United States Environmental Protection 1=1 m m Agency EPA/690/R-05/016F Final 5-16-2005 Provisional Peer Reviewed Toxicity Values for 4-Methyl-2-Pentanol (CASRN 108-11-2) Derivation of Subchronic and Chronic Oral RfDs 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 i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk 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 1 ------- MTD maximum tolerated dose MTL median threshold limit 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 Hg microgram |j,mol micromoles voc volatile organic compound 11 ------- 5-16-05 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 4-METHYL-2-PENTANOL (CASRN 108-11-2) Derivation of Subchronic and Chronic Oral RfDs 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes request that a frequently used PPRTV be reassessed. 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 ------- 5-16-05 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 No RfD for 4-methyl-2-pentanol is available on IRIS (U.S. EPA, 2003), in the HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). No documents for 4-methyl-2-pentanol are listed in the CARA lists (U.S. EPA 1991, 1994). Neither ATSDR (2003), NTP (2003), IARC (2003), nor WHO (2003) have produced documents regarding 4-methyl-2-pentanol. Literature searches of the following databases were conducted from 1993 through January 2003 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. Previously, TOXLINE was searched for the years 1992-1994 in March 1994 and 1965-1992 in June 1992. Additional literature searches from January 2003 through October 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. 2 ------- 5-16-05 REVIEW OF PERTINENT LITERATURE Human Studies No relevant data were located regarding the toxicity of 4-methyl-2-pentanol to humans following oral exposure. Animal Studies Information on the toxicity of 4-methyl-2-pentanol is sparse and essentially limited to acute data. A single dose range-finding LD50 value of 2590 mg/kg was estimated for 4-methyl-2- pentanol in male Wistar rats treated by gavage and observed for 14 days (Smyth et al., 1951). The chemical was administered in water but it is unclear if it was diluted or dispersed as it is slightly to moderately water soluble. Single dose oral toxicity was evaluated in mice (strain and sex not reported) treated by gavage with 4-methyl-2-pentanol as temporary emulsion (10-40%) in 1% aqueous Tergitol and observed for 7 days (McOmie and Anderson, 1949). 4-Methyl-2- pentanol doses of 1.0, 1.5 and 2.0 ml/kg caused anesthesia (loss of righting reflex) in 2/5, 5/5 and 5/5 mice, respectively, and mortality in 1/5, 4/5 and 5/5 mice, respectively. Based on the mouse mortality data, an LD50 value of 1.5 ml/kg (1212 mg/kg) was estimated for 4-methyl-2-pentanol (McOmie and Anderson, 1949). Hyperemia of the stomach wall and duodenum was a common gross pathology finding in the mice that died from treatment with the chemical. The effect of oral administration of 4-methyl-2-pentanol on the cholestasis induced by manganese-bilirubin or manganese alone was studied in rats (Vezina and Plaa, 1988). The experimental designs involved single and repeated (once daily for 3 days) gavage treatment prior to administration of the cholestatic agent. 4-Methyl-2-pentanol had the same minimal effective dose, 1.88 mmol/kg, for single and repeated exposure. 4-Methyl-2-pentanol did not induce cholestasis when administered without the cholestasis inducers. Other Studies Limited information exists regarding the pharmacokinetics of 4-methyl-2-pentanol. Granvil et al. (1994) examined the metabolism of 4-methyl-2-pentanol in mice. Groups of 8 male Charles River CD-I mice were administered a single intraperitoneal injection of 2.5 mmol/kg (255.5 mg/kg) of 4-methyl-2-pentanol and the concentrations of metabolites were measured in blood and brain 15, 30, 60 and 90 minutes after dosing. Parent compound, methyl isobutyl ketone (MIBK) and 4-hydroxymethyl isobutyl ketone were detected in blood and brain. Levels of 4-methyl-2-pentanol in blood and brain were highest (=82 |_ig/ml and = 73 |ig/g) at 15 minutes, levels of MIBK in blood and brain were also highest (=28 |ig/ml and =23 |ig/g) at 15 minutes and subsequently rapidly decreased at a similar rates, whereas 4-hydroxymethyl isobutyl 3 ------- 5-16-05 ketone in blood and brain peaked at ~34 |_ig/ml and =30 |ig/g after 30-60 minutes and only gradually decreased. In a recent study, Gingell et al. (2003) attempted to quantify the extent of metabolism of 4-methyl-2-pentanol to MIBK after administration of a single dose of either compound (approximately 500 mg/kg) to male rats by gavage in corn oil. Plasma levels of MIBK, 4- methyl-2-pentanol, and 4-hydroxymethyl isobutyl ketone were determined up to 8 hours after dosing. There were no deaths or clinical signs of toxicity in the study. 