis of the minimal non- tetrachloroethane in surface waters are generally much neoplastic effects observed in rats exposed to 13.3 mg/m3 less than this value (at least two orders of magnitude). (Schmidt et al., 1972) would fall within the range of the Therefore, it is likely that 1,1,2,2-tetrachloroethane does values presented here. not pose significant risk to aquatic organisms.
11.1.3 Sample risk characterization
Although data are insufficient to allow the confi- 12. PREVIOUS EVALUATIONS BY dent determination of a LO(A)EL or NO(A)EL for 1,1,2,2- INTERNATIONAL BODIES tetrachloroethane, minimal effects in rodents have been observed only at levels more than 50 000 times greater than those in the principal medium of exposure (air) in The International Agency for Research on Cancer the general environment. (IARC, 1987) has classified 1,1,2,2-tetrachloroethane in group 3 (not classifiable as to its carcinogenicity to Based on a sample estimate of exposure, indirect humans), based on inadequate evidence of carcinogen- exposure in the general environment is 14 to >160 or 1.4 icity in humans and limited evidence in animals. to >16 times less than guidance values that might be derived on the basis of available data on the dose– Information on international hazard classification response relationship for liver tumour induction in mice and labelling is included in the International Chemical (i.e. the TD0.05s divided by 5000 or 50 000, or 3.4–16 Safety Card reproduced in this document. :g/m3 or 0.34–1.6 :g/m3, respectively). It should also be noted, however, that indirect exposure in the general environment is likely overestimated here, as it is based on the range of mean concentrations for detected values, although 1,1,2,2-tetrachloroethane was detected in only approximately 50% of samples.
15 Concise International Chemical Assessment Document 3
13. HUMAN HEALTH PROTECTION AND 14. CURRENT REGULATIONS, EMERGENCY ACTION GUIDELINES, AND STANDARDS
Human health hazards, together with preventative Information on national regulations, guidelines, and protective measures and first aid recommendations, and standards is available from the International Register are presented in the International Chemical Safety Card of Potentially Toxic Chemicals (IRPTC) legal file. (ICSC 0332) reproduced in this document. The reader should be aware that regulatory 13.1 Advice to physicians decisions about chemicals taken in a certain country can be fully understood only in the framework of the In case of emergency, it is important to wash skin legislation of that country. The regulations and with soap and water after removing contaminated guidelines of all countries are subject to change and clothing. Like others of this class, 1,1,2,2-tetrachloro- should always be verified with appropriate regulatory ethane could generate some hyperexcitability of the authorities before application. heart. The prognosis following intoxication with this chemical is that rapid progression of jaundice indicates a poor outcome. In some instances, mild symptoms will persist up to 3 months and then progress to acute yellow atrophy and death. Anuria may persist for as long as 2 weeks and still be followed by complete recovery.
13.2 Health surveillance advice
Annual blood counts and monitoring of both liver and kidney function should be included in a health surveillance programme of individuals exposed to 1,1,2,2- tetrachloroethane.
13.3 Prevention
Because 1,1,2,2-tetrachloroethane decomposes on burning, maintenance workers must wait until all liquid and vapour have been cleared from the container or piping before performing any duty that generates heat.
Fire-fighters need to wear chemical-resistant clothing and positive self-contained breathing apparatus.
13.4 Spillage
It is very important in the case of spillage to use full protection, including respiratory protection, because 1,1,2,2-tetrachloroethane passes through the skin and, under the influence of air, moisture, and ultraviolet light, will decompose, producing toxic and corrosive gases, such as hydrogen chloride and phosgene.
The IDLH (Immediately Dangerous to Life or Health) value for this substance is very low, at 100 ppm (698 mg/m3) (NIOSH, 1994).
16 1,1,2,2-TETRACHLOROETHANE 0332 March 1995 CAS No: 79-34-5 Acetylene tetrachloride RTECS No: KI8575000 Symmetrical-tetrachloroethane UN No: 1702 S-tetrachloroethane
EC No: 602-015-00-3 CHCl2CHCl2 Molecular mass: 167.9
TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE
FIRE Not flammable. Gives off irritating NO open flames. In case of fire in the surroundings: or toxic fumes (or gases) in a fire. all extinguishing agents allowed.
EXPLOSION In case of fire: keep drums, etc., cool by spraying with water.
EXPOSURE STRICT HYGIENE!
Inhalation Abdominal pain. Cough. Ventilation, local exhaust, or Fresh air, rest. Artificial respiration Dizziness. Headache. Nausea. breathing protection. if indicated. Refer for medical Sore throat. Vomiting. attention.
Skin MAY BE ABSORBED! Dry skin. Protective gloves. Protective Remove contaminated clothes. Tremors (further see Inhalation). clothing. Rinse skin with plenty of water or shower. Refer for medical attention.
