United States Environmental Protection 1=1 m m Agency EPA/690/R-13/015F Final 1-08-2013 Provisional Peer-Reviewed Toxicity Values for Methylcyclohexane (CASRN 108-87-2) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Harlal Choudhury, DVM, PhD, DABT, National Center for Environmental Assessment, Cincinnati, OH Dan D. Petersen, PhD, DABT, National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY National Center for Environmental Assessment, Cincinnati, OH This document was externally peer reviewed under contract to Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). ------- CONTENTS COMMONLY USED ABBREVIATIONS ii BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVS 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4 HUMAN STUDIES 8 Oral Exposures 8 Inhalation Exposures 8 ANIMAL STUDIES 9 Oral Exposures 9 Inhalation Exposures 9 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 15 Acute Studies 17 DERIVATION 01 PROVISIONAL VALUES 18 DERIVATION OF ORAL REFERENCE DOSES 18 Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 18 Derivation of Chronic Provisional RfD (Chronic p-RfD) 19 DERIVATION OF INHALATION REFERENCE DOSES 19 Derivation of Subchronic Provisional RfC (Subchronic p-RfC) 19 Derivation of Chronic Provisional RfC (Chronic p-RfC) 19 ALTERNATIVE METHODS 20 CANCER WOE DESCRIPTOR 20 APPENDIX A. PROVISIONAL SCREENING VALUES 21 APPENDIX B. DATA TABLES 22 APPENDIX C. BMD OUTPUTS 23 APPENDIX D. REFERENCES 24 l Methyl cy cl ohexane ------- COMMONLY USED ABBREVIATIONS BMC benchmark concentration BMCL benchmark concentration lower bound 95% confidence interval BMD benchmark dose BMDL benchmark dose lower bound 95% confidence interval HEC human equivalent concentration HED human equivalent dose IUR inhalation unit risk LOAEL lowest-observed-adverse-effect level LOAELadj LOAEL adjusted to continuous exposure duration LOAELhec LOAEL adjusted for dosimetric differences across species to a human NOAEL no-ob served-adverse-effect level NOAELadj NOAEL adjusted to continuous exposure duration NOAELhec NOAEL adjusted for dosimetric differences across species to a human NOEL no-ob served-effect level OSF oral slope factor p-IUR provisional inhalation unit risk POD point of departure p-OSF provisional oral slope factor p-RfC provisional reference concentration (inhalation) p-RfD provisional reference dose (oral) RfC reference concentration (inhalation) RfD reference dose (oral) UF uncertainty factor UFa animal-to-human uncertainty factor UFC composite uncertainty factor UFd incomplete-to-complete database uncertainty factor UFh interhuman uncertainty factor UFl LOAEL-to-NOAEL uncertainty factor UFS subchronic-to-chronic uncertainty factor WOE weight of evidence 11 Methyl cy cl ohexane ------- FINAL 1-8-2013 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR METHYLCYCLOHEXANE (CASRN 108-87-2) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by a standing panel of National Center for Environment Assessment (NCEA) scientists and an independent external peer review by three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. The PPRTV review process provides needed toxicity values in a quick turnaround timeframe while maintaining scientific quality. PPRTV assessments are updated approximately on a 5-year cycle for new data or methodologies that might impact the toxicity values or characterization of potential for adverse human health effects and are revised as appropriate. It is important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current information available. When a final Integrated Risk Information System (IRIS) assessment is made publicly available on the Internet (www.epa.gov/iris). the respective PPRTVs are removed from the database. DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the site in question and the risk management decision that would be supported by the risk assessment. Other U.S. Environmental Protection Agency (EPA) programs or external parties who may choose to use PPRTVs are advised that Superfund resources will not generally be used to respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program. QUESTIONS REGARDING PPRTVS Questions regarding the contents and appropriate use of this PPRTV assessment should 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). 