The Risk Assessment Information System

Toxicity Summary for METHYL ISOBUTYL KETONE

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.

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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

July 1995

Prepared by Rosmarie A. Faust, 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 Lockheed Martin Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Methyl isobutyl ketone (MIBK) (CAS Reg. No. 108-10-1), a clear liquid with a characteristic odor, is a ketone with the chemical formula of CH₃COCH₂CH(CH₃)₂ (Budavari et al. 1989). It is widely used as a solvent for various paints, lacquers, varnishes, adhesives, and rubber cements and as an extractant for mineral oils. The most likely exposures to MIBK are by inhalation of the vapors and by skin contact (NIOSH 1978). MIBK is released to the environment in effluents and emissions from its manufacturing and use facilities, in automotive exhaust gases, and from disposal of consumer products containing MIBK (HSDB 1993).

MIBK is readily absorbed following inhalation (Hjelm et al. 1990) and, by analogy to other ketones (Parmeggiani 1983), is expected to be absorbed through the skin. Metabolism of MIBK involves an oxidative hydroxylation, followed by reduction to the secondary alcohol (DiVincenzo et al. 1976).

Targets for MIBK toxicity appear to be the central nervous system, gastrointestinal tract, liver, kidneys, fetus, and mucous membranes. At high concentrations, MIBK is a central nervous system depressant, inducing ataxia, narcosis, and death in experimental animals (Krasavage et al. 1982, Specht et al. 1940, Specht 1938). Human exposure to lower concentrations has resulted in central nervous system effects such as headache, weakness, vertigo, insomnia, and somnolence. Gastrointestinal effects including nausea, vomiting, loss of appetite, heart burn, and intestinal pain were reported also (Linari et al. 1964, Hjelm et al. 1990). MIBK has been shown to exert synergistic effects on n-hexane neurotoxicity in hens (Abou-Donia et al. 1985). Although MIBK is a central nervous system depressant, peripheral neuropathy similar to that induced by other ketones has not been documented.

Slightly enlarged livers were reported in some workers exposed to MIBK in workplace air (Linari et al. 1964). Increased liver weights were also reported in male and female rats orally exposed for 90 days (Microbiological Associates 1986) and in rats and mice exposed by inhalation for periods ranging from 2 to 14 weeks (Phillips et al. 1987, MacEwen et al. 1971). MIBK has been shown to potentiate carbon tetrachloride-induced liver injury in rats (Pilon et al. 1988). In male and female rats, subchronic oral exposure produced increased kidney weights and nephropathy (Microbiological Associates 1986) and subchronic inhalation exposure resulted in hyalin droplet degeneration of the proximal tubules and some reversible tubular necrosis (Phillips et al. 1987). These effects were not seen in other species tested. Rats and mice exposed by inhalation to high concentrations of MIBK (3000 ppm) during organogenesis demonstrated maternal and fetal toxicity but no teratogenicity (Bushy Run Research Center 1984).

Exposure to MIBK has been shown to irritate the conjunctiva and mucous membranes of the nose and throat (Hjelm et al. 1990, Elkins 1959). MIBK may also produce dermatitis, with skin lesions varying from erythema to small areas of peeling (Linari et al. 1964).

The U.S. Environmental Protection Agency (EPA) (1994) calculated an oral reference dose (RfD) of 8E-1 mg/kg/day for subchronic exposure and 8E-2 mg/kg/day for chronic exposure to MIBK, based on a no-observed-adverse-effect level (NOAEL) of 250 mg/kg/day from a 13-week gavage study with rats (Microbiological Associates 1986). Lethargy, increased liver and kidney weights, and increased urinary protein levels were identified as critical effects. The chronic oral

RfD has been withdrawn from EPA's Integrated Risk Information System (IRIS) pending further review (EPA 1995). EPA (1994) calculated an inhalation reference concentration (RfC) of 8E-1 mg/m³ for subchronic exposure and 8E-2 mg/m³ for chronic exposure to MIBK, based on a no-observed-effect level (NOEL) of 50 ppm from a 90-day inhalation study with rats (Union Carbide Corporation 1983). Increased liver weights and kidney effects were identified as critical effects. The inhalation RfC is currently under review by the RfD/RfC Work Group (EPA 1995).

