The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for METHYLENE CHLORIDE

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

September 1993

Prepared by Cheryl B. Bast, Ph.D., Chemical Hazard Evaluation and Communication Program, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *, Oak Ridge, Tennessee.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Methylene chloride (CH₂Cl₂, CAS No. 75-09-2), also known as dichloromethane is a colorless volatile liquid with a penetrating ether-like odor. In industry, methylene chloride is widely used as a solvent in paint removers, degreasing agents, and aerosol propellants; as a polyurethane foam-blowing agent; and as a process solvent in the pharmaceutical industry. The compound is also used as an extraction solvent for spice oleoresins, hops, and caffeine (ATSDR, 1989; IARC, 1986).

Methylene chloride is readily absorbed from the lungs, the gastrointestinal tract, and to some extent through the skin. Metabolism of methylene chloride produces CO₂ and CO, which readily binds with blood hemoglobin to form carboxyhemoglobin (CO-Hb). The primary adverse health effects associated with methylene chloride exposure are central nervous system (CNS) depression and mild liver effects. Neurological symptoms described in individuals occupationally exposed to methylene chloride included headaches, dizziness, nausea, memory loss, paresthesia, tingling hands and feet, and loss of consciousness (Welch, 1987). Major effects following acute inhalation exposure include fatigue, irritability, analgesia, narcosis, and death (ATSDR, 1989). CNS effects have also been demonstrated in animals following acute exposure to methylene chloride (Weinstein et al., 1972; Berger and Fodor, 1968).

Impaired liver function has been associated with occupational exposure to methylene chloride (Welch, 1987). Liver effects have also been documented in a number of inhalation studies with laboratory animals. Subchronic exposure of rats, mice, dogs, and monkeys caused mild hepatic effects such as cytoplasmic vacuolization and fatty changes (U.S. EPA, 1983; Haun et al., 1972; Weinstein and Diamond, 1972; Heppel, 1944). Hepatocellular foci, fatty changes, and necrosis were reported following chronic inhalation exposure of rats and mice (Nitschke et al., 1986a; NTP, 1986). Chronic oral exposure to methylene chloride via drinking water resulted in histopathological alterations of the liver in rats and mice (NCA, 1982, 1983). In addition, inhalation exposure of rats caused nonspecific degenerative and regenerative changes in the kidneys (U.S. EPA, 1983; Haun et al., 1972).

A subchronic and chronic oral reference dose (RfD) of 6E-2 mg/kg/day for methylene chloride has been calculated by U.S. EPA (1993a,b). This value is based on a NOAEL of 5.85 mg/kg/day derived from a chronic drinking water study with rats (NCA, 1982). This same study was adapted for the derivation of the subchronic and chronic reference concentration (RfC) of 3E+0 mg/m³ (NOAEL, 694.8 mg/m³) (U.S. EPA, 1993a).

Studies of workers exposed to methylene chloride have not recorded a significant increase in cancer cases above the number of cases expected for nonexposed workers (Hearne et al., 1987; Ott et al., 1983a; Friedlander et al., 1978). However, long-term inhalation studies with rats and mice demonstrated that methylene chloride causes cancer in laboratory animals. Mice exposed via inhalation to high concentrations of methylene chloride (2000 or 4000 ppm) exhibited a significant increase of malignant liver and lung tumors compared with nonexposed controls (NTP, 1986). Rats of both sexes exposed to concentrations of methylene chloride ranging from 500 to 4000 ppm showed increases of benign mammary tumors (Nitschke et al., 1988a; NTP, 1986; Burek et al., 1984). An inhalation study with rats and hamsters revealed sarcomas of the salivary gland in male rats, but not in female rats or hamsters (Burek et al., 1984). Liver tumors observed in rats and mice that ingested methylene chloride in drinking water for 2 years provided suggestive evidence of carcinogenicity (NCA, 1982, 1983). Based on inadequate evidence of carcinogenicity in humans and on sufficient evidence in animals, U.S. EPA (1993b) has placed methylene chloride in weight-of-evidence group B2, probable human carcinogen. A slope factor and unit risk of 7.5E-3 (mg/kg/day)^-1 and 2.1E-7 (ug/L)^-1, respectively, (U.S. EPA, 1993b) was derived for oral exposure to methylene chloride. The inhalation unit risk is 4.7E-7 (ug/m³)^-1 (U.S. EPA, 1993b).