4-Hydroxymethyl isobutyl ketone was the major material in the plasma following dosing with MIBK or 4-methyl- 2-pentanol with similar areas-under-the-curve (AUC) and in both cases achieving maximum concentration at 9 hours after dosing. The plasma levels of MIBK and AUC were also comparable after MIBK or 4-methyl-2-pentanol administration. By comparing combined AUCs for MIBK and 4-hydroxymethyl isobutyl ketone, it was estimated that the extent of metabolism of 4-methyl-2-pentanol to MIBK was at least 73%. DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC RfDs FOR 4-METHYL-2-PENTANOL Oral toxicity data for 4-methyl-2-pentanol are from a few limited acute studies (Smyth et al., 1951; McOmie and Anderson, 1949; Vezina and Plaa, 1988). Due to the nature of the existing data and lack of subchronic, chronic, developmental and reproductive toxicity studies, information on 4-methyl-2-pentanol is insufficient for derivation of a provisional subchronic or chronic RfD. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Gingell, R, J-F. Regnier, D.M. Wilson et al. 2003. Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl ketone in male rats. Toxicol. Lett. 136: 199-204. Granvil, C.P., M. Sharkawi and G.L. Plaa. 1994. Metabolic fate of methyl-n-butyl ketone, methyl isobutyl ketone and their metabolites in mice. Toxicol. Lett. 70: 263-267. IARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ 4 ------- 5-16-05 McOmie, W.A. and H.H. Anderson. 1949. Comparative toxicologic effects of some isobutyl carbinols and ketones. Univ. Calif. Berkeley Publ. Pharmacol. 2: 217-230. NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html Smyth, H.F., Jr., C.P. Carpenter and C.S. Weil. 1951. Range-finding toxicity data: List IV. A.M.A. Arch. Ind. Hyg. Occup. Med. 4: 119-122. 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. July. EPA/540/R-97/036. NTIS PB97-921199. U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer 2002. EPA 822-R-02-038. Online. http://www.epa. gov/waterscience/drinking/ standards/dwstandards .pdf U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa.gov/iris/ Vezina, M. and G.L. Plaa. 1988. Methyl isobutyl ketone metabolites and potentiation of the cholestasis induced in rats by a manganese-bilirubin combination or manganese alone. Toxicol. Appl. Pharmacol. 92: 419-427. WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm 5 ------- 9-22-2005 Provisional Peer Reviewed Toxicity Values for 4-Methyl-2-pentanol (CASRN 108-11-2) Derivation of Subchronic and Chronic Inhalation RfCs 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 i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk 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 1 ------- MTD maximum tolerated dose MTL median threshold limit 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 Hg microgram |imol micromoles VOC volatile organic compound 11 ------- 9-22-2005 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 4-METHYL-2-PENTANOL (CASRN 108-11-2) Derivation of Subchronic and Chronic Inhalation RfCs 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program sometimes request that a frequently used PPRTV be reassessed. 