1 Methyl cy cl ohexane ------- FINAL 1-8-2013 INTRODUCTION Methylcyclohexane (CAS No. 108-87-2) is a cyclohexane (ChemlDplus, 2011) that is a flammable, colorless liquid with a faint odor at room temperature (PubChem, 2011). The molecular formula is C7H14. Table 1 provides a list of its physicochemical properties. Table 1. Physicochemical Properties of Methylcyclohexane (CASRN 108-87-2)a Property (unit) Value Boiling point (°C) 100.9 Melting point (°C) -127 Density (g/cm3) 0.7694b Vapor pressure (mm Hg at 25°C) 46 pH (unitless) Not available Solubility in water (mg/L at 25°C) 14 Relative vapor density (air =1) 3.39b Molecular weight (g/mol) 98.18606° aSource (unless otherwise noted): ChemlDplus (2011). bSource: HSDB (2011). °Source: PubChem (2011). A summary of available toxicity values for methylcyclohexane from U.S. EPA and other agencies/organizations is provided in Table 2. 2 Methyl cy cl ohexane ------- FINAL 1-8-2013 Table 2. Summary of Available Toxicity Values for Methylcyclohexane (CASRN 108-87-2) Source/Parameter" Value (Applicability) Notes Reference Date Accessed Cancer IRIS NV NA U.S. EPA, 2011 1-25-2011 HEAST NV NA U.S. EPA, 2003 1-25-2011 IARC NV NA IARC, 2011 1-25-2011 NTP NV NA NTP, 2005 1-25-2011 CARA HEEP NV Did not derive a quantitative cancer assessment due to inadequate data U.S. EPA, 1994 1-25-2011 CalFPA NV NA CalEPA, 2008 1-25-2011 Noncancer ACGIH 8-hour REL-TWA: 400 ppm (1600 mg/m3) NA ACGIH, 2008 1-25-2011 ATSDR NV NA ATSDR, 2010 1-25-2011 CalEPA NV NA CalEPA, 2008, 2009 1-25-2011 NIOSH 10-hour REL-TWA: 400 ppm (1600 mg/m3) NA NIOSH, 2010 1-25-2011 OSHA PEL-TWA: 500 ppm (2000 mg/m3) NA OSHA, 2010 1-25-2011 IRIS NV NA U.S. EPA, 2011 1-25-2011 Drinking water NV NA U.S. EPA, 2009 6-18-2012 HEAST Subchronic and chronic RfCs: 3 mg/m3 Based on the occurrence of kidney lesions in male rats Kinkead et al., 1985a 1-25-2011 CARA HEEP NV Declined to derive values due to inadequate data U.S. EPA, 1994 1-25-2011 WHO NV NA WHO, 2011 1-25-2011 aSources: Integrated Risk Information System (IRIS) database; Health Effects Assessment Summary Tables (HEAST); International Agency for Research on Cancer (IARC); National Toxicology Program (NTP); California Environmental Protection Agency (CalEPA); American Conference of Governmental Industrial Hygienists (ACGIH); Agency for Toxic Substances and Disease Registry (ATSDR); National Institute for Occupational Safety and Health (NIOSH); Occupational Safety and Health Administration (OSHA); Chemical Assessments and Related Activities (CARA) list; Health and Environmental Effects Profile (HEEP); World Health Organization (WHO). NA = not applicable; NV = not available; PEL-TWA = permissible exposure limit-time weighted average; REL-TWA = recommended exposure limit-time weighted average. 3 Methyl cy cl ohexane ------- FINAL 1-8-2013 Literature searches were conducted on sources published from 1900 through June 18, 2012 for studies relevant to the derivation of provisional toxicity values for methylcyclohexane, CAS No. 108-87-2. Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National Service Center for Environmental Publications [NSCEP] and National Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web of Science (searches Current Content database among others); World Health Organization; and Worldwide Science. The following databases outside of HERO were searched for relevant health information: ACGM, AT SDR, CalEPA, U.S. EPA IRIS, U.S. EPAHEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) Table 3 provides an overview of the relevant databases for studies on methylcyclohexane and includes all potentially relevant and repeated short-term-, subchronic-, and chronic-duration studies. The phrase "statistical significance," as it is used throughout the document, indicates a ^-value of <0.05. 