1. INTRODUCTION

Methylene chloride (CH₂Cl₂, CAS No. 75-09-2), also known as dichloromethane, is a halogenated aliphatic hydrocarbon with a molecular weight of 84.94. It is a colorless liquid with a penetrating ether-like odor, a boiling point of 39.75C, and a density of 1.3348 (20C/4C). It is soluble in about 50 parts of water and is miscible with alcohol and ether (Budavari et al., 1989; IARC, 1986). The vapor is not flammable and when mixed with air is not explosive (Budavari et al., 1989); however, methylene chloride reacts vigorously with some metals. When heated to decomposition, it emits highly toxic fumes of phosgene (Sax, 1984). Methylene chloride is not known to occur naturally; it is produced by hydrochlorination of methanol or chlorination of methane or methyl chloride. Methylene chloride is widely used in a variety of industrial and commercial applications. It is used as a solvent in paint removers, degreasing agents, and aerosol propellants; as a polyurethane foam-blowing agent; as a process solvent in the pharmaceutical industry; and as an extraction solvent for spice oleoresins, hops, and caffeine (ATSDR, 1989; IARC, 1986).

Human exposures to methylene chloride are highest in occupational settings and near industrialized urban areas. Consumers may be exposed to significant amounts of methylene chloride vapor in such products as paint strippers and thinners, water repellents, wood stain and varnishes, and spray paint (ATSDR, 1989). Most of the methylene chloride released to the environment enters the atmosphere, while smaller amounts enter surface water and ground water. The chlorination of drinking water also produces methylene chloride. In the atmosphere, reaction with photochemically generated hydroxyl radicals is expected to be the predominant removal mechanism. Losses of methylene chloride from water are primarily due to volatilization (U.S. EPA, 1989).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Humans and animals readily absorb methylene chloride from the lungs and the gastrointestinal tract into systemic circulation. The compound is also absorbed to some extent through intact skin (ATSDR, 1989; U.S. EPA, 1989). DiVincenzo and Kaplan (1981) exposed groups of 4-6 volunteers to 50, 100, 150, or 200 ppm methylene chloride for 7.5 hours. Pulmonary absorption (measured as concentration in expired air) was rapid during the first hour, then began to decrease as steady-state was approached. Following cessation of exposure, methylene chloride concentrations in exhaled air dropped rapidly. U.S. EPA (1980) reported lung absorption efficiencies of 31-75%. The absorption of methylene chloride increased with exposure concentration, length of exposure, and activity level. The absorption of methylene chloride also appears to be related to degree of obesity in humans (Engstrom and Bjurstrom, 1977). When exposed to 750 ppm for 1 hour, obese subjects absorbed 30% more methylene chloride than lean subjects.

Studies with rats and mice showed that methylene chloride is almost completely absorbed from the gastrointestinal tract of both species following daily gavage treatment with 50 or 200 mg/kg/day (rats) or 50 or 1000 mg/kg/day (mice) for 14 days (Angelo et al., 1986a,b). The presence of methylene chloride in various tissues of rats following immersion of the tails indicates that the compound can be absorbed through the skin (NIOSH, 1976).