No studies were available to evaluate the carcinogenicity of MIBK. Furthermore, EPA has not assigned a weight-of-evidence classification for carcinogenicity.

1. INTRODUCTION

Methyl isobutyl ketone (MIBK) (CAS Reg. No. 108-10-1), also known as isopropylacetone, 4-methyl-2-pentanone, and hexone (Budavari et al. 1989), is a ketone with the chemical formula of CH₃COCH₂CH(CH₃)₂ and a molecular weight of 100.16 (ACGIH 1986). It is a clear liquid with a characteristic ketone odor, a boiling point of 115.8C, a freezing point of -84.7C, and a specific gravity of 0.8017 at 20C (ACGIH 1986). It is moderately soluble in water (1.91%) and miscible with alcohol, benzene, and ether (Budavari et al. 1989). MIBK has a vapor pressure of 7.5 mm mercury at 25C and a closed cup flash point of 64F (18C) (ACGIH 1986).

MIBK is produced by the selective catalytic hydrogenation of mesityl oxide (Parmeggiani 1983). It is widely used as a solvent for synthetic resinous paints; lacquers; varnishes; adhesives; rubber cements; aircrafts dopes with cellulose acetate-butyrate bases; 2,4-D; and DDT. As an extractant, it is used in dewaxing mineral oils, refining tall oil, and cleaning metals (NIOSH 1978).

MIBK is released to the environment in effluents and emissions from its manufacturing and use facilities, in automotive exhaust gases, and from disposal of consumer products containing MIBK. In soil, water, and air, MIBK may be removed by photolysis and volatilization. The major photooxidation products are acetone and, in the presence of nitrogen oxides, peroxyacetylnitrate. The most probable route of exposure by occupationally exposed individuals and by the general population are inhalation and dermal contact (HSDB 1993).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Specific studies on the oral absorption of MIBK were not available, but absorption from the gastrointestinal tract can be inferred from systemic toxic effects observed after subchronic administration (Microbiological Associates 1986).

MIBK appears to be readily absorbed following inhalation. Hjelm et al. (1990) exposed human volunteers for 2 hours to 10, 100, or 200 mg/m³ (41, 410, or 820 ppm) of MIBK during light physical exercise on four different occasions. The relative pulmonary uptake was about 60%, and the total uptake increased linearly with exposure concentration.

Although no data were available regarding the dermal absorption of MIBK, by analogy to other ketones (Parmeggiani 1983), MIBK is expected to be absorbed through the skin.

2.2 DISTRIBUTION

In human volunteers exposed for 2 hours to 10, 100, or 200 mg/m³ (41, 410, or 820 ppm) of MIBK during light physical exercise, the concentration of MIBK rose rapidly in blood and

leveled off during the second half of the exposure but did not reach a plateau. No tendency for saturation kinetics was observed. The blood clearance was 1.6 L/hour/kg for all exposure concentrations. Two elimination phases from the blood were identified. The calculated half-times were 11 and 13 minutes for the faster elimination phase (0 to 30 minutes post-exposure) and 59 and 74 minutes for the slower phase (60 to 180 minutes post-exposure) after exposure to 100 and 200 mg/m³, respectively. In guinea pig serum, the half-life and clearance time for MIBK are 66 minutes and 6 hours, respectively (DiVincenzo et al. 1976). Fetal toxicity noted in offspring of rats and mice exposed to MIBK by inhalation indicates that the compound can cross the placenta (Bushy Run Research Center 1984).

2.3 METABOLISM

After a single intraperitoneal injection of 450 mg/kg of MIBK, guinea pigs metabolized MIBK by -1 oxidation to the corresponding hydroxy ketone, 4-hydroxy-4-methyl-2-pentanone, and by carbonyl reduction to the secondary alcohol, 4-methyl-2-pentanol. The latter metabolite may further be conjugated with sulfuric or glucuronic acids or may enter the intermediary metabolism to be eliminated as carbon dioxide or incorporated into tissues (DiVincenzo et al. 1976).

2.4 EXCRETION

The concentration of unchanged MIBK in the urine of volunteers after 2-hour exposures to 10, 100, or 200 mg/m³ (41, 410, or 820 ppm) of MIBK was proportional to the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 hours after exposure (Hjelm et al. 1990). The amount eliminated via exhalation was not measured, but the investigators cited studies showing that 2 to 3% of a MIBK dose may be eliminated unchanged via the lungs after exposure. No data on the excretion of MIBK via the biliary-fecal route were located.

