METHYLENE CHLORIDE CAS: 75-092 Dichloromethane CH2Ce ‘TLV-TWA, 50 ppm (174 mg/m’) ‘A2 — Suspected Human Carcinogen 1946-1847: MAC-TWA, 500 ppm 1948-1974: TLV-TWA, 509 ppm 1872: TLV-TWA, 20 ppm; proposed 1874: TLV-TWA, 100 ppm; proposed 1975: TLV-TWA, 100 ppm 1075: TLV-TWA, 200 ppm; proposed 11976-1900: TLV-TWA, 200 ppm 1976-1980: TLY-STEL, 280 ppm 1978: TLV-TWA, 100 ppm; STEL, $00 ppm; proposed 1981-1987: TLY-TWA, 109 ppm: STEL, 500 ppm 1986: TLV-TWA, 50 pom, A2, Suspected Hunan Carcinogen: proposed 1908-prosent: TLV-TWA, 50 pom, A2 Carcinogen 1992: Documentation revised Chemical and Physical Properties ‘Methylene chloride is a coloriess, volatile liquid. tt is ‘not flammable by standard tests in air but will burn under ‘extreme conditions. The sweetish, not unpleasant odor, although distinctive, is not a good indication of exposure because concentrations of 100 ppm reportedly are not easily perceptible to most people. The odor threshold ranges from 25 to 150 ppm and above 300 ppm most persons detect the odor. Chemical and physical proper- ties include: Molecular weight: 84.93 if 3266 at 20°C 15.1°C Boiling point: 40°C at 76 torr ‘Vapor pressure: 349 torr at 20°C; 440 torr at 25°C ‘Solubility: completely miscible with most organic sol- ‘vents; sparingly soluble in water, 1% to 1.2% by weight at room temperature ‘Conversion factor: 1 ppm = 3.53 mg/m? in air Major Uses or Sources of Occupational Exposure Methylene chloride is widely used in paint removers, as a solvent for plastics, as a degreasing agent, in propellant mixturas for aerosol containers, and as a blowing agent in foams. Liquid methylene chloride is painful and initating if splashed in the eyes or if confined (on the skin by gloves, clothing, or paint remover formu- lations. A bum can resutifit is not removed fromthe eyes and skin. Animal Studies A summary of animal and human toxicological data has been published by the U.S. Agency for Toxic Sub- stances and Disease Registry (ATSDR). Acute ‘The acute oral LDx of methylene chloride in rats is about 2000 mg/kg. According to Lehmann and Flury,® slight narcosis occurs at 4000-6100 ppm in several ‘species of animals. The lethal concentration for an expo- ‘sure of 7 hours is about 15,000 ppm." Subchronic Rats exposed 8 hours/day for 75 days at 1300 ppm ‘methylene chloride showed slight liver changes that were not found at 50 days.” Cats exposed 4-8 days at 7200 ppm for 4 weeks were found to have kidney and liver changes. Heppel and associates found that daily 7- hour exposures at 5000 ppm for 6 months had no dis- ‘cemible effect on dogs and rabbits and only a reduction inthe rate of growth was seen in guinea pigs. When dogs, uinea pigs, monkeys, rabbits, and rats were exposed 4 hours/day for 7.5 weeks at 10,000 ppm, only the dogs and guinea pigs developed liver injury. More recent stud- jes confirm the low, acute and subacute toxicity of methylene chloride.*” Chronie/Carcinogenicity ‘The onrcinogenic potential of methylene chloride has been studied in three species of laboratory rodents (ham sters, rats, and mice) with quite divergent results. In ‘hamsters, to oncogenic or toxicological effects were ‘observed in a 2-year study. Burek et al. found no adverse effects on malignancies in groups of 95 ham sters of each sex exposed 6 hoursiday, 5 days/week at 500, 1500, or 3500 ppm. Carboxyhemoglobin was ele- vated, but all other toxicological parameters were unat- fected by exposure at any level. Hamsters reportedly “had less extensive spontaneous geriatric changes (than the controls), had exposure-related decreased mortality (females), and lacked evidence of definitive target organ toxicity." Exposure-related effects were observed in male and female Sprague-Dawley rats at allthree ofthe methylene chloride concentrations. There was evidence of a dose- ‘elated increased incidence of sarcomas in the ventral midcervical area in the region of the salivary glands. The number of salivary tumiors® in the male rats exposed at 3500 ppm was statistically significant: at 1500 ppm, five tumors were observed; at 500 ppm, none; the control (group had one such tumor. The presence of a common viral disease complicated interpretation of the carcino- ‘genic responses. No such response was observed in the female rats of this study. A single tumor of a similar type was observed