2.2. DISTRIBUTION

Following absorption, methylene chloride concentrations rapidly increase in the blood to reach equilibrium levels that depend primarily on exposure concentrations. A fairly uniform distribution to heart, liver, and brain is reported (U.S. EPA, 1980). Biopsy and analysis of subcutaneous fat of obese and lean human subjects following exposure to 750 ppm methylene chloride for 1 hour showed a substantial accumulation in adipose tissue (10.2 and 8.4 mg/kg wet tissue, 1 and 4 hours postexposure, respectively). Although the concentrations in fat were slightly lower in the obese, the total amount of body fat resulted in greater total accumulation of methylene chloride (Engstrom and Bjurstrom, 1977).

Methylene chloride crosses the placenta (Anders and Sunram, 1982). The compound has been detected in fetuses of pregnant women who had been chronically exposed to methylene chloride in the work place. It has also been found in milk of lactating women a few hours into a work shift (U.S. EPA, 1980).

2.3. METABOLISM

Extensive toxicokinetic studies have shown that methylene chloride is metabolized in vivo by two pathways: (1) a mixed function oxidase (MFO) pathway mediated by the P-450 system yielding CO and CO₂ and (2) a glutathione-dependent (GST) pathway yielding only CO₂. Other metabolites of methylene chloride include formaldehyde and formic acid (ATSDR, 1989). The detection of formic acid in the urine of workers exposed to methylene chloride has led investigators to suggest that methylene chloride is first metabolized to formaldehyde and then to formic acid (Kuzelova and Vlask, 1966). The MFO pathway is saturable at air concentrations of a few hundred ppm. However, the GST pathway shows no indication of saturation at inhaled concentrations up to 10,000 ppm (ATSDR, 1989). Biotransformation of methylene chloride occurs primarily in the liver, but also occurs in the lungs and kidneys (NTP, 1986).

Although some CO is exhaled, a significant amount is involved in the formation of carboxymethemoglobin (CO-Hb). The formation of CO-Hb leads to interference with normal oxygen transport capabilities of blood, resulting in oxygen deprivation and secondary toxic effects. Bioconversion of CO and formation of CO-Hb continues after exposure (U.S. EPA, 1980).

2.4. EXCRETION

Excretion of methylene chloride from the body occurs primarily via expired air from the lungs as unchanged parent compound or as CO and CO₂, the primary metabolites. The absorbed dose is a major determinant of the elimination product. At low exposure concentrations, a large percentage of administered methylene chloride is metabolized and eliminated as CO and CO₂. At higher concentrations, more of the unchanged parent compound is exhaled in expired air (ATSDR, 1989). A small fraction of absorbed methylene chloride is also eliminated in the urine. Methylene chloride and formic acid were detected in the urine of humans exposed by inhalation to 100 or 200 ppm methylene chloride for 24 hours (DiVincenzo et al., 1972).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Information on the acute oral toxicity of methylene chloride in humans was not available.

3.1.1.2. Animal

Oral LD₅₀ values for methylene chloride of 2121 mg/kg for rats and 1987 mg/kg for mice indicate that the two species are similarly susceptible to the lethal effects of methylene chloride (ATSDR, 1989).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic oral toxicity of methylene chloride in humans was not available.

3.1.2.2. Animal

No adverse effects on behavior, body weight, survival, or clinical chemistry were observed in male and female Wistar rats exposed to drinking water containing 125 ppm methylene chloride/L for 3 months. Histopathological examination of internal organs revealed no lesions (Bornmann and Loeser, 1967). Minor hematological changes and clinical chemistry parameters that reflected impaired liver function were observed in F344 rats and B6C3F₁ mice exposed to drinking water containing 1500, 4500, or 15,000 ppm methylene chloride for 90 days (Kirschman et al., 1986). A dose-related decrease of urinary pH was seen in all treated groups of rats and increased kidney weights in female rats exposed to the highest dose. Some mid-dosed female and high-dosed male and female rats had centrilobular necrosis of the liver. Mild centrilobular fatty changes of the liver occurred in mice at greater than or equal to 4500 ppm.

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the chronic oral toxicity of methylene chloride in humans was not available.