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 MIBK in humans was not available.

3.1.1.2 Animal

Oral LD₅₀ values for the rat, mouse, and guinea pig are 2080, 2671, and 1600 mg/kg, respectively (RTECS 1993).

In common with other ketones, MIBK potentiates liver injuries induced by haloalkanes. Gavage treatment of rats with 0.3 to 20 mmol/kg of MIBK prior to a challenge with carbon tetrachloride (CCl₄) administered intraperitoneally at doses up to 0.5 mL/kg resulted in a dose-dependent potentiation of CCl₄-induced hepatotoxicity (Pilon et al. 1988). MIBK can also potentiate cholestasis in rats. Daily gavage administration of 3.75 to 15 mmol/kg of MIBK for 3 or 7 days followed by intravenous doses of 5 to 25 mg/kg sodium taurolithocholate produced an enhanced decrease in bile flow after taurolithocholate challenge (Plaa and Ayotte 1985). Administration of the two major MIBK metabolites, 4-methyl-2-pentanol and 4-hydroxy-MIBK (1.8 to 15 mmol/kg for 3 days by gavage) followed by a challenge with intravenously injected manganese or a manganese-bilirubin combination (4.5 to 6 mg manganese/kg) also potentiated the acute cholestatic response induced by manganese or manganese-bilirubin alone (Vezina and Plaa 1988).

3.1.2 Subchronic Toxicity

3.1.2.1 Human

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

3.1.2.2 Animal

In a gavage study, male and female Sprague-Dawley rats were administered 0, 50, 250, or 1000 mg/kg/day of MIBK for 90 days (Microbiological Associates 1986). Clinically, animals receiving the highest dose showed reduced weight gain in the absence of decreased food intake and appeared lethargic following dosing. Increased liver weights and alterations in clinical chemistry indicative of hepatotoxicity (increased alanine aminotransferase, alkaline phosphatase, and cholesterol levels) in the absence of histological lesions were seen in high dose animals. High renal toxicity, characterized by increased kidney weights, increased incidence of nephropathy, and increased blood urea nitrogen, serum potassium, urinary protein, and ketone levels, was observed also. Liver and kidney effects were present to a significantly lower degree in rats receiving 250 mg/kg/day. The lowest dose had no observable adverse effects.

3.1.3 Chronic Toxicity

Information on the chronic oral toxicity of MIBK in humans or animals was not available.

3.1.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of MIBK in humans or animals following oral exposure was not available.

3.1.5 Reference Dose

3.1.5.1 Subchronic

• ORAL RfD: 8E-1 mg/kg/day (EPA 1994)
• NOAEL: 250 mg/kg/day
• UNCERTAINTY FACTOR: 300
• PRINCIPAL STUDY: Microbiological Associates, 1986
• COMMENTS: The same study was used for the derivation of the subchronic and chronic RfD.

3.1.5.2 Chronic

• ORAL RfD: 8E-2 mg/kg/day (EPA 1994)
• NOAEL: 250 mg/kg/day
• UNCERTAINTY FACTOR: 3000
• PRINCIPAL STUDY: Microbiological Associates 1986
• COMMENTS: The RfD is based on the results of a 13-week gavage study with rats. Critical effects included lethargy and, in females, increased liver and kidney weights and increased urinary protein levels. The oral RFD was withdrawn from IRIS and is currently under review (EPA 1995).

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Exposure to 50-105 ppm MIBK for 15 to 30 minutes produced gastrointestinal disturbances and central nervous system effects in a few workers (Parmeggiani 1983).

In a study on sensory thresholds for various ketones, Silverman et al. (1946) exposed 12 men and 12 women to several concentrations of MIBK for 15 minutes. The highest concentration that most subjects found to be tolerable during an 8-hour period was 100 ppm. At 200 ppm, the odor was objectionable and eye irritation was noted; exposure to concentrations greater than or equal to 200 ppm produced nose and throat irritation.