in one rat of each sex exposed at 4000ppm in a study described subsequently.” While itis not possible to absolutely ascribe the apparent increase to the viral infection, the Science Advisory Board of the U.S. Environmental Protection Agency (EPA) concluded that these tumors should not be used for calculation of car- ccinogenic risk to humans. This is consistent with the many reasons suggested by Burek et al." for which the ‘tumor should not be considered definitely related to ‘methylene chloride exposure, Definite hepatic effects were seen in male and fe- male rats at all three exposure concentrations of methylene chloride after 12 months of exposure. Burek et al. state" ‘The liver was the primary target organ in rats with slight exposure-related effects in both sexes, at 500, 1500, or 3500 ppm. Liver effects included increased hepatocellular vacuolization (consis- tent with fatty change) in both sexes at 500, 1500, and 3500 ppm; increased multinucleated hepatocytes in the central lobular region in fe- males exposed to 500, 1500, or 3500 ppm; and increased foci and areas of altered hepatocytes in females exposed to 3500 ppm. Liver effects first appeared atter 12 months of exposure, pro- gressed slightly from 12 to 18 months, but were unchanged in severity thereafter. There was no increase in hepatocellular carcinomas. Carboxyhemoglobin was also increased at all expo- sure concentrations. In female rats exposed at 3500 ppm, mortality was increased during the last 6 months of the study. Mortalty was considered to be related to numerous benign mammary tumors which were large and often ulcerated. According to the investigators, Male and female rats exposed to methylene chloride had increased numbers of benign mam- mary tumors per animal. Despite the increased ‘number of benign mammary tumors, there was 1 indication of an increased number or inci- dence of malignant mammary tumors in either male or female rats exposed to methylene chlo- ride. The significance of this benign mammary tumor response is unknown. However, the Spra- gue-Dawley rats used in this study normally have a high incidence of mammary tumors. The incidence varies from study to study but normally exceeds 80% in femaes and about 10% in males in our laboratory. Therefore, the predisposition of this strain to these mammary tumors plus the high methylene chloride exposure concentra- tions may have resulted in an increased benign mammary tumor response. Nitschke et al. from the same laboratory extended this study by exposing groups of 90 male and 90 female. ‘Sprague-Dawley rats at 0, 50, 200, or 500 ppm 6 hours/day, 5 days/week for 2 years. According to the authors’ abstract,” The metabolism of methylene chloride to carbon monoxide resulted in elevated blood car- boxyhemoglobin levels in all treatment groups. Repeated exposure to the solvent had no infu- ence on the metabolism to carbon monoxide. The liver of female rats inhaling 500 ppm methylene chioride showed an increased hepato- celular vacuolization and muttinucleated hepato- cytes. The incidence of multinucleated hepatocytes in females inhaling 200 ppm was not significantly different from controls. ‘An increase in the incidence of benign mam- mary tumors (adenomas, fibromas, and fibro- adenomas) was observed in female rats inhaling ‘methylene chloride. The increase observed in females inhaling 50 or 200 ppm was judged to be consistent with a difference in the housing arrangement for the control group and was not an effect of methylene chloride exposure. The number of benign mammary tumors observed per tumor-bearing female rat was 2.0, 2.3, 2.2, and 2.7 in rats inhaling 0, 50, 200, and 500 ppm, respectively. Female rats from the 500/0 group showed effects similar to rats exposed at 500 ppm for 24 months. These rats had an increased incidenos of both multinucleated hepatocytes and benign mammary tumorstumor-bearing rat. An in- creased incidence of hepatocellular vacuoliza- tion was not observed in these animals. However, the incidence of lesions in animals from the 0/500 group did not differ from that of the control group. In conclusion, slight exposure-related effects were observed in the liver and mammary tissue of female rats inhaling 500 ppm methylene chlo- ride, Female rats exposed at 200 ppm methylene chloride exhibited equivocal liver