3.1.3.2. Animal

Drinking water studies conducted by the National Coffee Association (NCA, 1982, 1983; also reported by Serota et al., 1986a,b) exposed F344 rats to 0, 5, 125, or 250 mg/kg/day and B6C3F₁ mice to 0, 60, 125, 185, or 250 mg/kg/day of methylene chloride for 104 weeks. Slight effects on hematological parameters and serum chemistry were seen in rats. Treatment-related liver effects, most prominently increased foci of cellular alterations and fatty changes, occurred in rats at all doses except the lowest. In mice, histomorphologic alterations of the liver were observed only in males and females receiving the highest dose.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental and reproductive toxicity of methylene chloride in humans following oral exposure was not available.

3.1.4.2. Animal

Administration of 125 ppm methylene chloride in drinking water for 91 days did not affect the estrus cycle or reproduction of male and female rats (Bornmann and Loeser, 1967).

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD: 6E-2 mg/kg/day (U.S. EPA, 1993a)
NOAEL: 5.85 mg/kg/day
LOAEL: 52.58 mg/kg/day
UNCERTAINTY FACTOR: 100
PRINCIPAL STUDY: NCA, 1982
COMMENTS: The same study applies to the subchronic and chronic RfD. The study is described in Section 3.1.3.2.

3.1.5.2. Chronic

ORAL RfD: 6E-2 mg/kg/day (U.S. EPA, 1993b)
NOAEL: 5.85 mg/kg/day
LOAEL: 52.58 mg/kg/day
UNCERTAINTY FACTOR: 100
CONFIDENCE: Study: High Data Base: Medium RfD: Medium
VERIFICATION DATE: 11/06/85
PRINCIPAL STUDY: NCA, 1982
COMMENTS: The same study applies to the subchronic and chronic RfD. The chronic RfD was based on a no-observed-adverse-effect level (NOAEL) of 5.85 mg/kg/day in male rats derived from the 2-year drinking water study described in Section 3.1.3.2. Histopathological lesions of the liver were seen at 52.58 mg/kg/day which was considered the lowest-observed-adverse-effect level (LOAEL). The uncertainty factor includes two factors of 10 for intra- and interspecies variability.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Humans exposed to high concentrations of methylene chloride for short time periods may experience central nervous system effects, including narcosis, irritability, analgesia, and fatigue (ATSDR, 1989). Human volunteers exposed by inhalation to methylene chloride concentrations exceeding 300 ppm for 4 hours exhibited decreased auditory and visual functions; exposure to approximately 800 ppm for 4 hours resulted in impaired performance of most psychomotor functions (Winneke, 1974). Exposure to 25,000 ppm for 2 hours was not lethal. Exposure to 7,200 ppm caused paresthesia of the extremities after 8 minutes, acceleration of the pulse after 16 minutes, and congestion of the head, a sensation of heat, and slight irritation of the eyes during the first 20 minutes. At 2300 ppm, nausea occurred after a 30-minute exposure (Sax, 1984). Exposure to very high (unspecified) concentrations of methylene chloride has lead to rapid unconsciousness and death, but prompt removal from exposure usually leads to complete recovery (Torkelson and Rowe, 1981). Accidental deaths have been reported as a result of acute methylene chloride exposure during paint stripping operations (Stewart and Hake, 1976; Bonventre et al., 1977). In fatal poisonings, cardiac injury and heart failure have been reported as cause of death (U.S. EPA, 1980).