Hjelm et al. (1990) studied the irritative and central nervous system effects in volunteers exposed to 10, 100, or 200 mg/m³ (41, 410, or 820 ppm) of MIBK for 2 hours during light physical exercise. Irritation of the eyes, nose, and throat as well as vertigo were reported at all concentrations but occurred more frequently at 100 and 200 mg/m³. Headache was reported at the two higher concentrations and nausea at 200 mg/m³. No significant effects were observed from exposure on the performance of a simple reaction time task or a test of mental arithmetic.

3.2.1.2 Animal

RTECS (1993) lists an inhalation LC₅₀ of 23,300 mg/m³ (95,530 ppm) for the mouse. Smyth et al. (1951) exposed groups of 6 rats to MIBK vapors for 4 hours. All rats exposed to 2000 ppm survived, but all rats exposed to 4000 ppm died. Exposure to 19,500 ppm MIBK induced anesthesia in 7/10 mice within 30 minutes; after cessation of exposure, the animals recovered rapidly. Exposure to concentrations above 20,000 ppm produced anesthesia within 30 minutes and death in most mice (Krasavage et al. 1982).

Specht et al. (1938, 1940) reported that exposure to 1000 ppm caused little or no irritation of the eyes and nose of guinea pigs (the investigators conducting the study, however, experienced eye and nose irritation). During the first 6 hours, the animals exhibited a decreased respiratory rate that was attributed to a low grade narcosis. Exposure to 16,800 ppm caused immediate signs of eye and nose irritation followed by salivation, lacrimation, ataxia, and death. Nine of ten animals died within 6 hours of exposure. At 28,000 ppm, half of the guinea pigs died within 45 minutes. Examination of tissues showed fatty livers and congestion of the brain, lungs, and spleen.

MacEwen et al. (1971) exposed rats continuously to 100 or 200 ppm MIBK for 2 weeks. Observed effects included increased absolute and relative kidney weights, toxic nephrosis of the proximal tubules (100 and 200 ppm), and increased absolute and relative liver weights (200 ppm). No adverse effects were seen in mice, dogs, and Rhesus monkeys similarly exposed to MIBK.

In a more recent, 2-week study, Phillips et al. (1987) exposed Fischer 344 rats and B6C3F₁ mice to 100, 500, or 2000 ppm MIBK, 6 hours/day, 5 days/week. At 2000 ppm, a slight increase in absolute and relative liver weights was observed in male rats. Histologically, increases in regenerative tubular epithelia and hyalin droplets in the kidneys were observed in male rats exposed to 500 or 2000 ppm. No treatment-related effects were reported in female rats and in mice of both sexes.

Rats exposed to 25 ppm MIBK (duration not given) showed a slight increase in pressure lever response. Exposure of baboons to 20 to 40 ppm (duration not given) did not impair discriminatory behavior, but exposure to 50 ppm produced delayed behavioral response times (Geller et al. 1978, 1979).

3.2.2 Subchronic Toxicity

3.2.2.1 Human

The duration of exposure in the studies presented in this subsection was not reported. However, because exposures occurred in the occupational setting, they are expected to be of either subchronic or chronic duration. Linari et al. (1964) reported on a study of 19 workers who were exposed daily to MIBK for 20 to 30 minutes during an 8-hour work shift for an unspecified time period. The MIBK concentrations in workplace air ranged from 80 to 500 ppm. More than half the workers commonly experienced weakness, loss of appetite, headache, burning of the eyes, stomach ache, nausea, vomiting, and sore throat. Insomnia, somnolence, heart burn, and intestinal pain were less frequent. Four workers had slightly enlarged livers and six workers had colitis. Clinical chemistry tests were within the normal range. Five years later, 14 of the 19 workers were re-examined by Armeli et al. (1968). Improved ventilation reduced exposure levels to 50 to 105 ppm and also reduced most of the earlier symptoms. Slight liver enlargement persisted in two workers, and a few gastrointestinal and central nervous system effects were still reported.

One group of workers exposed to 100 ppm MIBK developed headache and nausea, whereas another group complained only of respiratory irritation. Tolerance to MIBK seemed to develop during the work week but was lost over the weekend. Most of these effects were not reported at 20 ppm (Elkins 1959).

Although effects on the peripheral nervous system have been reported in workers exposed to ketones, particularly methyl-n-butyl ketone (NIOSH 1978), peripheral neuropathy has not been reported as a result of exposure to MIBK.

