3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone

Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P262, P264, P270, P280, P301+P316, P302+P352, P308+P316, P316, P318, P321, P330, P361+P364, P405, and P501 (click each P-code to see the statement)

Environmental Health Criteria 216: Disinfectants and DIsinfectant By-Products (1999) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. EHC publications are monographs designed for scientists and administrators responsible for the establishment of safety standards and regulations. This series issued by the International Programme on Chemical Safety (IPCS), provides basic scientific risk evaluation of a wide range of chemicals and groups of chemicals.

Reproductive and Cancer Hazard Assessment Section, Office of ENvironmental Health Hazard Assessment, California Environmental Protection Agency; Evidence on the Carcinogenicity of MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone). Final. (December 2000)

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for 3-CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5H)-FURANONE (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency & who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing & use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors & benches, & ... interior of fume hoods & airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple & sensitive. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms & sides & fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, & monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type & amt of carcinogen & efficiency with which it can be removed. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for 3-CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5H)-FURANONE (12 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Groups of male BALB/cABOM mice (initial numbers unspecified), 4 weeks of age, were administered an intraperitoneal injection of 7 mg/kg bw azoxymethane or 0.9% sodium chloride (vehicle control) once a week for 2 weeks. One week later, animals were administered 0 or 20 mg/kg bw MX (94% pure dissolved in sterile water at pH 3.4-4.0) intrarectally three times weekly for 6 weeks to give a total MX dose of 360 mg/kg or 40 mg/kg bw MX three times weekly over 4 weeks, giving a total MX dose of 480 mg/kg. All mice were killed 15 weeks after the start of the experiment, 6 or 8 weeks after the last dose. The small intestine, colon and cecum were removed. The colon and cecum were scored for altered crypt foci and small intestine, colon and cecum were scored for tumors ... . Neither dose of MX increased the incidence of aberrant crypt foci per colon when compared with sodium chloride or azoxymethane. ... Most mice in every treatment group, including the vehicle control, had small tumors (0.3-0.6 mm, 1-16 per small intestine). One mouse receiving azoxymethane and 40 mg/kg bw MX had a colon tumor ... . (The IARC Working Group noted the inadequacy of the strain and dose of azoxymethane.)

Ten-week-old male Long-Evans rats were treated in their drinking water for 17 weeks with 0.4 g/L potassium bromate, 1.8 g/L chloroform, 0.7 g/L bromodichloromethane (BDCM), 0.07 g/L 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or a mixture of the four chemicals or distilled water. Cecal nitroreductase (NR), azoreductase (AR), dechlorinase (DC), beta-glucuronidase (GLR), beta-galactosidase (GAL), and beta-glucosidase (GLU) were assayed. No change in GLU or GLR activity was detected after treatment. BDCM treatment reduced DC and GAL activities and elevated NR and AR activity. GAL, AR, and NR activities were significantly different after treatment with bromate, chloroform, BDCM, and MX, but not the mixture. DC activity after chloroform-, MX-, or BDCM-treatment was significantly below control levels. The present study shows that changes in intestinal microbial metabolism do occur after treatment with individual and a mixture of DBPs but the changes were not additive in the mixture group.

Male and female Eker rats were exposed via drinking water to individual or a mixture of disinfection byproducts (DBPs) for 4 or 10 months. Potassium bromate, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), chloroform, and bromodichloromethane were administered at low concentrations of 0.02, 0.005, 0.4 and 0.07 g/L, respectively, and high concentrations of 0.4, 0.07, 1.8 and 0.7 g/L, respectively. Low and high dose mixture solutions were comprised of all four chemicals at either low concentrations or high concentrations, respectively, Following necropsy, each kidney was examined microscopically for preneoplastic lesions (atypical tubules and hyperplasias) and tumors. While some of the mixture responses observed in male rats did fall within the range expected for an additive response, especially at the high dose, predominantly antagonistic effects on renal lesions were observed in response to the low dose mixture in male rats and the high dose mixture in female rats. These data suggest that current default risk assessments assuming additivity may overstate the cancer risk associated with exposure to mixtures of DBPs at low concentrations.