3.2.1.2. Animal

Inhalation LC₅₀ values for methylene chloride listed by ATSDR (1989) range from 14,155 ppm (6-hour exposure) to 26,710 ppm (20-minute exposure) for mice. The LC₅₀ for guinea pigs exposed for 6 hours is 11,600 ppm. Short-term inhalation studies showed that exposure to high concentrations of methylene chloride produces central nervous system effects in several species. Slight narcosis was seen in dogs exposed to 6000 ppm after 2 hours, in guinea pigs after 2.5 hours, and in rabbits and cats after 3-4 hours (Weinstein et al., 1972); deep narcosis occurred in rats exposed to 16,000-18,000 ppm for 6 hours (Berger and Fodor, 1968).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Unspecified neurological symptoms were reported by a group of 46 male workers who had been exposed to methylene chloride concentrations ranging from 75 to 100 ppm (duration of exposure not reported) (Cherry et al., 1980). A follow-up study on 29 of the exposed workers provided no evidence of neurological or behavioral impairment or cardiac abnormalities. Exposure of 56 workers to a 9:1 methylene chloride:methanol atmosphere caused mental and physical tiredness and sleepiness. These parameters were significantly different only for the morning shift and correlated with blood CO-Hb levels at the end of the shift (Cherry et al., 1983). Welch (1987) reported that workers from various industries experienced a variety of CNS effects, such as headaches, dizziness, nausea, memory loss, paresthesia, tingling hands and feet, and loss of consciousness. Workers were exposed to methylene chloride levels measured up to 100 ppm and duration of exposure was 6 months to 2 years.

Ott et al. (1983a) found no excess mortality from circulatory system diseases among employees of a fiber production plant that used methylene chloride as a solvent. Workers were exposed for at least three months to a time-weighted-average concentration of 140 ppm methylene chloride. In a related study on cardiac function, Ott et al. (1983b) examined EKGs of 50 workers from two fiber-producing plants. Data from the plant where exposure concentrations ranged from 60-474 ppm (time-weighted-average) were compared with data from a similar plant not using methylene chloride. No significant changes in ventricular or supraventricular ectopic activity, nor ST-wave segment depression were associated with exposure to methylene chloride.

A case of hepatitis was reported in a worker who had used methylene chloride in combination with other solvents. Although exposure levels were not reported, methylene chloride levels in the serum were significantly higher than those reported for other solvents. Several workers exposed to solvents in similar work environments had abnormal liver function tests (Welch, 1987).

3.2.2.2. Animal

In early experiments, Heppel et al. (1944) exposed rats, rabbits, and guinea pigs to 5000 ppm methylene chloride, 7 hours/day, 5 days/week for up to 6 months. Decreased growth in guinea pigs was the only observed adverse effect. Exposure to 10,000 ppm, 4 hours/day, 5 days/week for up to 8 weeks caused fatty liver changes in guinea pigs and dogs, but no adverse effects in rats and rabbits.

A number of subchronic inhalation experiments were initiated due to a concern of potential exposure of astronauts to methylene chloride vapors emanating from materials used in spacecrafts. A summary of these studies was presented by U.S. EPA (1983). Mice exposed to 25 or 100 ppm methylene chloride continuously for 14 weeks had increases in spontaneous motor activity and at the lower concentration but not at the higher concentration. Rats subjected to the same exposure protocol had nonspecific renal tubular degeneration and regeneration and hepatic fatty changes and cytoplasmic vacuolization at both exposure levels. Exposure to the same concentrations produced increased carboxymethemoglobin levels in monkeys at both concentrations and in dogs only at 125 ppm. Exposure of the same four species to 1000 or 5000 ppm resulted in signs of severe toxicity at 5000 ppm: narcosis was observed during the first 24 hours and pronounced lethargy for the remainder of the exposure period. All rats survived, but high rates of mortality occurred in mice, dogs, and monkeys. Common findings in all species were liver and kidney damage.

Exposure of ICR mice to 100 ppm methylene chloride for 10 weeks produced centrilobular hepatic fat accumulation and decreased glycogen levels in mice (Weinstein and Diamond, 1972). Cytoplasmic vacuolization and fatty liver changes were also reported in rats and dogs exposed to 25-100 ppm methylene chloride for 100 days. Rats additionally exhibited nonspecific renal tubular degenerative and regenerative changes (Haun et al., 1972).

