United States Environmental Protection Agency EPA/690/R-02/01 OF Final 5-31-2002 Provisional Peer Reviewed Toxicity Values for Derivation of a Chronic Inhalation RfC Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 Isobutanol (CASRN 78-83-1) ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit 1 ------- NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor microgram (imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR ISOBUTANOL (CASRN 78-83-1) Derivation of a Chronic Inhalation RfC Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. INTRODUCTION An RfC for isobutanol is not available on IRIS (U.S. EPA, 2001) or in the HEAST (U.S. EPA, 1997). The CARA database (U.S. EPA, 1991, 1994a) lists a Health and Environmental Effects Profile (U.S. EPA, 1986a) and Reportable Quantity Document (1986b); neither of which derived an RfC for isobutanol. ATSDR has not published a Toxicological Profile for isobutanol (ATSDR, 2000). ACGIH (2000) recommends a ceiling limit (TLV/C) of 50 ppm (152 mg/m3) for isobutanol. This TLV value is based on the potential for acute toxic effects by analogy to n- butanol (ACGIH, 1991). In its 1989 ruling, OSHA (1989) established a PEL ceiling limit of 50 ppm (150 mg/m3), based on analogy with n-butanol (irritation and narcosis). However, when this ruling was vacated in 1993, the PEL reverted to the previously established 8-hour PEL-TWA of 100 ppm (300 mg/m3) (OSHA, 2000). NIOSH established a REL ceiling limit of 50 ppm (150 2 ------- 5-31-2002 mg/m3) for isobutanol by concurrence with the 1989 OSHA PEL limit and has established an ILDH value of 8000 ppm (NIOSH, 2000). IARC (2000), WHO (1987), and NTP (2000) were searched, but contained no relevant information. Updated literature searches were conducted from 1985 to November 2000 for studies relevant to the derivation of an RfC. The databases searched were: TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK. REVIEW OF THE PERTINENT LITERATURE Human Studies Isobutanol can be absorbed through the lungs in humans (Browning, 1965). No studies addressing systemic toxicity of isobutanol inhalation in humans were located. In employees exposed repeatedly to approximately 300 mg/m3, no significant health effects were observed, although irritation of the eyes and throat were reported in other studies where the vapor concentrations were higher (NIOSH, 1978). Neither the duration nor range of exposures were provided in the secondary citation. WHO (1987) reports an odor threshold for isobutanol of approximately 1.5 ppm (4.5 mg/m3). Animal Studies Kushneva et al. (1983) reported inhalation LC50 values for isobutanol of 19,200 mg/m3 in rats, 15,500 mg/m3 in mice, 19,900 mg/m3 in guinea pigs, and 26,250 mg/m3 in rabbits. Smyth et al. (1954) observed no deaths in rats exposed to a saturated atmosphere of about 49,000 mg/m3 for 2 hours, but found that 2/6 rats died after exposure to about 24,600 mg/m3 for 4 hours. Mortality was reported among mice exposed to about 48,300 mg/m3 for 250 minutes or about 32,200 mg/m3 for 300 minutes (Weese, 1928). A report by the International Programme in Chemical Safety (WHO, 1987) includes comments on a study wherein an unspecified number of rats were exposed continuously to isobutanol at 0.1, 0.5, or 3 mg/m3 for 4 months (Tsulaya et al., 1978). This secondary citation reports a depression of leg withdrawal response to electrical stimuli and minor hematological changes (reduced hemoglobin content, decreased erythrocyte count, and reduced activity of certain serum enzymes) at 0.5 or 3 mg/m3, but not at 0.1 mg/m3. In addition, WHO (1987) cites a study (Kushneva et al., 1983) that reported airway irritation in rats and rabbits at 15,700 mg/m3 following a single 4-hour exposure. Three days after the exposure, hematological changes and dystrophia of hepatocytes and olfactory neurons in the brain were noted. At 8000 mg/m3 the changes were similar but less severe. An isobutanol concentration of 1300 mg/m3 reduced the number of lymphocytes in bone marrow. At 100 mg/m3, only respiratory depression was observed. No other information concerning this study was available from the secondary citation. 