3.2.2.2 Animal

Fischer 344 rats and B6C3F₁ mice were exposed to 0, 50, 250, or 1000 ppm MIBK, 6 hours/day, 5 days/week for 14 weeks (Phillips et al. 1987). Exposure to MIBK produced no clinical signs of toxicity. At 1000 ppm, slight but statistically significant (p less than 0.01) increases in liver weight and liver/body weight ratios were observed in male rats and male mice. Liver weights were also slightly increased in male mice exposed to 250 ppm. However, there were no gross or microscopic liver lesions related to MIBK exposure. Clinical chemistry values indicative of liver injury were also within the normal ranges. The observed liver changes were attributed to a compensatory response to an increased metabolic load due to MIBK. The only microscopic change observed was an increase in the incidence and extent of hyalin droplets in the proximal tubular cells of the kidneys of male rats exposed to 250 or 1000 ppm MIBK. No histologic changes were found in the peripheral nervous system.

MacEwen et al. (1971) exposed rats, dogs, and Rhesus monkeys continuously to 100 ppm MIBK for 90 days. No significant changes were seen in clinical chemistry and hematology parameters in the three species tested. Rats exhibited increased liver and kidney weights as well as hyalin droplet degeneration of the proximal kidney tubules and some reversible tubular necrosis. Adverse kidney effects were not seen in dogs or monkeys.

Spencer et al. (1975) reported that rats exposed to MIBK for 5 months at levels up to 1500 ppm showed minimal subclinical plantar nerve damage. This effect was later attributed to trauma sustained during activity in cages with wire-mesh floors (Spencer and Schaumburg 1976).

Abou-Donia et al. (1985) showed that simultaneous exposure of hens to mixtures of 1000 ppm n-hexane and 100, 250, 500, or 1000 ppm MIBK vapors for 90 days markedly increased the neurotoxic action of the weak neurotoxicant n-hexane, progressing from early stages of ataxia to paralysis. The clinical signs of neurotoxicity were accompanied by degenerative changes of the axon and myelin of the spinal cord and peripheral nerves. Hens continuously exposed to 1000 ppm MIBK without n-hexane for 90 days developed leg weakness with subsequent recovery, while inhalation of the same concentration of n-hexane produced mild ataxia. No histopathological changes in the spinal cord and peripheral nerves were seen in hens treated with MIBK, and the histopathological changes in hens treated with n-hexane were considered equivocal.

3.2.3 Chronic Toxicity

Information on the chronic toxicity of MIBK by the inhalation route of exposure in humans or animals was not available.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

Information on the developmental and reproductive toxicity of MIBK by the inhalation route of exposure in humans was not available.

3.2.4.2 Animal

Pregnant F344 rats and CD-1 mice received whole body exposures of 0, 300, 1000, or 3000 ppm MIBK, 6 hours/day on days 6-15 of gestation (Bushy Run Research Center 1984). Exposure to 3000 ppm resulted in maternal toxicity consisting of clinical signs (rats and mice), decreased body weight gains and decreased food consumption (rats), increased mortality (mice), increased relative kidney weights (rats), and increased absolute and relative liver weights (mice). Treatment-related fetal toxicity, expressed as significantly reduced fetal body weight and retardation of skeletal ossification was seen in rats and mice at 3000 ppm. Exposure to 300 or 1000 ppm resulted in no observable treatment-related maternal, embryonal, or fetal toxicity and no teratogenicity in either species.

3.2.5 Reference Concentration

3.2.5.1 Subchronic

• INHALATION RfC: 8E-1 mg/m³ (2E-1 mg/kg/day) (EPA 1994)
• NOEL: 50 ppm
• UNCERTAINTY FACTOR: 100
• PRINCIPAL STUDY: Union Carbide Corporation 1983
• COMMENTS: The principal study was also reported by Phillips et al. (1987) (see Sect. 3.2.2.2). The same study was used for the derivation of the subchronic and chronic RfC. The subchronic RfC was derived from methodology that is not current with the interim inhalation methodology used by the RfD/RfC Work Group (EPA 1994).