Eyes Redness. Pain. Face shield or eye protection in First rinse with plenty of water for combination with breathing several minutes (remove contact protection. lenses if easily possible), then take to a doctor.
Ingestion Abdominal pain. Nausea. Vomiting Do not eat, drink, or smoke during Do NOT induce vomiting. Rest. (further see Inhalation). work. Refer for medical attention.
SPILLAGE DISPOSAL PACKAGING & LABELLING
Ventilation. Collect leaking and spilled liquid in T+ Symbol Airtight. Do not transport with food sealable containers as far as possible. Absorb R: 26/27-51/53 and feedstuffs. Marine pollutant. remaining liquid in sand or inert absorbent and S: (1/2-)38-45-61 remove to safe place. Do NOT let this chemical UN Hazard Class: 6.1 enter the environment (extra personal protection: UN Pack Group: II complete protective clothing including self-contained breathing apparatus).
EMERGENCY RESPONSE STORAGE
Transport Emergency Card: TEC (R)-719 Separated from strong bases, food and feedstuffs. Cool. Keep in the dark. NFPA Code: H3; F0; R1 Well closed. Keep in a well-ventilated room.
Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 1999 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 0332 1,1,2,2-TETRACHLOROETHANE
IMPORTANT DATA
Physical State; Appearance Routes of Exposure COLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR. The substance can be absorbed into the body by inhalation of its vapour, through the skin and by ingestion. Physical Dangers The vapour is heavier than air. Inhalation Risk A harmful contamination of the air can be reached rather Chemical Dangers quickly on evaporation of this substance at 20C. The substance decomposes on burning under influence of air, moisture and UV light, producing toxic and corrosive gases Effects of Short-term Exposure including hydrogen chloride and phosgene. Reacts violently The substance irritates the eyes and the respiratory tract. The with alkali metals, strong bases and many powdered metals substance may cause effects on the central nervous system, producing toxic and explosive gases. Attacks plastic and kidneys and liver, resulting in depression of the central nervous rubber. system, kidney impairment and liver impairment. Exposure may result in unconsciousness. Exposure may result in death. Occupational Exposure Limits TLV: 1 ppm; 6.9 mg/m3 (as TWA) (skin) (ACGIH 1994-1995). Effects of Long-term or Repeated Exposure MAK: 1 ppm; 7 mg/m3; skin, B (1992). The liquid defats the skin. The substance may have effects on the central nervous system and liver, resulting in impaired functions.
PHYSICAL PROPERTIES
Boiling point: 146C Vapour pressure, Pa at 25C: 780 Melting point: -44C Relative vapour density (air = 1): 5.8 Relative density (water = 1): 1.6 Relative density of the vapour/air-mixture at 20C (air = 1): 1.031 Solubility in water, g/100 ml at 20C: 0.29 Octanol/water partition coefficient as log Pow: 2.39
ENVIRONMENTAL DATA The substance is toxic to aquatic organisms. This substance may be hazardous to the environment; special attention should be given to its impact on the ozone layer.
NOTES Use of alcoholic beverages enhances the harmful effect. The odour warning when the exposure limit value is exceeded is insufficient. Do NOT use in the vicinity of a fire or a hot surface, or during welding.
ADDITIONAL INFORMATION
LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information
© IPCS 1999 1,1,2,2-Tetrachloroethane
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20 1,1,2,2-Tetrachloroethane and ethylenes. Annals of the New York Academy of Sciences, NTP (1990) Carcinogenesis studies of trichloroethylene (without 534:521–530. epichlorohydrin) (CAS No. 79-01-6) in F344/N rats and B6C3F1 mice (gavage studies). Research Triangle Park, NC, US Mirsalis JC, Tyson CK, Steinmetz KL, Loh EK, Hamilton CM, Department of Health and Human Services, National Institutes of Bakke JP, Spalding JW (1989) Measurement of unscheduled Health, National Toxicology Program (NTP TR 243). DNA synthesis and S-phase synthesis in rodent hepatocytes following in vivo treatment; testing of 24 compounds. NTP (1991a) Range finding studies: developmental toxicity — Environmental and molecular mutagenesis, 14:155–164. 