4 Methyl cy cl ohexane ------- FINAL 1-8-2013 Table 3. Summary of Potentially Relevant Data for Methylcyclohexane (CASRN 108-87-2) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL' BMDL/ BMCLa LOAEL' Reference Notesb Human 1. Oral Acute0 ND Short-termd ND Long-term6 ND Chronicf ND 2. Inhalation Acute0 ND Short-termd ND Long-term0 ND Chronicf 36-42 male and female workers, inhalation, -11.4 yr 6 ppm (20 mg/cu.m) (mean personal atmospheric concentration), in addition to exposure to other solvents Induces the cytochrome P450-dependent pathway ND ND ND Mason etal., 1994 NA Exposure duration unknown 108 pregnant patients, inhalation, case-control study, unknown exposure duration Unknown mixture of solvents Relative risk (RR) for spontaneous abortion following high exposure to solvents was 3.85, (confidence interval [CI] = 1.24-11.9); RR for low exposure was 1.58 (CI = 0.62-4.06) ND ND ND Agnesi et al., 1997 Carcinogenic ND Animal 1. Oral (mg/kg-d)a Subchronic ND Chronic ND Developmental ND 5 Methyl cy cl ohexane ------- FINAL 1-8-2013 Table 3. Summary of Potentially Relevant Data for Methylcyclohexane (CASRN 108-87-2) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL' BMDL/ BMCLa LOAEL' Reference Notesb Reproductive ND Carcinogenic ND 2. Inhalation (mg/m3)a Subchronic 4, sex unreported, rabbit, 10 wk 0, 169, 261,816 No adverse effects 4570 DU None Treonetal., 1943a NA 1, sex unreported, rhesus monkey, 10 wk 261 No adverse effects ND DU ND Treonetal., 1943b NA Chronic 65/65, F344 rat, inhalation, 12 mo 0, 268, 1339 Renal hyaline droplet-induced nephropathy in males (not relevant to humans) ND DU ND Kinkead et al., 1985a American Petroleum Institute, 1985 Air Force Medical Research Lab, 1985 NA 0/200, C57BL/6J mouse, inhalation, 12 mo 0, 268, 1339 No adverse effects found ND DU ND Kinkead et al., 1985b American Petroleum Institute, 1985 Air Force Medical Research Lab, 1985 NA 100/0, Syrian golden hamster, inhalation, 12 mo 0, 268, 1339 No biologically significant associations found ND DU ND Kinkead et al., 1985c American Petroleum Institute, 1985 Air Force Medical Research Lab, 1985 NA 4/4, Beagle dog, inhalation, 12 mo 0, 268, 1339 No significant associations found ND DU ND Kinkead et al., 1985d American Petroleum Institute, 1985 Air Force Medical Research Lab, 1985 NA 6 Methyl cy cl ohexane ------- FINAL 1-8-2013 Table 3. Summary of Potentially Relevant Data for Methylcyclohexane (CASRN 108-87-2) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL3 BMDL/ BMCL3 LOAEL3 Reference Notesb Developmental No data Reproductive No data Carcinogenic 65/65, F344 rat, inhalation, 12 mo 0, 268, 1339 Testicular tumor incidences of 0/11, 5/10, and 2/11 in the control, low-exposure, and high-exposure groups, respectively NA DU NA Kinkead et al., 1985a American Petroleum Institute, 1985 Air Force Medical Research Lab, 1985 NA ""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to a human equivalent concentration (HEC in mg/m3) for inhalation noncancer and cancer effects. HECexresp = (mg/m3) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood gas partition coefficient. HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood gas partition coefficient. bNotes: IRIS = utilized by IRIS, date of last update; PS = principal study; PR = peer reviewed; NPR = not peer reviewed; NA = not applicable. 0 Acute = Exposure for 24 hr or less (U.S. EPA, 2002). dShort-term = Repeated exposure for >24 hr <30 d (U.S. EPA, 2002). "Long-term = Repeated exposure for >30 d <10% lifespan (based on 70 yr typical lifespan) (U.S. EPA, 2002). fChronic = Repeated exposure for >10% lifespan (U.S. EPA, 2002). DU = data unsuitable; NA = not applicable; ND = no data; NDr = not determined; NI = not identified; NP = not provided; NR = not reported; NR/Dr = not reported but determined from data; NS = not selected; NV = not available. 