The genotoxic responses of mixtures of four chlorohydroxyfuranones (CHFs), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), 3-chloro- 4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) and 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), were compared with the genotoxicity of the individual compounds. Genotoxicity was evaluated in the Salmonella reversion assay (Ames test), the in vitro Chinese hamster ovary (CHO) cell Hprt mutation assay, and in the CHO chromosome aberration test. When tested individually, the concentrations of the chemicals that were chosen for the mixtures induced no or only a modest increase in the genotoxic effects, and caused little or no cytotoxicity. In the Ames test, the genotoxic responses caused by the mixtures of CHFs did not follow simple additivity. Synergism was observed with strains TA97 and TA98, and antagonism with strain TA100. In the CHO/Hprt mutation assay, the mutagenic response of the mixtures was inconsistent, with near additivity seen with a mixture of CHFs that resulted in 12% cell survival. In contrast, the four CHFs together consistently caused more structural chromosome damage (mainly chromatid-type breaks and exchanges) compared to the sum of net effects of the four CHFs tested alone. Also, a potentiating effect was consistently seen for the cytotoxicity of the CHF mixtures both in the CHO/Hprt mutation assay and the chromosome aberration test...

For more Interactions (Complete) data for 3-CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5H)-FURANONE (7 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 98(SRC), determined from a log Kow of 1.13(2) and a regression-derived equation(3), indicates that 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is expected to have high mobility in soil(SRC). Volatilization of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.5X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(4). 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.6X10-6 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data for soil were not available(SRC, 2008).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 98(SRC), determined from a log Kow of 1.13(2) and a regression-derived equation(3), indicates that 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.5X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(6), an estimated BCF of 1.5(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). 14C-Labeled 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone was reduced in drinking water 9.4% and in humus-rich surface water 13.1% at pH 5.5, 20 °C, after 14 days, however it was not specified whether the 14C reduction was due to hydrolysis or biodegradation(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, which has an estimated vapor pressure of 1.6X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.2 days(SRC), calculated from its rate constant of 1.4X10-11 cu cm/molecule-sec at 25 °C(SRC)that was derived using a structure estimation method(3). Particulate-phase 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone may be removed from the air by wet or dry deposition(SRC). 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

/AQUATIC SPECIES/ ... The effect of exposure to MX on cytochrome P450 2E1 (CYP2E1)-like activity and total glutathione (GSH) in the liver of the small fish model, medaka (Oryzias latipes) /was examined/ ... Both medaka liver microsome preparations and S-9 fractions catalyzed the hydroxylation of p-nitrophenol (PNP), suggesting CYP2E1-like activity in the medaka. Male medaka exposed for 96 hr to the CYP2E1 inducers ethanol and acetone under fasted conditions showed significant increases in PNP-hydroxylation activity. Furthermore, total reduced hepatic GSH was reduced in fish fasted for 96 hr, indicating that normal feeding is a factor in maintaining xenobiotic defenses. Exposure to MX ... induced significant increases in hepatic CYP2E1-like activity, however MX exposure did not alter hepatic GSH levels...

/AQUATIC SPECIES/ The cytotoxicity, in Salmonella /of/ ... 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and its structural analogue 3,4-dichloro-5-hydroxy-2[5H]-furanone (mucochloric acid, MCA), was studied in freshly isolated rainbow trout hepatocytes and gill epithelial cells by determining 86Rb-leakage and decrease in fluorescence intensity in calcein AM-loaded cells. The acute toxicity of the compounds to Daphnia magna was studied by determining the concentration causing immobilization of the organism. MX proved to be more toxic than MCA both in the cellular assays and in the acute toxicity test with D. magna. MX was more toxic to hepatocytes than to gill epithelial cells. The uptake of (14C)MX was also much more efficient in hepatocytes than in gill epithelial cells. The uptake of (14C)MX in hepatocytes was not inhibited by taurocholic acid in excess, indicating that MX is not taken up by the carrier complex responsible for the uptake of taurocholate in the hepatocytes. Both the acute toxicity to D. magna and cytotoxicity of MX and MCA was rather low (EC50 values > 0.1 mM) and /it was concluded/ that it is very unlikely that MX and MCA at concentrations occurring in recipients receiving chlorination effluents from pulp mills or chlorinated domestic sewage, as regards their acute toxicity, implies a risk for aquatic animals.

/AQUATIC SPECIES/ Isolated mussel (Mytilus edulis L.) digestive gland cells were analyzed using the single-cell gel electrophoresis or "comet" assay to assess the ability of potential aquatic contaminants to induce DNA strand breaks (SBs) and to investigate the potential application of this technique as part of an aquatic biomonitoring regime. Freshly prepared cell suspensions from digestive gland were exposed in vitro to ... 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX, 0-200 uM) ... for 1 hr in the dark at 15 °C in the presence of the DNA repair inhibitor cytosine-beta-D-arabinofuranoside (araC). DNA strand breakage was measured using the comet assay. There were significant concentration-dependent increases in the percentage of DNA in the comet tail (mean values+/-SD) for all doses compared with controls (P<0.05) with ... MX (up to 34. 3+/-2.2% at 200 uM) ...