1,1,2,2-tetrachloroethane when administered via feed in CD Sprague-Dawley rats. Research Triangle Park, NC, US Mitoma C, Steeger T, Jackson SE, Wheeler KP, Rogers JH, Department of Health and Human Services, National Institutes of Milman HA (1985) Metabolic disposition study of chlorinated Health, National Toxicology Program (NTP-91-RF/DT-017). hydrocarbons in rats and mice. Drug chemistry and toxicology, 8(3):183–194. NTP (1991b) Range finding studies: developmental toxicity — 1,1,2,2-tetrachloroethane (repeat) when administered via feed in Navrotskiy VK, Kashin LM, Kulinskoya IL (1971) [Comparative Swiss CD-1 mice. Research Triangle Park, NC, US Department of assessment of the toxicity of a number of industrial poisons when Health and Human Services, National Institutes of Health, inhaled in low concentrations for prolonged periods.] Trudy Szed National Toxicology Program (NTP-91-RF/DT-020). Gigiena Ukrainskoi, 8:224–226 (in Russian) [cited in ATSDR, 1994]. NTP (1993) 1,1,2,2-Tetrachloroethane. C: C3554. Sperm motility vaginal cytology evaluation in rodents. 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Paolini M, Sapigni E, Mesirca R, Pedulli GF, Corongiu FP, Dessi Nestmann ER, Lee EG-H (1983) Mutagenicity of constituents of MA, Cantelli-Forti G (1992) On the hepatotoxicity of 1,1,2,2- pulp and paper mill effluent in growing cells of Saccharomyces tetrachloroethane. Toxicology, 73:101–115. cerevisiae. Mutation research, 119:273–280. Pawlisz AV, Peters RH (1995) Effects of sublethal exposure on Nestmann ER, Lee EG-H, Matula TI, Douglas GR, Mueller JC lethal body burdens of narcotic organic chemicals in Daphnia (1980) Mutagenicity of constituents identified in pulp and paper magna. Environmental science and technology, 29(3):613–621. mill effluents using the Salmonella mammalian-microsome assay. Mutation research, 79:203–212. Price NH, Allen SD, Daniels AU, Yates WG (1978) Toxicity data for establishing “immediately dangerous to life or health” (IDLH) Nichols JW, McKim JM, Lien GJ, Hoffman AD, Bertelsen SL, values (NTIS PB87-163531) [cited in ATSDR, 1994]. Gallinat CA (1993) Physiologically-based toxicokinetic modelling of three waterborne chloroethanes in channel catfish, Richter JE, Peterson SF, Kleiner CF (1983) Acute and chronic Ictalurus punctatus. Aquatic toxicology, 27:83–112. toxicity of some chlorinated benzenes, chlorinated ethanes, and tetrachloroethylene to Daphnia magna. Archives of Nimitz JS, Skaggs SR (1992) Estimating tropospheric lifetimes environmental contamination and toxicology, 12:679–684. and ozone-depletion potentials of one- and two-carbon hydrofluorocarbons and hydrochlorofluorocarbons. Environmental Roldan-Arjona T, Garcia-Pedrajas MD, Luque-Romero FL, Hera science and technology, 26(4):739–744. C, Pueyo C (1991) An association between mutagenicity of the Ara test of Salmonella typhimurium and carcinogenicity in NIOSH (1994) NIOSH pocket guide to chemical hazards. US rodents for 16 halogenated aliphatic hydrocarbons. Department of Health and Human Services, Public Health Mutagenesis, 6(3):199–205. 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Gigiena Truda i Professional’nye Zabolevaniya, 2:30–34 (in Veith GD, Call DJ, Brooke LT (1983) Structure–toxicity Russian). relationships for the fathead minnow, Pimephales promelas: Narcotic industrial chemicals. Canadian journal of fisheries and Shah JJ, Heyerdahl EK (1988) National ambient volatile organic aquatic sciences, 40:743–748. compounds (VOCs) database update. Report prepared by Nero and Associates, Inc., Portland, OR, for Office of Research and Vogel EW, Nivard MJM (1993) Performance of 181 chemicals in Development, US Environmental Protection Agency, Research a Drosophila assay predominantly monitoring interchromosomal Triangle Park, NC (EPA/600/3-88-010a; NTIS No. PB88- mitotic recombination. Mutagenesis, 8(1):57–81. 195631). Walbridge CT, Fiandt JT, Phipps GL, Holcombe GW (1983) Shmuter LM (1977) [The effect of chronic exposure to low Acute toxicity of ten chlorinated aliphatic hydrocarbons to the concentration of ethane series chlorinated hydrocarbons on fathead minnow (Pimephales promelas). Archives of specific and nonspecific immunological reactivity in animal environmental contamination and toxicology, 12:661–666. experiments.] Gigiena Truda i Professional’nye Zabolevaniya, 8:38–43 (in Russian). Warner JR, Hughes TJ, Claxton LD (1988) Mutagenicity of 16 volatile organic chemicals in a vaporization technique with Smith AD, Bharath A, Mallard C, Orr D, Smith K, Sutton JA, Salmonella typhimurium TA100. Environmental and molecular Vukmanich J, McCarty LS, Ozburn GW (1991) The acute and mutagenesis, 11 (Suppl. 11):111. chronic toxicity of ten chlorinated organic compounds to the American flagfish (Jordanella floridae). Archives of Williams G (1983) DNA repair tests of 11 chlorinated environmental contamination and toxicology, 20:94–102. hydrocarbon analogs final report EPA contract. US Environmental Protection Agency, Office of Toxic Substances Smyth HF Jr, Carpenter CP, Weil CS, Pozzani UC, Striegel JA, (Document No. 40+8324292) [cited in ATSDR, 1994]. Nycum JS (1969) Range-finding toxicity data — List VII. American Industrial Hygiene Association journal, 30:470–476. Wittsiepe J (1990) Occurrence of vinyl chloride and other