7 Methyl cy cl ohexane ------- FINAL 1-8-2013 HUMAN STUDIES Oral Exposures No studies were identified. Inhalation Exposures The effects of inhalation exposure to methylcyclohexane alone have not been evaluated in humans. Four epidemiological inhalation studies were performed (Mason et al., 1994; Laire et al., 1997; Agnesi et al., 1997; Kraut et al., 1991), all of which reported exposure to mixtures of solvents that contained methylcyclohexane. These studies were reviewed in the previous PPRTV on methylcyclohexane (U.S. EPA, 2005). The summaries below are quoted directly from the previous PPRTV as denoted by the italicized and indented text with changes to the text within the quotes indicated in brackets. No additional literature was identified. Mason et al., 1994 A battery of liver function tests were performed [on] a group of 42 factory workers from the United Kingdom [who] had been occupationally exposed to solvents for an average of 11.4 years (Mason et al., 1994). For this group, the geometric means of the personal atmospheric concentrations for methylcyclohexane, n-heptane, toluene, and xylene were 6, 7, 4, and 1.2 ppm (20, 30, 20, and 20 mg/m3), respectively. [The results of this group] were compared against tests [that were performed on] two control groups of workers [who were not exposed to these solvents] (41 subjects with normal liver function and 36 subjects with abnormal liver function). The solvent-exposed group exhibited statistically significant elevations [of] urinary bile acids (1.1-fold), urinary 6fi-hydroxycortisol (1.7-fold), and the ratio of 6fi-hydroxycortisol to urinary free Cortisol (2.1-fold) compared [with] the control group [that had] normal liver function[s]. No differences were seen between these two groups [in terms of] serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, y-glutamyltransferase, bilirubin, or urinary D-glucaric acid [levels]. No significant differences were seen for any end point measured between the solvent-exposed group and the control group selected for having abnormal liver function. The authors considered the observed changes in serum bile acids and urinary 6fi-hydroxycortisol to be sensitive markers of solvent-induced hepatotoxicity. Laire et al, 1997 A case-control study was conducted [on] 21 [print] shop workers who had workedfor an average of 15 years; [21 controls were usedfor comparisons] (Laire et al., 1997). The authors measured workplace concentrations of 25 different solvents; the average concentrations of methylcyclohexane ranged from 0 9.5 mg/m3 (< 5% of the total concentration of [the] measured solvents). The case group exhibited statistically significant increases in sleep apnea (2.8-fold), complaints regarding mood (1.3-fold), and decreased hand-eye coordination (1.2-fold). 8 Methyl cy cl ohexane ------- FINAL 1-8-2013 Agnesi et al., 1997 A case-control study compared 133 female shoe industry workers who had spontaneous abortions with 108pregnant controls (Agnesi et al., 1997). Average ambient workplace concentrations of methylcyclohexane rangedfrom 30-120 mg/m (5-20% of the total concentration of [the] measured solvents). No evidence of any association was reported. Kraut et al., 1991 [An] investigation [into the occurrence] of cancer clusters (4 cases of Hodgkin 's disease, non-Hodgkin 's lymphoma, glioblastoma, and angiosarcoma) among professional New York Giants football players in New York found no link to environmental exposure to volatile organic compounds (Kraut etal., 1991). At the outdoor sports facilities [studied], the average concentrations of methylcyclohexane rangedfrom 0.1 0.4 ppb (0.4-1.6 g/m ; < 0.01% of the total concentration of [the] measured solvents). ANIMAL STUDIES Oral Exposures No studies were identified. Inhalation Exposures No short-term, developmental, or reproductive studies on the inhalation effects of exposure to methylcyclohexane to animals were identified. However, the effects of inhalation exposure to methylcyclohexane have been evaluated in one sub chronic-duration study that used rabbits and monkeys (Treon et al., 1943a,b, as cited in U.S. EPA, 2005) and one chronic-duration study that has been summarized in three different study reports (Kinkead et al., 1985; Air Force Medical Research Lab, 1985; American Petroleum Institute, 1985). For clarity, Kinkead et al. (1985) will be the citation used to refer to the overall study report. Individual studies involved rats, mice, hamsters, and dogs (Kinkead et al., 1985a,b,c,d). These studies were reviewed in the previous PPRTV on methylcyclohexane (U.S. EPA, 2005). The summaries below are quoted directly from the previous PPRTV as denoted by the italicized and indented text with changes to the text within the quotes indicated in brackets. No additional literature was identified. Treon et al., 1943a,b Groups of 4 young rabbits (sex and strain not specified) were exposed to vapors of0, 0.948, 1.46, or 4.57 mg/L (0, 948, 1460, or 4570 mg/m3) methylcyclohexane for 10 weeks, 5 days/week, 6 hours/day (300 hours total) (Treon et al., 1943a); one rhesus monkey (sex not specified) was exposed to 1460 mg/m [methylcyclohexane] for the same duration (Treon et al., 1943b). [The] use of control monkeys was not mentioned. Body weights and rectal temperature were measured daily. Blood samples were collected weekly (reported as before, during, and after exposure) [in order] to measure [the] red blood cell count, total leukocyte count, and hemoglobin concentration. Animals were sacrificed 2 months after cessation of exposure for gross and microscopic tissue examination (organs not specified). Slight decreases in temperature were seen in all exposed animals, but no adverse effects were observed. The study was inadequate for the monkey because no control was provided and the group size was too small. 9 Methyl cy cl ohexane ------- FINAL 1-8-2013 The calculated HECs for extrarespiratory effects, assuming a blood:gas partition coefficient of 1, are 0, 169, 261, and 816 mg/m based on the results of the rabbit experiment "3 (Treon et al., 1943a) and 261 mg/m based on the results of the monkey experiment (Treon et al., 1943b). Treon et al, 1943a 3 3 For this study, 4570 mg/m (816 mg/m HEC) methylcyclohexane was [determined to be the] NOAEL [based on the results of] rabbits [that were] exposed intermittently for 10 weeks. Kinkead et al, 1985a,b,c,d Kinkead et al. (1985) exposed groups of 65 male and 65 female Fischer 344 rats (Kinkead et al., 1985a), 100 male Syrian Golden hamsters (Kinkeadetal., 1985c), 200female C57BL/6Jmice (Kinkeadetal., 1985b), and 4 male and 4 female purebred beagle dogs (Kinkead et al., 1985d) to nominal concentrations of0, 400, or 2000 ppm methylcyclohexane vapor for 6 hours/day, 5 days/week for 1 year. Three different lots of the test agent were used: they were 98.50-98.66% pure with the only identified impurities being n-heptane (0.74-0.97%) and toluene (0.52-0.60%). In addition to the omission of exposure on weekends, animals were also not exposed during holidays; animals were apparently exposed [for] 243 days total. Two exposure chambers were used for each concentration; the measured mean concentrations of methylcyclohexane were 401.5, 398.9, 1998, and 2009 ppm. The report did not indicate how the animals were housed; the pair-averaged chamber concentrations were 400.2 ppm 3 3 (1607.2 mg/m ) and 2004ppm (8045 mg/m ). Mortality incidence was not directly reported. The animals were observed hourly during exposure. Food consumption was not measured, but food was available only during nonexposure periods. Body weights of [the] rats, hamsters, and dogs were measured every two weeks during exposure. For the mice, group weights were measured monthly (data not provided). Blood samples were collectedfrom dogs every two weeks during the exposure period. At the end of the 1-year exposure period, 10 male and 10 female rats, 20 mice, and 10 hamsters were scheduled for sacrifice from each group. The data for animals [that were] sacrificed at the end of the 1-year exposure period were grouped with the data [of the] animals that died during the exposure period; thereby, the numbers of animals that died during exposure may be inferred. The remaining rodents were observedfor 1 year, [and] body weights [were] measured monthly prior to sacrifice. [In] the rodent groups, blood was collectedfrom rats prior to necropsy, following [1-year of exposure]. All dogs were observed for 5 years postexposure before sacrifice with blood samples collected every 6 months. Blood analyses included [the measurement of] hematology, electrolytes, glucose, creatinine, bilirubin, serum protein, albumin, alanine amino transferase, aspartate amino transferase, and alkaline phosphatase [levels]. At sacrifice, organ weights were collected only from rats and dogs (organs not specified; data not shown). All animals were necropsied at death, [andhistopathological] examination of "approximately 33 tissues" [was performed]. The report provided lesion incidence data [were] "abbreviated to exclude lesions of very low incidence " (Kinkead et al., 1985). 