3 ------- 5-31-2002 In two separate experiments, Weese (1928) exposed mice to isobutyl alcohol intermittently. In the first experiment, mice were exposed to 2125 ppm (6440 mg/m3) of isobutyl alcohol for 223 hours in a series of intermittent experiments (9.25 hours in duration each) without any significant effects. In the second experiment, Weese reported that the narcotic inhalation dose in mice over a total of 136 hours is 6400 ppm (19,400 mg/m3). Slight changes in liver and kidney were observed (reversible fatty degeneration of the liver and kidneys). No mortality occurred, and the narcotic effects were reported to be transient with no lasting effects (Weese, 1928). No further details concerning this study are available. A more recent study was conducted to determine the relative acute neurotoxicity of solvents using electrically-invoked seizures (Frantik et al., 1994). Male SFP-Wistar rats and female mice of the H strain were used. The isoeffective air concentration (i.e., the dose capable of causing a 30% depression of electrically-induced seizures) for isobutanol was determined to be 3800 ppm (11,500 mg/m3) in rats and 2500 ppm (7580 mg/m3) in mice after 4 or 2 hours of exposure, respectively. This acute, subnarcotic effect occurred at nearly the same isobutanol concentration as respiratory irritation. A developmental toxicity study by Klimisch and Hellwig (1995) was conducted in rats (female, SPF-Wistar) and rabbits (female, Himalayan) exposed to isobutanol at 0, 0.5, 2.5, or 10 mg/L (0, 500, 2500, or 10,000 mg/m3) for 6 hours/day for days 6-15 postcoitum (25 rats/group) and days 7-19 postinsemination (15 rabbits/group). Animals were weighed at 3-day intervals and observed daily. Rats were sacrificed on day 20 of gestation and rabbits on day 29 of gestation. All dams underwent gross necropsy and the uterus was weighed. Fetuses were weighed and examined externally. Soft tissue and skeletal examinations were conducted on all rabbit fetuses. Visceral examinations were conducted on approximately half the rat fetuses and skeletal examinations on the remaining rat fetuses in each litter. There was no alteration in intact uterine weight in either species. When compared at 3-day increments throughout exposure, maternal weight gain in the exposed rabbits was not statistically significantly different from controls. However, when evaluated for the entire exposure period (days 7-19), maternal weight gain in rabbits at the high concentration was decreased to approximately 63% of the control weight gain, but rebounded following cessation of exposure. Maternal weight gain in the low and mid- concentration rabbit groups were approximately 99 and 93% of control values. There was no alteration in maternal weight gain of the rats. There were no alterations in developmental endpoints in either species. The LOAEL for maternal toxicity in the rabbits is 10,000 mg/m3, and the NOAEL is 2500 mg/m3. There were no alterations in developmental endpoints in either species. The developmental NOAEL for the rabbits is 10,000 mg/m3, the highest concentration tested. For the rats, the maternal and developmental NOAEL in this study is 10,000 mg/m3. In a study by Monsanto (1996) (the range finding study for Li et al., 1999), 40 male CD rats (5 rats/group at 8 weeks age and 5 rats/group at 16 weeks age) were exposed for 6 hours/day, 5 days/week for 2 weeks to isobutanol at 0, 750, 1500, or 3000 ppm (0, 2274, 4550, or 9095 mg/m3). This study examined the following parameters: clinical signs, food consumption, body weight, hematology, ophthalmoscopic examination, a functional observational battery, and 4 ------- 5-31-2002 complete individual necropsy, with histopathology of major organs at termination. A marginal decrease in response to external stimuli (i.e., failure to respond to tapping on the exterior walls of the chamber) was observed in subjective assessments at 2274 mg/m3 (with greater effect at higher doses). At 4550 mg/m3 or 9095 mg/m3, general CNS depression and labored breathing occurred, which ceased upon removal from the chamber. There were no differences in observed response between control and treated rats when they were examined outside the exposure chamber. No treatment-related changes in any other endpoints were reported. Li et al. (1999) studied the subchronic neurotoxic effects of isobutanol in adult male and female Sprague Dawley rats in two experiments. Rats were exposed to 0, 250, 1000, or 2500 ppm (0, 758, 3032, or 7580 mg/m3) of isobutanol for 6 hours/day, 5 days/week for 3 months. In the first experiment, 20/sex were assigned to control and 758 mg/m3 groups, while 10/sex/group were assigned to the other two concentration levels. Body weight and food consumption were measured weekly. Animals were