halogenated C1- and C2-hydrocarbons in German surface water. Stoner GD (1991) Lung tumors in strain A mice as a bioassay for Organohalogen compounds, 4:425–434. carcinogenicity of environmental chemicals. Experimental lung research, 17:405–423. Woodruff RC, Mason JM, Valencia R, Zimmering S (1985) Chemical mutagenesis testing in Drosophila. 5. Results of 53 Storm DL (1994) Chemical monitoring of California’s public coded compounds tested for the National Toxicology Program. drinking water sources: public exposures and health impacts. In: Environmental mutagenesis, 7:677–702. Wang RGM, ed. Water contamination and health. Integration of exposure assessment, toxicology, and risk assessment. New Yllner S (1971) Metabolism of 1,1,2,2-tetrachloroethane-14C in York, NY, Marcel Dekker, Inc., pp. 67–124. the mouse. Acta Pharmacologica et Toxicologica, 29:499–512.
Story DL, Meierhenry EF, Tyson CA, Milman HA (1986) Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital. Toxicology and industrial health, 2(4):351–362.
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22 1,1,2,2-Tetrachloroethane
APPENDIX 1 — SOURCE DOCUMENTS APPENDIX 2 — CICAD PEER REVIEW
Government of Canada (1993) The draft CICAD on 1,1,2,2-tetrachloroethane was sent for review to institutions and organizations identified by IPCS after contact with IPCS national Contact Points and Participating Copies of the Canadian Environmental Protection Act Institutions, as well as to identified experts. Comments were (CEPA) Priority Substances List Assessment Report for 1,1,2,2- received from: tetrachloroethane (Government of Canada, 1993) may be obtained from the: Department of Health, London, United Kingdom Commercial Chemicals Branch Department of Public Health, Albert Szent-Gyorgyi Environment Canada 14th Floor, Place Vincent Massey University Medical School, Szeged, Hungary 351 St. Joseph Blvd. Direccion General de Salud Ambiental, Subsecretario de Hull, Quebec Regulacion y Fomento Sanitario, San Luis Potosi, Canada K1A 0H3 Mexico Environmental Health Centre Finnish Institute for Occupational Health, Helsinki, Health Canada Finland Address Locator: 0801A Tunney’s Pasture International Agency for Research on Cancer, Lyon, Ottawa, Ontario France Canada K1A 0L2 Ministry of Health and Welfare, International Affairs Copies of the unpublished Supporting Documentation Division, Government of Japan, Tokyo, Japan related to human health effects that formed the basis for preparation of the above-mentioned report may be obtained National Institute for Working Life, Solna, Sweden from the Environmental Health Centre at the address noted above. United States Department of Health and Human Services (Agency for Toxic Substances and Disease Registry; Initial drafts of the Supporting Documentation and National Institute of Environmental Health Sciences) Assessment Report for 1,1,2,2-tetrachloroethane were prepared by staff of Health Canada and Environment Canada. The United States Environmental Protection Agency (Office of environmental sections were reviewed externally by Dr P. Pollution Prevention and Toxics; National Center for Cammer (Cammer and Associates), Dr D. Muir (Department of Environmental Assessment, Office of Research and Fisheries and Oceans), Dr D. Singleton (National Research Development; Office of Drinking Water) Council of Canada), and Dr K. Woodburn (Dow Chemical Canada Inc.). Sections related to the assessment of human exposure and health effects were peer reviewed by Dr J. Domoradzki (Dow Chemical Company, USA, Supporting Documentation only), Dr R. Bull (Washington State University, USA), and the Information Department of BIBRA Toxicology International, UK, and subsequently approved by the Standards and Guidelines Rulings Committee of the Bureau of Chemical Hazards of Health Canada. The final Assessment Report was reviewed and approved by the Environment Canada/Health Canada CEPA Management Committee.