3.2.5.2 Chronic

• INHALATION RfC: 8E-2 mg/m³ (2E-2 mg/kg/day) (EPA 1994)
• NOEL: 50 ppm
• UNCERTAINTY FACTOR: 1000
• PRINCIPAL STUDY: Union Carbide Corporation 1983
• COMMENTS: The principal study was also reported by Phillips et al. (1987) (see Sect. 3.2.2.2). The RfC is based on increased liver weights and kidney effects observed in a 90-day inhalation study with rats. The chronic RfC was derived from methodology that is not current with the interim inhalation methodology used by the RfD/RfC Work Group (EPA 1994). An inhalation RfC is under review by the RfD/RfC Work Group (EPA 1995).

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Humans

Information on the acute toxicity of MIBK by other routes of exposure in humans was not available.

3.3.1.2 Animals

RTECS (1993) lists intraperitoneal LD₅₀s of 400, 260, and 800 mg/kg for the mouse, rat, and guinea pig, respectively. Studies reviewed by Krasavage et al. (1982) showed that a single dermal application of MIBK (amount not reported) produced transient erythema in rabbits, but daily applications of 10 mL for 7 days caused drying and flaking of the skin. Moderate irritation of rabbit skin was reported 24 hours after application of 500 mg MIBK. When applied to guinea pig skin, 5 or 10 mL undiluted MIBK held in contact for 24 hours under an occlusive wrap produced slight skin irritation.

When instilled into the rabbit eye, 0.1 mL of undiluted MIBK produced some irritation within 10 minutes, inflammation and swelling after 8 hours, and exudate with swelling and inflammation after 24 hours (Krasavage et al. 1982).

Cunningham et al. (1989) reported that mice injected intraperitoneally with 5 mmol/kg of MIBK 30 minutes before administration of ethanol (4 g/kg intraperitoneally) significantly prolonged the duration of ethanol-induced loss of the righting reflex, which was attributed to a reduced elimination rate of ethanol.

3.3.2 Subchronic Toxicity

3.3.2.1 Human

Some workers who were exposed daily for 20 to 30 minutes to MIBK at concentrations ranging from 80 to 500 ppm in workplace air developed dermatitis. The skin lesions varied from erythema to small areas of peeling and disappeared when protective gloves and creams were used, suggesting that dermal contact was largely responsible for the observed dermal effects (Linari et al. 1964).

3.3.2.2 Animal

Several subchronic studies explored the neurotoxic potential of MIBK. In unpublished studies reported by Krasavage et al. (1982), rats were administered intraperitoneal injections of 10, 30, or 100 mg/kg MIBK, 5 times weekly; after 2 weeks, the doses were increased to 20, 60, or 100 mg/kg and continued for 33 weeks. The only observed effects were lower body weights during weeks 3 and 4 and transient anesthesia during week 1 in high-dose animals. Toxic neuropathy was not observed at any dose level. No evidence of neurotoxicity was reported in dogs administered daily subcutaneous doses of 300 mg/kg MIBK for 11 months. Desquamation of the skin with no clinical or histologic evidence of neurotoxicity was seen in guinea pigs that received dermal applications of MIBK (up to 2 mL, with or without dimethyl sulfoxide) for 31 weeks.

Spencer and Schaumburg (1976) injected cats subcutaneously with 150 mg/kg MIBK, twice daily, 5 times per week for up to 8.5 months. The chemical was tolerated well, and no detectable peripheral or central nervous system damage was observed.

3.3.3 Chronic Toxicity

Information on the chronic toxicity of MIBK 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 MIBK 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

1. Liver: Subchronic oral exposure to MIBK produced increased liver weights and changes in clinical chemistry values indicative of hepatotoxicity in rats. MIBK potentiates the hepatotoxicity of CCl₄ and cholestasis induced by taurolithocholate in rats.
2. Kidney: Subchronic oral exposure to MIBK produced increased kidney weights, nephropathy, and changes in clinical chemistry values indicative of renal toxicity in rats.
3. Central nervous system: Subchronic oral exposure to MIBK produced lethargy in rats.

3.4.1.2 Other target organs

Information on other target organs for oral exposure to MIBK was not available.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target organs

Although duration of exposure was not specified in the human studies, occupational exposure to MIBK suggests subchronic or chronic inhalation exposure to MIBK.