observed during exposure for subjective assessments of reaction to brushing and tapping the exterior walls of the chamber. Each rat received at least 70 exposures, but was not exposed on the day they underwent neurobehavioral testing. Behavioral tests (functional observational battery [FOB] and motor activity) were conducted on all but 5 animals/sex in the control and 758 mg/m3 groups. Behavioral tests were conducted prior to initiation of exposure and during the 4th, 8th and 13th weeks of exposure. Animals were not exposed to isobutanol on the days of behavioral testing. Neuropathology evaluation was conducted on 5/sex/group that underwent behavioral testing and full histopathology (adrenals, brain, eyes, heart, kidneys, liver, lungs, three sections of the nose, ovaries, uterus, vagina/testes and epididymes, skin and spleen) and clinical pathology (including hematological evaluations) were conducted on an additional 5/sex/group. The remaining animals underwent gross necropsy. In the second experiment, 40 male rats (10/concentration level) were tested on a schedule- controlled operant behavior (SCOB) task. Animals performed on the SCOB prior to each exposure during the exposure period, but only the data collected during the pretest week and the 4th, 8th and 13th weeks of exposure were statistically analyzed, d-Amphetamine and chlorpromazine were used as positive controls for the SCOB. The study was well-designed, employing appropriate positive and negative controls, and well-reported (reporting on all parameters, including clinical observations). Slight increases (9-10%) in hematocrit, erythrocyte count, and hemoglobin in five female rats achieved statistical significance at the highest concentration. The authors did not attribute any toxicological significance to these alterations. The small number of rats examined and the fact that the blood chemistry was only assessed at the end of the study make it difficult to interpret these results. As noted in the range-finding study (Monsanto, 1996), a decreased response to external stimuli occurred during exposure early in this study. This effect occurred at all doses of isobutanol and was slight except for a few rats in the 7580 mg/m3 group early in the study where the effect was more pronounced. At times other than during the exposures, differences in behavior were not observed between treated and control animals. Moreover, no differences were noted during the functional observational battery, including several measurements of responsiveness, conducted within 24 hours of the end of the preceding exposure. There was stable baseline performance and no significant concentration time interactions in any SCOB parameters. 5 ------- 5-31-2002 DERIVATION OF A PROVISIONAL RfC The database is inadequate for deriving an RfC. There are no long-term studies in humans and limited studies in animals. The only findings in Li et al. (1999) were subjective observations of alterations in responsiveness to stimuli and alterations in some hematological parameters. These findings are difficult to interpret and cannot definitively be considered adverse. Decreased response to external stimuli (brush and tap on exterior chamber wall) occurred in rats only during exposure to concentrations of 758 to 7580 mg/m3. Similar decreased responsiveness was also reported in Monsanto (1996) at 750 ppm (2274 mg/m3) or greater. However, these are subjective measures made by observers and no incidence or other supporting data are reported. There were negative findings in the more rigorous FOB, motor activity and SCOB tests and neuropathological alterations. The highest concentration tested, 2500 ppm (7580 mg/m3) is, therefore, considered a NOAEL. IRIS (U.S. EPA, 2001) lists an oral RfD for isobutanol of 3E-01 mg/kg-day based on an NOEL for hypoactivity and ataxia in rats in a subchronic study (U.S. EPA, 1986c). In this study, the dose level, duration and incidence supporting the clinical observations were reported. Li et al. (1999) note that a transient reduction in responsiveness is often associated with inhalation exposure to high concentrations of solvents which exhibit general and non-specific narcotic effects. Such nonspecific CNS depression as a result of inhalation exposure to high concentrations of solvents is also discussed in a textbook chapter by Spencer and Schaumburg (2000). The observations of altered reactivity in Li et al. (1999), only while the animals were in the