Agency for Toxic Substances and Disease Registry (ATSDR, 1994)
Copies of the draft ATSDR profile for 1,1,2,2- tetrachloroethane (ATSDR, 1994) may be obtained from:
Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road, NE, E-29 Atlanta, Georgia 30333 USA
The profile has undergone the following ATSDR internal reviews: Green Border Review, Health Effects Review, Minimal Risk Level Review, and Quality Assurance Review. In addition, a peer review panel, which included Dr Martin Alexander (Cornell University, USA), Mr Lyman Skory (private consultant, USA), and Dr James Withey (Health Canada), was assembled.
23 Concise International Chemical Assessment Document 3
APPENDIX 3 — CICAD FINAL REVIEW Professor S. Tarkowski, Department of Environmental Health Hazards, The Nofer Institute of Occupational Medicine, Lodz, BOARD Poland
Brussels, Belgium, 18–20 November 1996 Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna, Sweden
Members
Dr A. Aitio, Institute of Occupational Health, Helsinki, Finland Observers Dr K. Bentley, Director, Environment Policy Section, Commonwealth Department of Human Services and Health, Professor F.M.C. Carpanini,1 Director, Centre for Ecotoxicology Canberra, Australia and Toxicology of Chemicals (ECETOC), Brussels, Belgium Mr R. Cary, Toxicology and Existing Substances Regulation Mr R. Haigh,1 Head of Unit, Health and Safety Directorate, Unit, Health and Safety Executive, Merseyside, United Kingdom European Commission, Luxembourg Dr J. de Fouw, National Institute of Public Health and Mr B.U. Hildebrandt, Federal Ministry for the Environment, Environmental Protection, Bilthoven, The Netherlands Nature Conservation and Nuclear Safety, Bonn, Germany Dr C. DeRosa, Director, Division of Toxicology, Agency for Toxic Mr P. Hurst,1 Chemical and Consumer Policy Officer, Substances and Disease Registry, Atlanta, GA, USA Conservation Policy Division, World Wide Fund for Nature, Gland, Switzerland Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom Dr A. Lombard (Representative of CEFIC), ELF-ATOCHEM, Paris, France Dr W. Farland, Director, National Center for Environmental Assessment, Office of Research and Development, US Dr P. McCutcheon,1 Environment, Consumer Protection and Environmental Protection Agency, Washington, DC, USA (Chairperson) Nuclear Safety, European Commission, Brussels, Belgium
Dr R. Montaigne, Counsellor, Technical Affairs Department, Dr T.I. Fortoul, Depto. Biologia Celular y Tisular, National European Chemical Industry Council (CEFIC), Brussels, Belgium University of Mexico and Environmental Health Directorate of the Health Ministry, Mexico D.F., Mexico Dr M. Pemberton, ICI Acrylics, Lancashire, United Kingdom Dr H. Gibb, National Center for Environmental Assessment, US Dr A. Smith, Organisation for Economic Co-operation and Environmental Protection Agency, Washington, DC, USA Development, Environment Division, Paris, France Dr R.F. Hertel, Federal Institute for Health Protection of Consumers & Veterinary Medicine, Berlin, Germany Secretariat Mr J.R. Hickman, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada Dr M. Baril, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr T. Lakhanisky, Head, Division of Toxicology, Institute of Hygiene and Epidemiology, Brussels, Belgium (Vice- Dr L. Harrison, International Programme on Chemical Safety, Chairperson) World Health Organization, Geneva, Switzerland
Dr I. Mangelsdorf, Documentation and Assessment of Chemicals, Dr M. Mercier, Director, International Programme on Chemical Fraunhofer Institute for Toxicology and Aerosol Sciences, Safety, World Health Organization, Geneva, Switzerland Hanover, Germany Dr P. Toft, Associate Director, International Programme on Ms E. Meek, Head, Priority Substances Section, Environmental Chemical Safety, World Health Organization, Geneva, Health Directorate, Health Canada, Ottawa, Ontario, Canada Switzerland
Dr K. Paksy, National Institute of Occupational Health, Budapest, Hungary
Mr D. Renshaw, Department of Health, London, United Kingdom
Dr J. Sekizawa, Division of Chemo-Bio Informatics, National Institute of Hygienic Sciences, Tokyo, Japan
Dr H. Sterzl-Eckert, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany 1 Invited but unable to attend.