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 ------- 9-22-2005 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 No RfC for 4-methyl-2-pentanol (methyl isobutyl carbinol) is available on IRIS (U.S. EPA, 2005) or in the HEAST (U.S. EPA, 1997). No documents for 4-methyl-2-pentanol are listed in the CARA lists (U.S. EPA 1991, 1994). Neither ATSDR (2003), NTP (2003), IARC (2003), nor WHO (2003) have produced documents regarding 4-methyl-2-pentanol. Occupational exposure limits for 4-methyl-2-pentanol are based on acute data and intended to minimize the potential for irritation of the mucous membranes and eyes and to provide a margin of safety against acute anesthetic effects: ACGIH (2003) TLV-TWA of 25 ppm and TLV-STEL of 40 ppm, NIOSH (2003) REL-TWA of 25 ppm and REL-STEL of 40 ppm, and OSHA (2003) PEL-TWA of 25 ppm. Literature searches of the following databases were conducted from 1993 through January 2003 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. 2 ------- 9-22-2005 Previously, TOXLINE was searched for the years 1992-1994 in March 1994 and 1965-1992 in June 1992. Additional literature searches from June 1992 through May 2005 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical Abstracts and Biological Abstracts databases. REVIEW OF PERTINENT LITERATURE Human Studies The sensory response of an average of 12 human subjects (both sexes, but the number was not provided) to 15 minute exposures of several solvents including 4-methyl-2-pentanol were investigated by Silverman et al., 1946. For this chemical, the majority of subjects (number not indicated) reported irritation to eyes, nose and throat at greater than or equal to 50 ppm. The highest concentration that the majority of subjects estimated to be acceptable for an 8-hour exposure was 25 ppm. Animal Studies Inhalation information on this chemical is limited to acute exposure data. McOmie and Anderson (1949) exposed 10 mice (strain not given) in 4 groups to commercial grade vapor saturated air at 20°C (ca. 20 mg/1) for 4, 8.5, 10 and 15 hours. Anesthesia (observed as loss of righting reflex) was observed in 7 animals in the low dose group and all animals in the higher dose groups. Deaths occurred at the 10 and 15 hour groups only, 6 and 8 animals, respectively. Observed over time, the animals showed irritation, somnolence, anesthesia and death at 5 minutes, 1 hour, 4 hours and 10 hours, respectively. Exposure to the saturated vapor for 12 repeated exposures of 4 hours each caused no deaths. The authors offered that the mouse is more sensitive to the noxious vapors than guinea pigs and rats but data are not given. They also concluded that all of the compounds tested were central nervous system depressants. Carpenter et al., 1949, exposed a total of 6 (mixed male and female, number not given) albino rats (Sherman strain) for 4 hours to 2,000 ppm and was classified into a grouping of compounds that kills 2 to 4 animals at this concentration. Smyth et al, 1951, exposed 6 male albino rats (strain not given) for 2 hours to 2,000 ppm with a two week observation period. Deaths occurred in 5/6 animals. The experimental details for this study are given in Smyth and Carpenter, 1944. 3 ------- 9-22-2005 DERIVATION OF PROVISIONAL CHRONIC AND SUBCHRONIC RfCs FOR 4-METHYL-2-PENTANOL Since only limited acute inhalation information is available, derivation of a provisional subchronic or chronic RfC for this material is contraindicated. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2003. 2003 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Carpenter, C.P., H.F. Smyth Jr. and U.C. Pozzani. 1949. The assay of acute vapor toxicity, and the grading and interpretation of results on 96 chemical compounds. J. Indus. Hyg. Toxicol. 31: 343. 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. Duguay, A.B. and G.L. Plaa. 1993. Plasma concentrations in methyl isobutyl ketone- potentiated experimental cholestasis after inhalation or oral administration. Fund. Appl. Toxicol. 21:222-227. Duguay, A.B. and G.L. Plaa. 1995. Tissue concentrations of methyl isobutyl ketone, methyl n- butyl ketone and their metabolites after oral and inhalation exposure. Toxicol. Lett. 75: 51-58. IARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ McOmie, W.A. and H.H. Anderson. 1949. Comparative toxicologic effects of some isobutyl carbinols and ketones. Univ. Calif. Berkeley Publ. Pharmacol. 2: 217-230. NIOSH (National Institute for Occupational Safety and Health). 2003. NIOSH Pocket Guide to Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F 4 ------- 9-22-2005 NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nili.