3.2.3. Chronic Toxicity

3.2.3.1. Human

Epidemiological studies have not shown adverse effects in humans occupationally exposed to methylene chloride. A study of male workers at Eastman Kodak exposed primarily to methylene chloride concentrations of 30-120 ppm methylene chloride for up to 30 years did not reveal any indication of increased risk of death from circulatory disease or other causes compared with nonexposed workers or the general population (Friedlander et al., 1978).

3.2.3.2. Animal

Nitschke et al. (1988a) exposed male and female Sprague-Dawley rats by inhalation to 0, 50, 200, or 500 ppm methylene chloride, 6 hours/day, 5 days/week for 2 years. An increased incidence of hepatocellular vacuolization was observed in male and female rats exposed to 500 ppm; female rats also had an increased incidence of multinucleated hepatocytes. In another long-term bioassay, increased incidences of hemosiderosis, cytomegaly, cytoplasmic vacuolization, necrosis, granulomatous inflammation, and bile-duct fibrosis were observed in the livers of treated male and female F344/N rat and B6C3F₁ mice (NTP, 1986). The exposure concentrations were 1000, 2000, or 3000 ppm for rats and 2000 or 4000 ppm for mice.

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

A case-control study on possible causes of spontaneous abortions among 44 women working in the Finnish pharmaceutical industry showed an increased risk associated with exposure to several chemicals and solvents, including methylene chloride (Taskinen et al., 1986).

3.2.4.2. Animal

Nitschke et al. (1988b) evaluated reproductive parameters in F344 rats following exposure to concentrations of 0, 100, 500, or 1500 ppm methylene chloride over the course of two successive generations. No adverse effects on fertility, litter size and neonatal growth, or survival were noted in animals exposed to methylene chloride in either the F₀ or F₁ generation. Similarly, there were no treatment-related gross pathologic observations in either the F₀ or F₁ adults or the F₀ or F₁ weanlings.

In a 2-year NTP (1986) study, dose-related increases were observed in the incidences of testicular atrophy in male B6C3F₁ mice exposed to concentrations of methylene chloride ranging from 1000 to 4000 ppm, and increased incidence of ovarian and uterine atrophy was seen in female mice exposed to 2000 or 4000 ppm.

3.2.5. Reference Concentration

3.2.5.1. Subchronic

INHALATION RfC: 3E+0 mg/m³ (U.S. EPA, 1993a)
NOAEL: 694.8 mg/m³
UNCERTAINTY FACTOR: 100
PRINCIPAL STUDY: Nitschke et al., 1988a
COMMENTS: The same study applies to the subchronic and chronic RfC. The study is described in Section 3.2.3.2.

3.2.5.2. Chronic

INHALATION RfC: 3E+0 mg/m³ (U.S. EPA, 1993a)
NOAEL: 694.8 mg/m³
UNCERTAINTY FACTOR: 1000
PRINCIPAL STUDY: Nitschke et al., 1988a
COMMENTS: A 2-year inhalation study with rats served as the basis for the RfC. The RfC was based on a NOAEL of 200 ppm (694.8 mg/m³) and liver toxicity seen at 500 ppm (1737 mg/m³) as the critical effect. The uncertainty factor includes two factors of 10 for intra- and interspecies variability.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Humans

Dermatitis has been reported in individuals exposed to methylene chloride while using paint remover formulations (Torkelson and Rowe, 1981).

3.3.1.2. Animals

For mice, the subcutaneous and intraperitoneal LD₅₀ values for methylene chloride are 6452 and 1987 mg/kg, respectively (Kutob and Plaa, 1962; Klaassen and Plaa, 1966). Repeated dermal contact with methylene chloride, if allowed to evaporate, is mildly irritating to the skin of rabbits (Torkelson and Rowe, 1981).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of methylene chloride by other routes of exposure in humans or animals was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of methylene chloride by other routes of exposure in humans or animals was not available.