24 1,1,2,2-Tetrachloroethane
RÉSUMÉ D’ORIENTATION les animaux de laboratoire est considérée comme légère à modérée. D’après les résultats d’études de toxicité à court terme et subchronique, pour la plupart limitées, le La Direction de l’Hygiène du Milieu de Santé foie semble être l’organe cible le plus sensible. La plupart Canada a rédigé ce CICAD (document international des études disponibles ne permettent pas d’établir de succinct sur l’évaluation des risques chimiques) sur le NO(A)EL [dose sans effet (indésirable) observé] ni de 1,1,2,2-tétrachloréthane en s’inspirant d’un document du LO(A)EL [dose minimale suivie d’un effet (indésirable) Gouvernement du Canada (1993) qui évaluait les observé] fiable pour ce qui est de l’hépatotoxicité. conséquences potentielles pour la santé humaine d’une Cependant, des effets minimes sur le foie (augmentation exposition indirecte au 1,1,2,2-tétrachloréthane et les réversible de la teneur en lipides), ainsi que d’autres effets de cette substance sur l’environnement, ainsi que effets (augmentation de la concentration d’une étude entreprise par l’Agence pour les substances d’adrénocorticotropine et altérations réversibles des toxiques et l’enregistrement des maladies (ATSDR, 1994) paramètres hématologiques), ont été observés chez des en vue de caractériser les informations disponibles sur rats exposés à 13,3 mg/m3 pendant 9 mois. D’après les ses effets sanitaires indésirables et l’exposition du résultats d’études limitées et pour la plupart anciennes, public. L’examen du Gouvernement canadien a pris en des effets n’ont été observés sur la reproduction et le considération les données disponibles en septembre développement des animaux de laboratoire qu’à des 1992. Une recherche bibliographique détaillée a été doses qui provoquaient une diminution de poids. effectuée en août 1995 dans plusieurs bases de données en ligne pour identifier les références publiées postéri- L’ingestion sur une longue période de 1,1,2,2- eurement. L’appendice 1 donne des informations sur la tétrachloréthane a provoqué une augmentation de l’inci- nature du processus d’évaluation par les pairs et sur la dence des tumeurs du foie chez des souris B6C3F1 mâles disponibilité des sources documentaires. Les informa- et femelles. Toutefois, une exposition analogue n’a pas tions concernant l’examen par les pairs du présent été suivie d’une augmentation significative du nombre CICAD figurent à l’appendice 2. La publication de ce des tumeurs, quel que soit leur site, chez des rats CICAD a été approuvée à une réunion du Comité Osborne-Mendel, mais l’exposition a été limitée à d’évaluation finale qui s’est tenue à Bruxelles (Belgique) 78 semaines pour les deux espèces. D’après les résultats du 18 au 20 novembre 1996. La liste des participants à disponibles in vivo et in vitro, le 1,1,2,2-tétrachloréthane cette réunion figure à l’appendice 3. La fiche aurait tout au plus une faible activité génotoxique. Il ne internationale de sécurité chimique (ICSC 0332) déclenche pas la formation de foyers positifs à la (- concernant le 1,1,2,2-tétrachloréthane, établie par le glutamyltranspeptidase dans le foie des rats, mais il la Programme international sur la sécurité chimique (IPCS, favorise fortement. Le profil d’induction des tumeurs par 1993) est également reproduite dans le présent docu- le 1,1,2,2-tétrachloréthane est semblable à celui de l’acide ment. dichloracétique, son principal métabolite. Le mécanisme d’induction des tumeurs par le 1,1,2,2-tétrachloréthane Le 1,1,2,2-tétrachloréthane (CAS n/ 79-34-5) est est encore mal connu; pour plusieurs de ses métabolites, un produit synthétique volatil utilisé principalement on a émis l’hypothèse qu’il existerait un seuil. comme intermédiaire dans la synthèse d’autres hydro- carbures chlorés, bien que cette utilisation ait diminué Il a été démontré que l’exposition au 1,1,2,2- considérablement. Sa présence dans l’environnement tétrachloréthane inhibe l’activité de certaines bactéries résulte principalement d’émissions dans l’atmosphère, présentes dans l’environnement (la CI50 la plus faible où il persiste probablement plusieurs semaines. Il ne était de 1,4 mg/litre) et qu’il provoque l’immobilisation de semble pas que le 1,1,2,2-tétrachloréthane contribue à la Daphnia magna (CE50 à 48 heures $ 23 mg/litre). Chez destruction de l’ozone atmosphérique ni au réchauffe- les poissons d’eau douce, la CL50 la plus faible qui ait été ment mondial. Il est rapidement éliminé des systèmes signalée (96 heures) était de 18,5 mg/litre (Jordanella aquatiques et son potentiel de bioaccumulation est floridae), tandis que la concentration minimale suivie faible. L’inhalation est la principale voie d’exposition d’effet (LOEC) à plus long terme (réduction de la survie pour l’homme. des larves chez la même espèce) était de 7,2 mg/litre. Aucun renseignement n’a été découvert concernant les On dispose de très peu de données concernant effets de cette substance sur les organismes terrestres. les effets sur l’homme de l’exposition au 1,1,2,2-tétra- chloréthane. Son profil toxicologique n’a pas non plus Des valeurs guides à l’intention des autorités été caractérisé de façon précise. Étant donné qu’il est de compétentes ont été établies sur la base de la capacité du moins en moins utilisé, la majorité des données disponi- 1,1,2,2-tétrachloréthane à induire la formation de tumeurs bles proviennent d’études limitées relativement anci- du foie chez la souris, étant donné qu’il s’agit du critère ennes. La toxicité aiguë du 1,1,2,2-tétrachloréthane chez toxicologique pour lequel la relation dose-réponse est la