effects which may or may not be exposure related. Based upon the results of this study, a no-adverse- effect level was judged to be approximately 200 ppm methylene chloride. In another inhalation study,” rats were exposed at 1000, 2000, or 4000 ppm of methylene chloride 6 hoursiday, 5 dayshweek for 2 years. An increase in benign mammary tumors without any rise in malignant tumors was observed in female rats at all dosage levels and probably in male rats at 4000 ppm. No other tumor was found tobe increasedio statistically significantlevels ‘over controls. As discussed previously, one male and ‘one female high-dose rat had a salivary tumor. In a chronic drinking water study,” methylene chlo- ride was administered for 104 weeks at levels of 0, 5, 50, 125, or 250 mgkg of body weight/day in deionized water to groups of 85 Fischer 344 rats of each sex in order to evaluate the toxicity and carcinogenic potential ofmethylene chloride. An additional group received a level of 250 mofkg of body weightiday for 78 weeks followed by @ 26-week recovery period where only deionized water was presented. According to the authors’ ab- stract.® «.. Sactificas were performed at 26-week inter- vals. Statistically significant effects on body weight, water consumption, and food consump- tion were observed at the two highest levels. Minimal effects were noted on the hematologic and serum chemistry parameters monitored. ‘Treatment-related hepatic changes were noted histomorphologically in both sexes after 78 Weeks of treatment. These changes consisted of an increased incidence of fociareas of cellular alteration and of fatty change at all levels except the lowest. A decrease in the severity of fatty change was observed in the recovery group, while no difference was noted in the incidence of cellular aeration. An increased incidence of he- ppatic tumors, which was within historical control incidences, was noted in females treated at 50 and 250 mg/kg/day. Based upon an unexpected low incidence of similar tumors in the concurrent control groups and the absence of an increased incidence of hepatic tumors in the group treated at 125 mg/kg/day, this effect was not considered to be attributable to DCM treatment. Under the ‘experimental conditions ofthis study, there was, a “no-etfect” level at 5 mo/kg/day in both males and females. Mice exposed at 0, 2000, or 4000 ppm of methylene chloride for 2 years” had lung tumors occur at dose-re- {ated increased incidences in both male and female mice; i.e., alveolarfbronchiolar adenomas: males, 3/50, 19/50, 24/50; females, 2/50, 23/48, 26/48: alveolarforonchiolar ‘carcinomas: males, 2/50, 10/50, 28/50; females, 1/50, 19/48, 20/48. Cytologic degeneration of the liver was observed at increased incidences in high-dose male and high-dose female mice (males: 0/50, 0/49, 22/49; fe- males: 0/50, 23/48, 21/48). Incidences of hepatocellular ‘adenomas or hepatocellular carcinomas (combined) were increased in high-dose male and female mice (males: 22/50, 24/49, 32/49; females: 9/50, 16/48, 40/48). There were also dose-related increases in the numbers of mica bearing mutiple lung or liver neo- plasms. Dose-related increases were observed in the incidences of testicular atrophy in male mice and uterine and ovarian atrophy in female mice. ‘Serota et al." reported on a 2-year study in which groups of male and female mice were administered 0, 60, 125, 185, or 250 mg/kg/day of methylene chloride in deionized drinking water. According to the abstract." The high-dose male and female mice showed a transitory increase in mean leukocyte counts. ‘Treatment-related toxic changes were noted in both male and female livers at the highest dose. ‘There was a slight elevation but no dose-related trend of proliferative hepatocellular lesions in the treated males which was absent in the females. Neoplastic lesions observed in the study were homogeneous among all groups and were within historical control incidence range. Based upon the results ofthis study, a toxicological “no-ob- servable-effect level (NOEL)" was observed for DCM at 185 mofkg body weightiday in both sexes. Reproductive/Developmental No teratogenic effects were observed™" in pregnant rats that inhaled 4500 ppm methylene chloride during critical periods of gestation. These results confirmed those found in a previous study'* carried out at 1250 ppm on pregnant rats and mice. When fed in the diet to Wistar rats, no teratogenic effects were observed at doses as high as 600 mg/kg/day although maternal ‘weight was decreased." Exposure of rats at concentrations as high as 1500 ppm methylene chloride vapor 6 hours/day, 5 days/week did not affect any of the reproductive parameters @xam- ined in a two-genaration reproduction study."