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000 Table Z-l. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gOv/OshStd_data/1910_1000_TABLE_Z-l.html Silverman, L., H.F. Schulte and M.W. First. 1946. Further studies on sensory response to certain industrial solvent vapors. J. Ind. Hyg. Toxicol. 28: 262-266. Smyth, H.F. and C.P. Carpenter. 1944. The place of the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30:63. Smyth, H.F., Jr., C.P. Carpenter and C.S. Weil. 1951. Range-finding toxicity data: List IV. A.M.A. Arch. Ind. Hyg. Occup. Med. 4: 119-122. 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. July. EPA/540/R-97/036. NTIS PB97-921199. U.S. EPA. 2005. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa. gov/ iris/ Vezina, M., A.B. Kobusch, P. du Souich et al. 1989. Potentiation of chloroform-induced hepatotoxicity by methyl isobutyl ketone and two metabolites. Can. J. Physiol. Pharmacol. 68: 1055-1061. WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm 5 ------- 4-12-05 Provisional Peer Reviewed Toxicity Values for 4-Methyl-2-Pentanol (CASRN 108-11-2) Derivation of a Carcinogenicity Assessment 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 i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk 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 1 ------- MTD maximum tolerated dose MTL median threshold limit 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 Hg microgram |j,mol micromoles voc volatile organic compound 11 ------- 4-12-05 PROVISIONAL PEER REVIEWED TOXICITY VALUE FOR 4-METHYL-2-PENTANOL (CASRN 108-11-2) Derivation of a Carcinogenicity Assessment 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes request that a frequently used PPRTV be reassessed. 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 ------- 4-12-05 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 No cancer assessment for 4-methyl-2-pentanol is available on IRIS (U.S. EPA, 2003), in the HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). No documents for 4-methyl-2-pentanol are listed in the CARA lists (U.S. EPA 1991, 1994). Neither ATSDR (2003), NTP (2003), IARC (2003), nor WHO (2003) have produced documents regarding 4-methyl-2-pentanol. Literature searches of the following databases were conducted from 1993 through January 2003 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. Previously, TOXLINE was searched for the years 1992-1994 in March 1994 and 1965-1992 in June 1992. Additional literature searches from January 2003 through October 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. 2 ------- 4-12-05 REVIEW OF PERTINENT LITERATURE Human Studies No data were located regarding the carcinogenicity of 4-methyl-2-pentanol to humans by any route of exposure. Animal Studies No data were located regarding the carcinogenicity of 4-methyl-2-pentanol to animals by any route of exposure. PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION There are no data evaluating carcinogenicity of 4-methyl-2-pentanol in any species. Genotoxicity of 4-methyl-2-pentanol was evaluated in one study, which found the chemical to be nonmutagenic in S. typhimurium and E. coli bacteria. According to the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), the data are inadequate for an assessment of human carcinogenic potential for 4-methyl-2-pentanol. QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK Derivation of quantitative estimates of cancer risk for 4-methyl-2-pentanol is precluded by the lack of data demonstrating carcinogenicity associated with 4-methyl-2-pentanol exposure. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ATI, SRCH/iH ATI, SRCH Frames.html Shimizu, H., Y. Suzuki, N. Takemura et al. 1985. The results of microbial mutation test for forty-three industrial chemicals. Jpn. J. Ind. Health. 27: 400-419. 3 ------- 4-12-05 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. July. EPA/540/R-97/036. NTIS PB97-921199. U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer 2002. EPA 822-R-02-038. Online. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa.gov/iris/ U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. EPA/63 0/P-03/001F. WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm 4 ------- |