/AQUATIC SPECIES/ ...Two species of shellfish, Patunopecten yessoensis and Tapes japonica, /were exposed/ for 4 hr to artificial sea water in which ... 3-chloro-4-dichloromethyl-5-hydroxy-2(H)-furanone (MX) ... /was/ dissolved. ... DNA damage /was assessed/ in cells isolated from the gills using the alkaline single-cell gel electrophoresis (SCG) assay. A statistically significant increase in DNA damage was observed for all exposures ... T. japonica was exposed to sea water sampled from two Pacific Ocean coasts of Japanese local cities--Hachinohe (Aomori Prefecture, Tohoku) and Nakatsu (Oita Prefecture, Kyushu)--and three bay coasts of the industrial megalopolises--Tokyo, Osaka, and Kobe. A significant increase in DNA damage was observed after the exposure to sea water from Tokyo, Osaka, and Kobe, but not from Hachinohe and Nakatsu. These results suggested the utility of the alkaline SCG assay with shellfish gill cells for monitoring sea water genotoxicity.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=77439-76-0]

During a survey of 12 U.S. water treatment plants conducted between 2000-2002, the highest level of halogenated furanones (as a sum) occurred at a plant that disinfected water containing 11.3 mg/L of TOC and 0.27 mg/L of bromide with chlorine-chloramines (2380 ng/L in plant effluent drinking water) and at a plant that disinfected water containing 3.5 mg/L of TOC and 0.21 mg/L of bromide with chlorine dioxide-chlorine-chloramines (1000 ng/L in the distribution system). The authors noted that an effort was made to selects plants that treat water with high TOC and/or bromide to enable detection of priority disinfection byproducts. The median concentration of halogenated furanones (as a sum, measured in plant effluent) was 310 ng/L, with a 75th percentile concentration of 610 ng/L and a maximum concentration of 2,380 ng/L(1). /Halogenated furnanones/

3-Chloro-4-dichloromethyl)-5-hydroxy-2(5H)-furanone concentrations in six pairs of US drinking water plants from different geographical regions as defined by the EPA(1). [Table#7319]

The most potent bacterial mutagen in pulp mill effluents was identified as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). ... Research has shown that MX stability decreases with increasing pH in the range of pH 2 - 6. Most waste water treatment facilities operate at a pH of 6 - 7. Accordingly, MX should be deactivated and destroyed at pulp mills where the bleach plant effluent goes directly for conventional waste water treatment. However MX could pose a serious risk if mill effluents were discharged directly to receiving waters. This is particularly so in Canada and Northern Europe where lake and river waters may be slightly acidic due to poor buffering capacity, high humic acid content, and acid rain.

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

The Koc of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is estimated as 98(SRC), using a log Kow of 1.13(1)and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is expected to have high mobility in soil.

/ALTERNATIVE and IN VITRO TESTS/ ... 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) ... has been studied with respect to induction of cell death in promyelocytic leukemic HL-60 cells. Cells exposed to MX for 1 hr and further incubated for 3 hr, revealed no significant increase in the proportion of cells with compromised plasma membrane damage as judged by trypan blue or propidium iodide exclusion. However, flow cytometric studies and microscopic analysis of HL-60 cells after staining with Giemsa or Hoechst 33342, revealed that more than 30% of the cells exposed to 30-100 uM of MX, showed the characteristic morphology and biochemical markers of apoptosis. On the other hand, in cultures exposed to 300 uM MX, less than 5% of the cells appeared to be apoptotic (< G1 DNA) 3 hr after treatment, which is similar to control values. Microscopic analysis of Hoechst 33342-stained cells revealed that they were 'arrested' in the early stages of chromatin condensation, but these cells eventually became necrotic. Some decrease in the percentage of cells in S-phase was observed 3 hr after exposure to MX (10, 30 and 100 uM), but the induced cell death was not markedly cell stage specific. The characteristic ladder pattern of apoptotic cells was observed when DNA isolated from MX-exposed HL-60 cells was electrophoresed in agarose. The apoptotic process could also be detected by analysis with alkaline filter elution (AE), as a decrease in the total DNA recovered; and by single cell gel electrophoresis, as a decrease in the average number of cells/comets observable on each slide. With the protocols used no apparent increase in values in the normalized area above the curve (NAAC) (alkaline elution) or tail moments (single cell gel electrophoresis (SCGE)) were detected, indicating that apoptotic cells are not necessarily a confounding factor when assaying for genotoxicity with these techniques.