* Genotoxicity Studies The mutagenicity of methylene chloride has been studied in numerous test systems. The data have been ‘summarized and reviewed by Sivak"® who concluded that the available data were conflicting and sometimes irteproducible because of high volatility, poor aqueous solubilty, and lack of purty of test samples. Methylene chloride is a mutagen in bacteria, but # has not been shown to cause mutations in mammalian cells. it has been shown to cause chromosome aberrations in vitro, but not in vivo, and it did not induce micronuclei in vivo. Generally, sister-chromatid exchange studies have given negative results except for one in Chinese hamster ovary (CHO) calls at a concentration of 7% and with prolonged (24-hour) incubation. Tests in miscellaneous plant and animal systems have shown that methylene chloride is. - cytotoxic. Methylene chloride was not mutagenic in Drosophila except in one study where the dose exceeded the water solubilty of methylene chloride. Certified, but nat food grade, methylene chloride gave a positive re- sponse in one Fischer rat embryo cell cuture transforma- tion assay and only a weak response upon retesting under more stringent exposure conditions. Methylene chloride gave a positive response in the Simian ade- novirus-hamster cell system but did not induce in vitro neoplastic transformation of two mouse fibroblast cell lines (C3H-10T 1/2, BALB/C-3T3). Carbon-14 from “C- methylene chloride is associated with nonalkylated bases and nucleosides in DNA of rats and hamsters‘exposed by inhalation, indicating “C-1 (C-1 metabolic pool) incorporation by normal biosynthetic pathways. ‘The positive response inthe Ames assay and occasional responses in other genetic assays prevent a clear desig- nation of methylene chloride as not being genotoxic. However, the extensiveness of the negative data in well- validated mammalian cell systems, the absence of geno- toxic events in vivo, and the potentially important role of cytotoxicity in producing chromosome lesions fail to sup- port a genetic rationale for a carcinogenic response. The potential for “C-methylene chloride to alkylate target tissue DNA has been evaluated by Schumann et al" Rats and hamsters were exposed at 3500 ppm of ¢-methylene chloride for 1.5-3 hours; the DNA from liver and salivary tissue was isolated and purified. While “CG activity was associated with DNA in these tissues, it ‘appeared associated only with normal bases and nucleo- sides, indicating “C-1 incorporation by normal biosyn- thetic pathways (pooHabeling). Importantly, no alkylated bases or nucleosides were identified at low levels of detection [< 12 and 1 alkylation(s) per 10° nucleotides per {raction for nucleosides and bases, respectively). Similar in vivo experiments using mouse and rat lung and liver tissue were conducted by Green et al.” This study allowed for distinction between incorporation derived trom alkylation of DNA by methylene chloride or its ‘metabolites as opposed to incorporation via the normal C-1 metabolic pool. There was no evidence for the for- mation of DNA adducts in either species. Methylene chioride was assessed in both an in vivo— in vitro and an in vitro hepatocyte unscheduled DNA synthesis (UDS) assay in Fischer 344 rats and B6C3F1 mice. The in vivo evaluation used 2- and 6-hour expo- sures at 2000 and 4000 ppm of methylene chloride by inhalation. In the in vitro evaluation, hepatocytes were exposed for 8 hours at methylene chloride concentra- tions of up to 4000 ppm. Under the conditions of the ‘assays, methylene chloride did not induce UDS in either rats or mice."