inhalation chamber, reflect an acute, transient effect occurring during exposure to isobutanol and are not an appropriate basis for the derivation of an RfC. Klimisch and Hellwig (1995) identify a LOAEL (10,000 mg/m3) and NOAEL (2500 mg/m3) for maternal toxicity in rabbits, based on significantly (approximately 30%) depressed body weight gain in a developmental study. No developmental toxicity in rabbits nor maternal or developmental toxicity in rats was found. Similar decreases in maternal weight gain occurred in rats and rabbits exposed to similar concentrations of isopentanol (Klimisch and Hellwig, 1995). Developmental effects have been reported for subchronic exposure to n-butanol, but only at concentrations of 6000 ppm or greater (approximately 18,000 mg/m3) (Nelson et al., 1989). The decrease in maternal body weight gain occurring during isobutanol exposure in Klimisch and Hellwig (1995) is a non-specific, overt sign of toxicity occurring after short-term, high concentration exposure, and is not an appropriate endpoint as the basis for an RfC. Other inhalation studies in animals are not adequate to serve as the basis for an RfC, as they are of acute duration, do not identify a NOAEL, or are limited in study design or reporting. 6 ------- 5-31-2002 The RfC guidelines (U.S. EPA, 1994b) state that the minimum laboratory animal toxicologic database requirement for derivation of a low confidence RfC is a well-conducted subchronic inhalation bioassay that established an unequivocal NOAEL and LOAEL. As none of the available inhalation studies meet this criteria, derivation of an RfC is precluded. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed. Cincinnati, OH. 1: 815- 816. ACGIH (American Conference of Governmental Industrial Hygienists). 2000. TLVsŪ and BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological Exposure Indices. Cincinnati, OH. ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile Information Sheet. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Examined November 29, 2000. Online. http://www.atsdr.cdc.gov/gsql/toxpro2.html Browning, E. 1965. Toxicology and metabolism of industrial solvents. Amsterdam, Elsevier, p. 349. Frantik, E., M. Hornychova and M. Horvath. 1994. Relative acute neurotoxicity of solvents: Isoeffective air concentrations of 48 compounds evaluated in rats and mice. Environ. Res. 66: 173-185. IARC (International Agency for Research on Cancer). 2000. Cumulative Cross Index to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Klimisch, H.J. and J. Hellwig. 1995. Studies on the prenatal toxicity of 3-methyl-l-butanol and 2-methyl-l-propanol in rats and rabbits following inhalation exposure. Fund. Appl. Toxicol. 27: 77-89. Korsak, Z. and K. Rydzynski. 1994. Effects of acute combined inhalation exposure to n-butyl alcohol and n-butyl acetate in experimental animals. Int. J. Occup. Med. Environ. Health. 7(3): 273-280. Kushneva, V.S., G.A. Koloskova, J.G. Koltunova and V.T. Kirilenko. 1983. Experimental data to hygienic reglementation of isobutyl alcohol in the working zone. Gid. Tr. Lek. 1: 46-47 (in Russian), as cited by WHO, 1987. 7 ------- 5-31-2002 Li, A.A., D.C. Thake, T.A. Kaempfe et al. 1999. Neurotoxicity evaluation of rats after subchronic inhalation exposure to isobutanol. Neurotoxicology. 20(6): 889-900. Monsanto Company. 1996. Exposure concentration range-finding study for a subchronic inhalation neurotoxicity study of isobutanol administered by whole-body inhalation to CD rats (Summary only). Produced for Chemical Manufacturers Association. U.S. EPA/OPTS Public Files, Fiche #OTS0558856. Nelson, B.K., W.S. Brightwell, A. Khan, J.R. Burg and P.T. Goad. 1989. Lack of selective developmental toxicity of three butanol isomers administered by inhalation to rats. Fund. Appl. Toxicol. 12:469-479. NIOSH (National Institute for Occupational Safety and Health). 1978. Occupational Health Guideline for Isobutyl Alcohol, p. 1-5. NIOSH (National Institute for Occupational Safety and Health). 2000. Documentation for Immediately Dangerous to Life or Health Concentrations: Isobutanol. Examined online December 2000. Online, http://www.cdc.gov/niosh/idlh/78831 .html NTP (National Toxicology Program). 2000. Management Status Report. Examined November 29, 2000. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html OSHA (Occupational Safety and Health Administration). 1989. 29 CFR Part 1910. Air Contaminants; Rule. Federal Register. 