3.3.4. Developmental and Reproductive Toxicity

Information on the developmental or reproductive toxicity of methylene chloride by other routes of exposure in humans or animals was not available.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

Liver: Subchronic and chronic exposure of aninals to methylene chloride in drinking water has produced changes in clinical chemistry parameters suggesting impaired liver function, centrilobular fatty changes, and necrosis.

3.4.1.2. Other Target Organs

Kidneys: Increased kidney weights and decreased urinary pH suggestive of renal effects were observed in animals subchronically exposed to methylene chloride in drinking water.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

Central nervous system: Neurological symptoms including headaches, dizziness, nausea, memory loss, paresthesia, tingling hands and feet, and loss of consciousness were reported in workers subchronically exposed to methylene chloride. Major effects following acute exposure include fatigue, irritability, analgesia, narcosis, and death. CNS effects have also been demonstrated in animals following acute exposure.
Liver: Chronic inhalation exposure of animals has produced hemosiderosis, cytomegaly, cytoplasmic vacuolization, necrosis, inflammation, and bile-duct fibrosis in animals. Fatty liver changes and cytoplasmic vacuolization were reported in subchronic studies. Impaired liver function has been associated with occupational exposure to methylene chloride.
Kidneys: Subchronic inhalation exposure of animals has produced nonspecific renal tubular degenerative and regenerative changes.

3.4.2.2. Other Target Organs

Reproduction: An increased risk of spontaneous abortions has been associated with occupational exposure to various chemicals and solvents, including methylene chloride. Chronic exposure of animals to methylene chloride has resulted in testicular atrophy in males and in uterine and ovarian atrophy in females.

3.4.3. Other Routes of Exposure

Skin: Dermal contact has produced skin irritation.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the carcinogenicity of methylene chloride in humans following oral exposure was not available.

4.1.2. Animal

In drinking water studies sponsored by the National Coffee Association (NCA, 1982, 1983), F344 rats were administered 0, 5, 50, 125, or 250 mg/kg/day and B6C3F₁ mice were administered 0, 60, 125, 185, or 250 mg/kg/day of methylene chloride for 104 weeks. A statistically significant (pless than 0.05) increased incidence of hepatocellular carcinomas and neoplastic nodules (combined) was seen in female rats treated with 50 or 250 mg/kg/day compared with concurrent controls. These incidences were within historical control ranges. Male rats showed no increase in liver tumors. In the mouse study, there was an increased incidence of hepatocellular carcinomas and neoplastic nodules in male mice that was not statistically significant nor dose-related. Female mice did not have an increased liver tumor incidence. Methylene chloride was not considered carcinogenic under the conditions of this study. However, a later evaluation by EPA (U.S. EPA, 1985) regarded this study as suggestive, but not conclusive evidence for carcinogenicity of methylene chloride.

4.2. INHALATION EXPOSURES

4.2.1. Human

Friedlander et al. (1978) found no increase in cancer-related deaths in a group of 751 male Eastman Kodak workers primarily exposed to methylene chloride at concentrations of 30-120 ppm for up to 30 years compared with those observed in unexposed workers or the general population. Subsequently, Hearne et al. (1987) evaluated an expanded cohort (1013 workers) for cancer mortality. Compared with the general population, there was no statistically significant excess of deaths from malignant neoplasms, respiratory cancer, or liver cancer in exposed workers. An increase in the incidence of pancreatic cancer (8 observed vs. 3.1 expected) was observed but was not statistically significant.

There was no excess of cancer mortality among employees of a fiber production plant who were exposed for at least three months to time-weighted-average concentrations of 140 ppm methylene chloride (Ott et al., 1983a).