/GENOTOXICITY/ ... One chlorohydroxyfuranone, 3-chloro-4-dichloromethyl-5-hydroxy-2[5H]-furanone (MX), a potent bacterial mutagen, induces 232 +/- 89 DNA strand breaks.(cell-uM)-1 in human CCRF-CEM cells over a concentration range of 4.4 to 220 uM. This constitutes a DNA damage potency comparable to dimethylsulfate (DMS). ... The DNA strand-breaking potential of MX is inactivated by prior incubation with a rat liver S9 homogenate.

/GENOTOXICITY/ 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) induced DNA strand-breakage (measured by fluorometric analysis of DNA unwinding) in human white blood cells at sub-cytotoxic doses (1.0-1000 uM; 60 min exposure). Although a dose-dependent decrease in glutathione levels was observed with MX, this is not necessarily the causative factor in the observed DNA damage, since no strand breakage was seen on depletion of cellular glutathione to 23% of control by diethylmaleate. In addition, the strand scission does not appear to be mediated by elevation of intracellular calcium as no MX-induced release of calcium stores was observed. Strand breakage may, however, be Ca(2+)-dependent as evidenced by inhibition following deprivation of Ca2+ by Quin-2...

/GENOTOXICITY/ ... 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a potent bacterial mutagen and chlorine-disinfection byproduct, was ... tested in MCL-5 cells as well as in two other human B-lymphoblastoid cell-lines, AHH-1 TK+/- and h1A1v2 cells, which differ from each other and from MCL-5 cells in the amounts of cytochrome P450 enzymes they can express. MX was mutagenic to all three cell-lines, but there was no apparent correlation between cytochrome P450 enzyme expression and the mutagenicity of MX...

/GENOTOXICITY/ ... Single cell gel electrophoresis (SCGE) and flow cytometry were used to detect DNA damage and apoptosis in human fetal hepatocytes (L-02) treated with MX. ... DNA damage was found to increase in L-02 cells treated with MX in a dose-response manner. On treatment levels of 100 and 300 umol/L, MX led to significant increase of DNA damage in comparison to the solvent controls (DMSO) (P < 0.05, and P < 0.01 respectively). Statistically significant increases of L-02 cell apoptosis were observed in all MX treated groups in comparison to the solvent controls (DMSO) (P < 0.001)...

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone's formation is a result of addition of chlorine or other disinfectants used to control contaminants in drinking water reacting with naturally occurring organic and inorganic matter present in raw water(1,2); this may result in its release to the environment(SRC).

AEROBIC: Microbial and biological degradation of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in drinking and surface water samples were studied using 14C- labeled 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone. Samples collected from a humus-rich lake in Finland and drinking water processed from this lake were incubated at atmospheric conditions for two days in order to evaporate any free chlorine. 10-20 ug of the 14C-labeled 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone were added to the water samples at concentrations of 0.5-1.0 ug/mL and incubated at 20 °C in the dark for 14 days at pH values of 5.5 and 8. At pH 5.5, 9.4% 14C reduction was observed in drinking water and 13.1% was observed in surface water. At pH 8, 25.0% 14C reduction was observed in drinking water and 17.7% reduction was observed in surface water. The chemical stability of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone decreases sharply above pH 6, when 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone transforms to an open chain structure. 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone losses due to hydrolysis or biodegradation was not specified. The authors suggested that the open-chain form of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone may hydrolyze rapidly(1).

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone

Group 2B: Possibly carcinogenic to humans

Volume 84: (2004) Some Drinking-water Disinfectants and Contaminants, including Arsenic

2004

2002

An estimated BCF of 1.5 was calculated for 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone(SRC), using a log Kow of 1.13(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low (SRC).