* ‘The UDS study resus are consistent with those of the DNA binding studies, and these result tend to rein- force the view that neither methylene chloride nor its ‘metabolites interact directly with mammalian DNA (i isnot "genotoxic”). It this view is corract, the mechanism of carcinogenesis in the BEC3F'1 mouse under the con- ditions of the National Toxicology Program (NTP) bioas- say is most likely indirect. The major interspecies di ferences in tumor expression would not then be unex- pected. Furthermore, itis easier to explain the observed 1no-effect level in the drinking water bioassays""? on the toasis of an indirect, nongenotoxic mechanism. Pharmacokinetic/Metabolism Studies The metabolism of methylene chloride to carbon monoxide and the subsequent production of carboxy- hemoglobin (COHb) has been studied in animals and ‘man. In the rat, metabolism appears to be saturable with disproportionately less COHb formed and more un- changed methylene chloride expired as exposure in- creased." Human Studies Considering the widespread usage of methylene chloride, reports of human injury are few. Moskowitz and Shapiro®® reported four cases of poisoning with one fatality, apparently due to narcotic action. Collier®” re- ported two cases of poisoning in painters who suffered from headache, giddiness, stupor, initabilty, nurrbness, and tingling in the limbs. Kuzelova and Viasak™ noted complaints of headache, fatigue, andirrtation of the eyes ‘and respiratory passages by workers exposed at concen- trations up to 5000 ppm. Neurasthenic disorders were found in 50% of the workers exposed, and digestive disturbances were found in 30%. Three acute poison- ings, one involving loss of consciousness, were recorded without serious aftereffects. Generally, there has been ‘complete recovery if exposure is terminated before an- esthetic death occurs. Weiss™ stated that a chemist developed toxic ‘encephalosis with acoustical and optical delusions and hallucinations atter being exposed to methylene chloride for 1 year. Concentrations frequently exceeded 500 ppm:; values of 660, 800, and 3600 ppm were noted with the latter concentration near the floor. Golubovskii and Kamchatnova™ found liver disease in workers exposed to methylene chioride and methanol which they attributed to the former. Exposure concentra tions were not reported. In the early 1940s, methylene chloride was consid- ered the least toxic of the chlorinated hydrocarbon sol- vents when a safe industrial air limit of 500 ppm was proposed by Heppel et al" and later adopted by the TLV Committee as protective enough to prevent any signifi- cant narcotic effects or liver injury. ‘Subsequently, Stewart et al. reported that signifi- cant quantities of carbon monaxide and COHb were pro- duced in humans receiving single exposures at 500-1000 ppm of methylene chloride. The COHb concentrations reported by Stewart approximated those considered abjec- tionable if due to inhalation of carbon monoxide. More extensive examination of carbon monoxide production from methylene chloride was later reported by the same investigators.°° Human volunteers, exposed to methylene chloride at 1000 ppm for 2 hours (2000 ppm-hours, one-haif of the concentration x time [Ct] permitted for an 8-hour exposure at 500 ppm) produced ‘COHb levels in excess of those permitted in industry from exposure to carbon monoxide alone. This finding of the body's capacity to metabolize methylene chloride to carbon monoxide was confirmedby Ratney et al.” in a amall group of workers exposed ‘at 180-200 ppm methylene chloride. Such dally, re- peated exposures resulted in a 9% COHb equilibrium blood concentration which decreased to half that value bby the next day's start of work, indicating a possible secondary source of carbon monoxide such as auto ‘exhaust or smoking. The differential increment in percent COHD of 4.5% from a 1-day exposure at 180-200 ppm of methylene chloride is approximately the same as that developed fram a daily exposure to carbon monoxide at 50 ppm. DiVincenzo et al." found that humans exposed at 100 ppm methylene chloride for 8 hours had a COHD level of 3.22% + 0.22%, whereas an 8-hour exposure at 150 ppm produced a 5.39% + 0.06% COHb level, and an ‘8-hour exposure at 200 ppm resulted in a COHb level of 6.8% £0.65%. In an extensive study. several healthy adults of both sexes ware exposed from two to ten times to methylene chloride vapor at concentrations of 0, 50, 100, 250, or 500 ppm for periods of 2, 3. and 7.5 hours in a controlled environment chamber. These studies were ‘designed to simulate the type of exposure encountered in the industrial