54(12): 2630-2631. OSHA (Occupational Safety and Health Administration). 2000. OSHA Standard 1915.1000 for Air Contaminants. Part Z, Toxic and Hazardous Substances. Examined online December, 2000. Online. http://www.osha-slc.gov/OshStd data/1915 1000.html Smyth, H.F. Jr., C.P. Carpenter, C.S. Weil and U.C. Pisonia. 1954. Range-finding toxicity data: ListV. Arch. Ind. Hyg. Occup Med. 10:61-68. Spencer, P.S. and H.H. Schaumburg. 2000. Experimental and Clinical Neurotoxicology, 2nd ed. Oxford University Press, p. 895. Tsulaya, V.T., N.V. Morenkova, L.E. Volokhova and V.M. Voronin. 1978. [Description of the biological properties of small concentrations of isobutyl alcohol.] Gig. I Sanit. 5: 6-9. (Russian) (Cited by WHO, 1987) 8 ------- 5-31-2002 U.S. EPA. 1986a. Health and Environmental Effects Profile for Isobutanol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1986b. Reportable Quantity Document for Isobutanol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1986c. Rat oral subchronic toxicity study. Final report. Compound: isobutyl alcohol. TRL Study # 032-002. Toxicity Research Laboratories, Ltd., Muskegon, MI. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1994a. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1994b. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of Research and Development, Washington DC. EPA/600/8-90/066F. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July. EPA/540/R-97/036. PB 97-921199. U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Examined December 2000. http://www.epa.gov/iris Weese, H. 1928. Comparative study of the activity and toxicity of the vapors of the lower aliphatic alcohols. Arch. Exp. Path. Pharmacol. 135:118-130. WHO (World Health Organization). 1987. Butanols: Four isomers: 1-butanol, 2-butanol, tert-butanol, and isobutanol. International Programme on Chemical Safety, Environmental Health Criteria Document No. 65: 93-118. WHO, Geneva. 9 ------- 5-31-2002 Provisional Peer Reviewed Toxicity Values for Isobutanol (CASRN 78-83-1) Derivation of an Oral Slope Factor Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit 1 ------- NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor microgram (imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR ISOBUTANOL (CASRN 78-83-1) Derivation of an Oral Slope Factor Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. INTRODUCTION A cancer assessment for isobutanol is not available on IRIS (U.S. EPA, 2001), in the HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2000). The CARA list (U.S. EPA, 1991, 1994) includes a Health and Environmental Effects Profile for Isobutanol (U.S. EPA, 1986), in which it is indicated that isobutanol should be assigned to cancer weight-of-evidence Group D, not classifiable as to human carcinogenicity, based on lack of data concerning carcinogenicity in humans and animals by any route of exposure. IARC (2000) has not evaluated isobutanol for carcinogenicity. The NTP (2000) Status Report for isobutanol does not include a chronic toxicity/carcinogenicity bioassay, although a negative genotoxicity study (Zeiger et al., 1988) is listed. ATSDR has not published a Toxicological Profile for isobutanol (ATSDR, 2000). Updated literature searches for cancer data were conducted from 1985 to present. The databases searched were TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK. 2 ------- 5-31-2002 REVIEW OF THE PERTINENT LITERATURE Human Studies No studies were located regarding the carcinogenicity of isobutanol in humans following oral exposure. Animal Studies No studies were located regarding the carcinogenicity of isobutanol in animals following oral exposure. Other Studies Based on genotoxicity studies assessed by U.S. EPA (1986), isobutanol was not considered to be mutagenic. Update literature searches revealed two subsequent genotoxicity studies in which isobutanol also failed to demonstrate mutagenic activity (Zeiger et al., 1988; Mirvish et al., 1993). FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR ISOBUTANOL A provisional oral slope factor for isobutanol cannot be derived because human and animal oral cancer data are lacking. REFERENCES ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile Information Sheet. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Examined November 29, 2000. Online. http://www.atsdr.cdc.gov/toxpro2.html IARC (International Agency for Research on Cancer). 