4.2.2. Animal

Nitschke et al. (1988a) exposed male and female Sprague-Dawley rats by inhalation to 0, 50, 200, or 500 ppm methylene chloride, 6 hours/day, 5 days/week for 2 years. Compared with controls, female rats exposed to 500 ppm had a significantly (pless than 0.05) increased number of benign mammary tumors/tumor-bearing rat (adenomas, fibromas, and fibroadenomas), with no progression toward malignancy. Tumors observed in male rats were not significantly different from controls.

Another long-term inhalation study of methylene chloride exposed Sprague-Dawley rats and Syrian Golden hamsters to 0, 500, 1500, or 3500 ppm methylene chloride, 6 hours/day, 5 days/week for 2 years (Burek et al., 1984). Reduced survival was seen in female rats exposed to the highest concentration. Female rats showed a dose-related statistically nonsignificant increase in the number of benign mammary tumors/rat. A similar response was seen in male rats, but to a lesser degree. Male rats exposed to 3500 ppm also had a statistically significant (pless than 0.001) increased incidence of sarcomas in the region of the salivary gland. There was no evidence of a carcinogenic response in hamsters.

In an NTP (1986) study male and female F344/N rats and B6C3F₁ mice were exposed to methylene chloride by inhalation, 6 hours/day, 5 days/week for 2 years. The exposure concentrations were 0, 1000, 2000, or 4000 ppm for rats and 0, 2000, or 4000 ppm for mice. Mortality of male rats was high, but was not considered treatment-related. Reduced survival occurred also in female rats and in male and female mice. After adjustment for mortality, there was a significant increase of mammary tumors (fibroadenoma, adenoma, fibroma) in the high-dosed groups in male (pless than 0.05) and female rats (pless than 0.001). Female rats also exhibited an increased incidence of mononuclear cell leukemias. Among treated male and female mice, there were significantly increased incidences of hepatocellular carcinomas in high-dosed males (p=0.005) and in high-dosed and low-dosed females (pless than 0.001). The incidence of combined hepatocellular adenomas and carcinomas in high-dosed males was significantly (p=0.02) higher than controls. Also observed in mice was a significantly (pless than 0.001) increased incidence of alveolar/bronchiolar adenomas and carcinomas in low- and high-dosed males and females. In addition, there were dose-related increases in the number of lung tumors per animal multiplicity in both sexes of mice.

4.3. OTHER ROUTES OF EXPOSURE

4.3.1. Human

Information on the carcinogenicity of methylene chloride in humans by other routes of exposure was not available.

4.3.2. Animal

Theiss et al. (1977) injected Strain A male mice intraperitoneally with 0, 160, 400, or 800 mg/kg of methylene chloride up to three times weekly over a period of 5-6 weeks. Survival of the animals was poor. At the low dose, there was a marginally significant increase of pulmonary adenomas.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification -- Group B2; probable human carcinogen (U.S. EPA, 1993b)
Basis -- Inadequate human data and sufficient evidence of carcinogenicity in animals (increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in male and female mice, and increased incidence of benign mammary tumors in both sexes of rats, salivary gland sarcomas in male rats and leukemia in female rats) (U.S. EPA, 1993b).

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

SLOPE FACTOR: 7.5E-3 (mg/kg/day)^-1 (U.S. EPA, 1993b)
UNIT RISK: 2.1E-7 (ug/L)^-1 (U.S. EPA, 1993b)
PRINCIPAL STUDY: NTP, 1986; NCA, 1983
COMMENT: The slope factor is an arithmetic mean of slope factors derived from the NTP (1986) and the NCA (1983) data. The use of liver tumor data from the NTP inhalation bioassay was considered valid since methylene chloride is rapidly absorbed following either inhalation or ingestion (U.S. EPA, 1993b).

4.5.2. Inhalation

UNIT RISK: 4.7E-7 (ug/m³)^-1 (U.S. EPA, 1993b)
PRINCIPAL STUDY: NTP, 1986
VERIFICATION DATE: 04/06/89
COMMENT: The unit risk incorporates information on pharmacokinetics and metabolism of methylene chloride.

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Last Updated 10/31/97