1. Central nervous system: Headache, weakness, vertigo, insomnia, and somnolence are symptoms reported in humans exposed to MIBK. High concentrations induced ataxia and narcosis in experimental animals. Synergism of n-hexane-induced neurotoxicity by MIBK was reported in hens.
2. Mucous membranes: Eye, nose, and throat irritation commonly are associated with MIBK exposure.
3. Gastrointestinal tract: Nausea, vomiting, loss of appetite, heart burn, and intestinal pain have been reported in workers exposed to MIBK.
4. Liver: Slightly enlarged livers were reported in some workers exposed to MIBK. Increased liver weights were reported in rats and mice subchronically exposed to MIBK.
5. Kidneys: Rats subchronically exposed to MIBK developed hyalin droplet degeneration of the proximal tubules and some reversible tubular necrosis. These effects were not seen in other species.

   3.4.2.2 Other target organs

   Reproduction and Development: Exposure to high concentrations of MIBK during gestation produced maternal toxicity and fetal toxicity (reduced fetal body weights and retardation of skeletal ossification) in rats.

   3.4.3 Other Routes of Exposure

   3.4.3.1 Primary target organs

   Skin: Dermatitis has been reported following dermal exposure to MIBK.

   3.4.3.2 Other target organs

   Information on other target organs by other routes of exposure to MIBK was not available.

   4. CARCINOGENICITY

   4.1 ORAL EXPOSURES

   Information on the carcinogenicity of MIBK in humans or animals following oral exposure was not available.

   4.2 INHALATION EXPOSURES

   Information on the carcinogenicity of MIBK in humans or animals following inhalation exposure was not available.

   4.3 OTHER ROUTES OF EXPOSURE

   Information on the carcinogenicity of MIBK in humans or animals by other routes of exposure was not available.

   4.4 EPA WEIGHT-OF-EVIDENCE

   Classification--EPA has not assigned a weight-of-evidence classification for carcinogenicity to MIBK.

   4.5 CARCINOGENICITY SLOPE FACTORS

   No slope factors for carcinogenicity have been calculated.

   5. REFERENCES

   Abou-Donia, M. B., D. M. Lapadula, G. Campbell, and P. R. Timmons. 1985. The synergism of n-hexane-induced toxicity following subchronic (90 days) inhalation in hens: Induction of hepatic microsomal cytochrome P-450, Toxicol. Appl. Pharmacol. 81: 1-16.

   ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed, ACGIH, Cincinnati, OH, p. 402.

   Armeli, G., F. Linari and G. Martorano. 1968. [Clinical and hematochemical examinations in workers exposed to the action of a ketone (MIBK) repeated after five years.] Lav. Um. 20: 418-424. (Italian; cited in NIOSH 1978)

   Budavari, S., M. J. O'Neill, A. Smith, and P. E. Heckelman, Eds. 1989. The Merck Index, 11th ed. Merck & Co., Rahway, NJ, p. 820.

   Bushy Run Research Center. 1984. A Teratologic Evaluation of MIBK in Fischer 344 Rats and CD-1 Mice Following Inhalation Exposure, Final Report, EPA Doc. No. 50-8444071.

   Cunningham, J., M. Sharkawi, and G. L. Plaa. 1989. Pharmacologic and metabolic interactions between ethanol and methyl n-butyl ketone, MIBK, and methyl ethyl ketone, or acetone in mice, Fund. Appl. Pharmacol. 13: 102-109.

   DiVincenzo, G. D., C. J. Kaplan, and J. Dedinas. 1976. Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone and methyl ethyl ketone in guinea pig serum and their clearance, Toxicol. Appl. Pharmacol. 36: 511-522.

   Elkins, H. B. 1959. The Chemistry of Industrial Toxicology, John Wiley & Sons, New York, pp. 120-121.

   EPA (U.S. Environmental Protection Agency). 1994. Health Effects Assessment Summary Tables. Annual FY-94, prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, D.C., NTIS PB94-921199.

   EPA (U.S. Environmental Protection Agency). 1995. Integrated Risk Information System (IRIS), Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.

   Geller, I., J. R. Rowlands, and H. L. Kaplan. 1978. Effects of Ketones on Operant Behavior of Laboratory Animals, In: Voluntary Inhalation of Industrial Solvents, DHEW Publ. 79-779, pp. 363-376. (Cited in Krasavage et al. 1982)

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   Last Updated 10/31/97