25 Concise International Chemical Assessment Document 3 mieux établie. Il faut cependant noter que l’augmentation observée de l’incidence des tumeurs se limite actuellement à une espèce et qu’il existe des données qui, bien qu’incomplètes, laissent supposer que les tumeurs pourraient être induites par un mécanisme non génotoxique. Les doses associées à une augmen- tation de 5 % de l’incidence des tumeurs se situent entre 5,8 et 28 mg/kg de poids corporel par jour. Dans le cas de l’air (principale source d’exposition pour l’homme), si l’on divise ces doses par 5000 ou 50 000, on obtient des valeurs guides de 3,4–16 :g/m3 et 0,34–1,6 :g/m3 respectivement. Ces valeurs correspondent à ce que certains organismes considèrent comme un risque «pratiquement négligeable» (c’est-à-dire 10–5 à 10–6) pour un cancérogène génotoxique; il faut cependant noter qu’une marge plus faible serait peut-être appropriée compte tenu des arguments en faveur d’un mécanisme épigénétique d’induction des tumeurs. Les valeurs correspondantes pour l’ingestion sont respectivement de 1,2–5,6 et 0,12–0,56 :g/kg de poids corporel par jour. D’après une des estimations qui ont été faites, l’exposition indirecte dans un environnement normal est inférieure à ces valeurs, qui apportent déjà une marge de sécurité considérable, compte tenu des arguments selon lesquels le mécanisme d’induction des tumeurs par le tétrachloréthane pourrait impliquer un seuil.
26 1,1,2,2-Tetrachloroethane
RESUMEN DE ORIENTACIÓN ación de la sustancia química se halla en disminución, los datos disponibles se limitan principalmente a estudios iniciales limitados. La toxicidad aguda del Esta reseña de la evaluación química inter- 1,1,2,2-tetracloroetano en animales de laboratorio es de nacional del 1,1,2,2-tetracloroetano ha sido preparada leve a moderada. Sobre la base de los resultados de por la Dirección de Higiene del Medio de Health Canadá, estudios principalmente limitados a corto plazo y principalmente sobre la base de un informe preparado subcrónicos, parece que el hígado es el órgano diana por el Gobierno del Canadá (1993) para evaluar los más sensible. Si bien la mayor parte de los estudios efectos potenciales en la salud humana de la exposición disponibles son insuficientes para determinar con directa al 1,1,2,2-tetracloroetano en el medio ambiente confianza un nivel sin efectos (adversos) observados general y los efectos ambientales de esta sustancia, así [NO(A)EL] o el nivel más bajo con efectos (adversos) como un estudio preparado por la Agencia para el observados [LO(A)EL] de hepatotoxicidad, se han Registro de Sustancias Tóxicas y Enfermedades observado efectos mínimos en el hígado (aumento (ATSDR, 1994) con objeto de caracterizar información reversible del contenido de lípidos) y otros parámetros sobre los efectos adversos en la salud y la exposición (aumento de los niveles de hormona adrenocortico- del público. En el estudio del Gobierno del Canadá trópica y alteraciones reversibles en los parámetros (1993) se examinaron datos identificados hasta hematológicos) en ratas expuestas a 13,3 mg/m3 durante septiembre de 1992. En agosto de 1995 se hizo una no más de nueve meses. Sobre la base de estudios búsqueda exhaustiva de la bibliografía existente en limitados, principalmente de determinación de la dosis e varias bases de datos en línea con objeto de identificar investigaciones iniciales, se han observado efectos en la toda referencia publicada con posterioridad a los reproducción y en el desarrollo en animales experimen- trabajos incorporados en este estudio. En el apéndice 1 tales solamente con dosis que ocasionaban reducción se presenta información sobre la naturaleza de la revisión del peso corporal. científica y la disponibilidad de las fuentes documentales. En el apéndice 2 se presenta información La ingestión prolongada de 1,1,2,2-tetracloro- sobre la revisión científica de esta reseña. La presente etano hizo aumentar la incidencia de tumores del hígado reseña fue aprobada para publicación en una reunión de en ratones B6C3F1, tanto machos como hembras. Sin la Junta de Revisión Final, celebrada en Bruselas embargo, una