setting and consisted of both steady and fluctuating vapor concentrations. Exposure resutted in a prompt elevation of COHD. The elevation persisted longer than COHb from carbon monoxide alone because metabolism of the absorbed methylene chloride contin- ued after exposure ceased. This solvent-induced COHb is apparently added to the body burden of carbon mon oxide derived from other sources. This study™ corroborated previous single-exposure studies in that no deleterious effects upon the heath or performance of healthy adutts could be detected when they were repeatedly exposed at 250 ppm or less ‘methylene chioride for 7.5 hours/day, 5 dayshveek for 2 ‘weeks, or in the case of the male subjects, at 500 ppm ‘on 2 consecutive days. Among the parameters studied ‘were complete blood count; clinical chemistry (SMA 12); ‘electrocardiogram; serum triglycerides: blood pressure; subjective signs and symptoms; urinalysis (Combistix); Urinary urobilingen; neurological tests; electroencepha fogram; visual-evoked response; pulmonary function; and cognitive, alertness, time estimation, coordination, arithmetic, and inspection tests. ‘The increase in COHb was related to the magnitude of the vapor exposure. Both duration of exposure and vapor concentration were factors. In nonsmokers, 7.5- hour exposures at concentrations of 100 ppm for 5 days resutted in COHb elevation of about 5%. The odor was not objectionable at 250 ppm, and many subjects could ‘ot detect methylene chloride atthe 50 or 100 ppmlevals. Two epidemiologic studies of workers exposed 10 methylene chloride have been published.” While both studies are of good quality, neither is large enough to be definitely inconsistent with a prion extrapolations based ‘on mouse liver tumors. The second study." however, strongly indicated that no increase in lung tumors had ‘occurred. An excess of pancreatic tumors was noted (8 ‘observed versus 3.2 expected) in an update™ to the second” study. Ott ot al. reported 7 deaths due to malignant neoplasms while 12.4 were expected in the methylene chloride-exposed workers. Friedlander et al.°” updated previous publications by studying mortality through 1984 of a study group of 751 male production workers who ‘were employedin 1964. “Atthat time, approximately 77% had worked with this compound for 10 years or longer. Also studied was a subsample of 252 men with a mini- ‘mum of 20 years methylene chloride experience prior to 1964." An all-cause SMR of 71 (significantly low) and 99, respectively, ware observed when upstate New York and Kodak-Rochester populations were used for compari- son. Thirty-nine malignancy deaths were observed com- pared with the 54.7 expected (SMR 71) based on upstate New York death rates and the 43.2 expected for Kodak Rochester (SMA 90). When those with a minimum of 20 years exposure in 1964 wore studied, 97 deaths were ‘observed versus 144.1 expected, based on upstate Now ‘York, and 107.9 expected, based on the Kodak popula- tion. No cause of death was statistically significant except {for lower-than-predicted cardiovascular deaths based on the state death rates. Friedlander et al. concluded,”” The most recent findings from a maturing cohort of Eastman Kodak Company employees with chronic exposure to methylene chloride (ap- proximate time-weighted average, 30-120 ppm) ‘were consistent with previous studies which showed no evidence of an increased mortality risk for lung cancer and cardiovascular disease. ‘Such a conclusion can be stated with a greater degree of certainty than was possible earlier because the number of expected deaths has approximately doubled since the original follow- up study was published. There was, in contrast, insufficient statistical power to address such rare disorders as male breast and liver cancer. ‘TLV Recommendation In order to provide a wider margin of safety for minimizing the potential for liver injury, a lowering of the recommended TLV-TWA from 100 ppm to 50 ppm was recommended for methylene chloride in the absance of ‘occupational exposure to carbon monoxide. This level should also provide protection against the possible weak carcinogenic etfects of methylene chloride which have been demonstrated in laboratory rats and mice. In view of the long history of methylene chloride use, including available epidemiologic studies without