2000. Cumulative Cross Index to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Mirvish, S.S., J. Williamson, D. Babcook and S-C Chen. 1993. Mutagenicity of isobutyl nitrite vapor in the Ames test and some relevant chemical properties, including the reaction of isobutyl nitrite with phosphate. Environ. Mol. Mutagen. 21(3): 247-252. 3 ------- 5-31-2002 NTP (National Toxicology Program). 2000. Management Status Report. Examined November 29, 2000. Online. http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html U.S. EPA. 1986. Health and Environmental Effects Profile for Isobutanol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Examined November 29, 2000. Online, http://www.epa.gov/ost/drinking/standards/ U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. http://www.epa.gov/iris Zeiger, E., B. Anderson, S. Haworth et al. 1988. Salmonella mutagenicity tests. IV. Results from the testing of 300 chemicals. Environ. Mol. Mutagen. ll(Suppl 12): 1-158. 4 ------- 5-31-2002 Provisional Peer Reviewed Toxicity Values for Isobutanol (CASRN 78-83-1) Derivation of an Inhalation Unit Risk Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit 1 ------- NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor microgram (imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR ISOBUTANOL (CASRN 78-83-1) Derivation of an Inhalation Unit Risk Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. INTRODUCTION A cancer assessment for isobutanol is not available on IRIS (U.S. EPA, 2001), in the HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2000). The CARA list (U.S. EPA, 1991, 1994) includes a Health and Environmental Effects Profile for Isobutanol (U.S. EPA, 1986), in which it is indicated that isobutanol should be assigned to cancer weight-of-evidence Group D, not classifiable as to human carcinogenicity, based on lack of data concerning carcinogenicity in humans and animals by any route of exposure. IARC (2000) has not evaluated isobutanol for carcinogenicity. The NTP (2000) Status Report for isobutanol does not include a chronic toxicity/carcinogenicity bioassay, although a negative genotoxicity study (Zeiger et al., 1988) is listed. ATSDR has not published a Toxicological Profile for isobutanol (ATSDR, 2000). Updated literature searches for cancer data were conducted from 1985 to present. The databases searched were TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK. 2 ------- 5-31-2002 REVIEW OF THE PERTINENT LITERATURE Human Studies No studies were located regarding carcinogenicity of isobutanol to humans by inhalation exposure. Animal Studies No studies were located regarding the carcinogenicity of isobutanol in animals following inhalation exposure. Other Studies Based on genotoxicity studies assessed by U.S. EPA (1986), isobutanol was not considered to be mutagenic. Update literature searches revealed two subsequent genotoxicity studies in which isobutanol also failed to demonstrate mutagenic activity (Zeiger et al., 1988; Mirvish et al., 1993). FEASIBILITY OF DERIVING A PROVISIONAL INHALATION UNIT RISK FOR ISOBUTANOL A provisional inhalation unit risk for isobutanol cannot be derived because human and animal inhalation cancer data are lacking. REFERENCES ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile Information Sheet. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Examined November 29, 2000. Online. http://www.atsdr.cdc.gov/toxpro2.html IARC (International Agency for Research on Cancer). 2000. Cumulative Cross Index to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Mirvish, S.S., J. Williamson, D. Babcook and S-C Chen. 1993. Mutagenicity of isobutyl nitrite vapor in the Ames test and some relevant chemical properties, including the reaction of isobutyl nitrite with phosphate. Environ. Mol. Mutagen. 21(3): 247-252. 3 ------- 5-31-2002 NTP (National Toxicology Program). 2000. Management Status Report. Examined November 29, 2000. Online. http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html U.S. EPA. 1986. Health and Environmental Effects Profile for Isobutanol. Prepared by the Office of Research and Development, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Examined November 29, 2000. Online, http://www.epa.gov/ost/drinking/standards/ U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. http://www.epa.gov/iris Zeiger, E., B. Anderson, S. Haworth et al. 1988. Salmonella mutagenicity tests. IV. Results from the testing of 300 chemicals. Environ. Mol. Mutagen. 1 l(Suppl 12): 1-158. 4 ------- |