exposición semejante no estuvo asociada (Bélgica), del 18 al 20 de noviembre de 1996. Los a un aumento significativo de tumores en ningún lugar participantes en la reunión de la Junta de Revisión Final en ratas Osborne-Mendel, aunque ambas especies sólo figuran en el apéndice 3. En el presente documento estuvieron expuestas durante un máximo de 78 semanas. también se reproduce la ficha internacional de seguridad Sobre la base de los resultados de valoraciones dispon- química (ICSC 0332) del 1,1,2,2-tetracloroetano, ibles in vivo e in vitro el 1,1,2,2-tetracloroetano tiene, producida por el Programa Internacional de Seguridad de como máximo, un potencial genotóxico débil. El 1,1,2,2- las Sustancias Químicas (IPCS, 1993). tetracloroetano fue un potente promotor, pero no un iniciador, de focos positivos a la (-glutamiltrans- El 1,1,2,2-tetracloroetano (No CAS 79-34-5) es peptidasa en el hígado de ratas. El perfil de inducción de una sustancia química sintética volátil que se utiliza tumores por el 1,1,2,2-tetracloroetano es semejante al del principalmente como precursor en la síntesis de otros ácido dicloroacético, su metabolito principal. La hidrocarburos clorados, aunque la utilización de esta información existente sobre el mecanismo de inducción sustancia ha disminuido significativamente. La libera- de tumores por el 1,1,2,2-tetracloroetano es incompleta; ción en el medio ambiente ocurre principalmente en con respecto a varios de sus metabolitos, se ha sugerido forma de emisiones en el aire ambiente, donde la que los tumores probablemente estén inducidos por sustancia química probablemente permanezca durante mecanismos para los cuales existe un umbral. varias semanas. No se prevé que el 1,1,2,2-tetracloro- etano contribuya al agotamiento del ozono estratosférico Se ha demostrado que la exposición al 1,1,2,2- ni al calentamiento de la atmósfera. Se elimina rápida- tetracloroetano inhibe la actividad de las bacterias mente de los sistemas acuáticos y probablemente no sea ambientales (la CI50 más baja comunicada ha sido de 1,4 objeto de bioacumulación. La exposición humana al mg/litro) y ocasiona inmovilización en Daphnia magna
1,1,2,2-tetracloroetano se hace principalmente por (valores de CE50 a las 48 horas de 23 mg/litro y superi- inhalación. ores). En las especies ictícolas de agua dulce, la CL50 más baja comunicada (a las 96 horas) ha sido de 18,5 Se dispone de muy pocos datos sobre los mg/litro en Jordanella floridae, mientras que la concen- efectos de la exposición al 1,1,2,2-tetracloroetano en el tración más baja con efectos observados (LOEC) tras la ser humano. El perfil toxicológico del 1,1,2,2-tetracloro- exposición a más largo plazo ha sido de 7,2 mg/litro; ésta etano tampoco se ha caracterizado bien; como la utiliz- dio lugar a una reducción de la supervivencia de las
27 Concise International Chemical Assessment Document 3 larvas en las mismas especies mencionadas más arriba. No se identificaron datos sobre los efectos de esta sustancia en organismos terrestres.
A fin de facilitar orientación a las autoridades pertinentes, se han determinado valores de orientación de muestra sobre la base del potencial del 1,1,2,2- tetracloroetano para inducir tumores hepáticos en ratones, porque éste es el parámetro toxicológico con respecto al cual se caracteriza mejor la relación de respuesta a la dosis. Sin embargo, es de señalar que los aumentos observados en la incidencia de tumores se limitan actualmente a una especie y hay datos, si bien incompletos, que sugieren que los tumores tal vez estén inducidos por un mecanismo no genotóxico. El potencial, expresado como la dosis asociada a un aumento del 5% en la incidencia de tumores, oscilaba entre 5,8 y 28 mg/kg de peso corporal por día. Los valores de orientación de muestra correspondientes al aire (la principal fuente de exposición humana), que se han calculado dividiendo esos márgenes de variación del potencial por 5000 ó 50 000, son de 3,4–16 :g/m3 y 0,34–1,6 :g/m3. Estos valores corresponden a los considerados por algunas autoridades como indicativos de riesgo «esencialmente insignificante» (es decir 10–5 a 10–6) para un carcinógeno genotóxico; sin embargo, es de señalar que tal vez sea apropiado considerar un margen más estrecho en vista de las indicaciones, si bien incompletas, que sugieren un mecanismo epigenético de inducción de tumores. Los valores correspondientes para la ingestión son de 1,2–5,6 :g/kg de peso corporal por día y 0,12–0,56 :g/kg de peso corporal por día. La exposición indirecta en el medio ambiente general, calculada sobre la base de una estimación de muestra de la exposición, es inferior a esos valores, que se consid- eran moderados en vista de los indicios, si bien incom- pletos, que sugieren que el 1,1,2,2-tetracloroetano tal vez induzca tumores por un mecanismo de umbral.
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