documentation of health-related injuries using the previous TLV guide-lines, a 50 ppm 8-hour TWA exposure should not pose a problem to this occupational work force. No STEL is ‘suggested at this time. The reader is encouraged to review the section on Excursion Limits in the “Introduc- tion to the Chemical Substances" in the current edition of the TLV/BEI Booklet for guidance and control of excur- sions above the TLV-TWA, even when the B-hour TWA is within the recommended limits. Combined carbon monoxide and the methylene chloride exposures yield additive increases in the COHb levels with rats. The appropriate TLV equation for mixtures should be used to determine if the mixed exposure to methylene chloride and carbon monoxide is acceptable. Other Recommendations (OSHA PEL: Methylene chloride was one of the nine substances in the 1989 rulemaking for which there were no changes to the existing PELs because OSHA was in the process of a 6(b) rulemaking. The current and prior OSHA PELs were 500 ppm as an -hour TWA, 1000ppm as an acceptable ceiling concentration, and 2000 ppm as ‘an acceptable maximum peak above the acceptable ceiling concentration for 5 minutes in any 2 hours.° NIOSH REL/DLH: The NIOSH REL for methylene chloride is to reduce exposure to the lowest feasible concentration because the substance is a potential hu- man carcinogen.” An IDLH value of 5000 ppm [NIOSH CARCINOGEN) was established by NIOSH for this chemical. ACGIH Rationale for TLVs that Ditter from the PEL or REL: The NIOSH REL for methylene chloride, expo- sure to the lowest feasible concentration, is based on an ‘enhancement of tumors of the lung, liver, salivary glands, ‘and mammary tissue in various rodent studies. ACGIH recognizes the weak carcinogenic effects of methylene chloride demonstrated in laboratory rats and mice but believes the current TLV-TWA of 50 ppm provides an adequate margin of safety. This position is based upon the long history of methylene chloride use, including epidemiologic studies, without documentation of health- related injuries at higher exposures, the lack of convinc- ing evidence to conclude that methylene chloride is genotoxic in animals, negative carcinogenic data from rodent studies using similar or lower administered doses, and demonstrable differences in metabolic and kinetic constants at different dose levels in various species including man, e.g., the glutathione-S-transferase path- way. The TLV for methylene chloride was established to provide a wider margin of safety in preventing liver injury and the long-term risk of cancer. Due to the public health significance of adverse heatth effects following exposure to methylene chloride, ACGIH will continue to study new data and interpretations of existing data for their rele- vance in revising the TLV. NTP Studies: NTP has tested methylene dichloride {orits long-term toxicology and carcinogenesis effects on three separate occasions. The frst study was by gavage in both sexes of Fischer 344 rats and BC3F1 mice; the study was considered inadequate and no data were reported. The second study was by inhalation and re- ported clear evidence of carcinogenicity in both sexes of the BEC3F1 mouse and the female Fischer 344 rat; some evidence of carcinogenicity was reported in the male Fischer rat. The third study, which has not been com- pleted, was designed to test the interaction of methylene chloride (one dose 500 mg/kg) when administered in com oll (doses 0, 2.5, 5, 10 mUKg) to 50 male rats. Genetic toxicology studies have not been conducted by the NTP; but the chemical has been selected for testing in the Salmonella assay. Carcinogenic Classification IARC: Group 2B, probably carcinogenic in humans. MAK: Group B, suspected of having carcinogenic poten- tial. NIOSH: Carcinogen, with no further classification. ‘TLV: A2, suspected human carcinogen. Other Nations ‘Australia: 100 ppm, Category 3, suspected ot having carcinogenic potential, proposed change 50 ppm (1990); Federal Republic of Germany: 100 ppm, short-term level 500 ppm, 30 minutes, twice per shift; justifiably sus- pected of having carcinogenic potential (1992); Sweden: 70 ppm, shod-term level 150 ppm, 15 minutes, skin (1991); United Kingdom: 100 ppm, 10-minute STEL 250 ppm (1981). References 1. 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