In-vitro data in bacteria and in mammalian cells indicate that MX is genotoxic. In addition, it causes DNA damage in vivo. Data on mutagenicity tests in vitro, mutation spectra and adduct formation suggest that the guanine moiety may be one target of MX in DNA. In addition, MX was 100-fold more mutagenic in the form of lactone (closed ring form) than in the open-ring conformation in vitro, suggesting that the closed-ring conformation may be responsible for the mutagenicity at physiological pH. However, examination of the structural and electronic properties of MX have not yet identified the form of interaction of MX with DNA. Studies on hormonal effects of MX suggest that it does not cause thyroid gland tumours in rats by the TSH-mediated promotion mechanism.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), and 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) promote foci formation in the two-stage cell transformation assay in vitro. These chlorohydroxyfuranones (CHFs) and their structural congener 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) inhibit gap junctional intercellular communication (GJIC) in Balb/c 3T3 mouse fibroblast cells. In the present study, the effects of MX, MCA, CMCF, and MCF on GJIC were evaluated in liver cells (WB-F344 rat liver epithelial cells), the target cells of MX-induced carcinogenicity, using the scrape-loading dye transfer technique. The CHFs inhibited GJIC after 1 hr exposure in a concentration-dependent fashion. The order of potency was MX>CMCF approximately MCA>MCF. In terms of the lowest observed effective concentrations, the difference in the potency was about 27-fold (MX 1.875 uM, MCF 50 uM). After a prolonged exposure period (12 hr), the inhibition of GJIC by MX and CMCF remained stable, but MCA and MCF exhibited increasing inhibitory effects. After removal of the CHFs, the GJIC slowly recovered. At the transcriptional level, CHFs caused essentially no change in the level of connexin43 (Cx43) mRNA. Preincubation of cells with the protein kinase C (PKC) inhibitor did not modify the response, but the specific MEK 1 inhibitor PD98059 decreased substantially the inhibition of GJIC by all four CHFs. Activation of the mitogen-activated protein kinases (MAPKs) signaling pathway was necessary for inhibition of GJIC. CHFs did not increase the basal phosphorylation state of the Cx43 protein, but all CHFs caused a concentration-dependent degradation of the Cx43 protein. The results indicate that all the studied CHFs inhibit GJIC in WB-F344 cells by altering Cx43 expression.

The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C-labelled compound. ... The mean elimination half-life of the radioactivity in blood (T1/2) /following oral administration/ was 3.8 hr. ... After an intravenous administration of 14C-MX, the T1/2 was much longer, 22.9 hr, and the total elimination half-life 42.1 hr.

... A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 hr postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid.

... MX is extensively detoxified in vivo and is unlikely to cause genetic damage in systemic tissues except at relatively high doses where detoxification pathways become saturated...

Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.

Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.

... Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 hr following oral administration of (14)C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 hr postdosing. ... Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.

The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C-labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half-life of the radioactivity in blood (T1/2 k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy-seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of 14C-MX, the T1/2 k10, was much longer, 22.9 hr, and the total elimination half-life (T1/2 beta), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.

In another experiment, a dose of 2 mg/kg (14C)MX was administered to Wistar rats and radioactivity was determined in tissues after 2 and 6 hr. After 2 hr, the highest amount of radioactivity was detected in kidneys, followed by the stomach, ileum, urinary bladder and liver. At 6 hr, the concentration of radioactivity was markedly decreased in kidneys and urinary bladder and to a lesser extent in the gastrointestinal tract.

... Excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) ... was evaluated in male Wistar rats ... dosed by gavage in deionized water at doses between 200 mg/kg and 600 mg/kg, for one animal at a time ... Urine was collected in metabolism cages up to 72 hr after dosing for chemical analysis of MX in urine. ... Only 0.03-0.07% of the dose (200 mg/kg or 300 mg/kg) was excreted in urine as intact MX...

For more Absorption, Distribution and Excretion (Complete) data for 3-CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5H)-FURANONE (7 total), please visit the HSDB record page.

Disinfection byproducts are formed when disinfectants used in water treatment plants react with bromide and/or natural organic matter (i.e., decaying vegetation) present in the source water. /Disinfection byproducts/

A project to isolate and identify the mutagenic components formed in pulp chlorination was initiated in 1979 at the Pulp and Paper Research Institute of Canada. Mutagenicity of the concentrates and fractions from the pulp chlorination process were tested for reverse mutations in Salmonella typhimurium strain TA100. Most of the mutagenicity was consistently found in one fraction, suggesting one primary mutagen. Because analytical techniques were not sufficiently advanced to easily identify the compound, the compound was called "Mutagen X" or "MX" After about a year of additional work, the chemical identity of MX was determined to be 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone.

In acidic solutions MX is a furanone, but at physiological pH it exists primarily in a ring-open form, namely Z-2-chloro-3-(dichloromethyl)-4-oxo-butenoic acid (z-MX), a fraction of which undergoes isomerization to its geometric isomer (E)-2-chloro-3-(dichloromethyl)-4-oxobutenoic acid (EMX).