10 Methyl cy cl ohexane ------- FINAL 1-8-2013 The report (Kinkead et al., 1985) did not indicate which statistical methods were used to evaluate [the] data, but did note, for most endpoints, if the values [of] the exposure groups were significantly different from controls: [i.e.,] p < 0.05 or p < 0.01. Some of the data presented in the report were analyzed by Fisher's exact test (p < 0.05) for this review to assess the statistical significance of [the] differences between [the] control and exposure groups. Exposed male rats exhibited reduced weight gain compared [with] control male rats; no statistical analyses were provided (Kinkead et al., 1985a). At both 1607.2 mg/m3 and 8045 mg/m , male rat body weights were decreased compared [with] controls (by less than 10%) from the [eighth] through the [twelfth] [months] of exposure. No changes in mortality incidence at the end of the 1-year exposure period were discernable. Analysis of the [histopathological] data available for male rats at the end of the 1-year exposure found a statistically significant elevation of testicular tumor incidence in the low-exposure group (0/11, 5/10, and 2/11 for the control, low-, and high-exposure groups, respectively); the authors did not indicate whether the tumors were benign or malignant. Additionally, the authors (Kinkead etal., 1985a) considered an increase in the incidence of renal tubular dilation with increasing concentration (1/11, 2/10, and 4/10 for control, low-, and high-exposure rats [, respectively]) at this time point to be biologically significant, although the effect was not statistically significant. No other evidence of kidney damage was reported in the male rat groups [that were] sacrificed at cessation of exposure (Kinkead etal., 1985a). Among [the] methylcyclohexane-exposed male rats (54-55/group)[that were] allowed to recover for 1 year prior to sacrifice (Kinkead et al., 1985a), body weights returned to normal within 10 months, but they again appeared to diverge at 12 months postexposure. Blood was collected from [only] 9 or 10 male rats/group at necropsy following the 1-year exposure [period]; statistically significant changes were observedfor some endpoints (decreased white blood cell counts and sodium [levels] in both exposure groups; decreased hemoglobin only in the high-exposure group; decreased hematocrit, potassium, sodium and creatinine [levels] only in the low-exposure group). Although the authors did not consider any of these effects to be biologically significant, the decrease in white blood cell counts (to around 80% of [the] control values in both the low- and high-exposure groups, statistically significant at both concentrations) may represent an exposure-related adverse effect. A similar decrease in white blood cell counts was observed in similarly exposedfemale rats, but not in similarly exposed male or female dogs for whom samples were measured more frequently (see below). Differential counts were not reportedfor the rat or dog groups (Kinkead et al., 1985a,d). The background incidence of "progressive renal nephropathy" was high in all [male rats that were allowed a recovery period], and was not significantly different [from any other] group (49/53, 52/55, and 52/52for the control, low-, and high-exposure groups, respectively). The high-exposure [male rat group that was allowed to recover] exhibited statistically significant elevations in the incidences of kidney medullary mineralization (1/53, 2/55, and 19/52 for the control, low-, and high-exposure groups, respectively) and hyperplasia of the papillary epithelia (1/53, 1/53, and 23/52, respectively). The authors (Kinkead et al., 1985a) considered these renal lesions to be a progression 11 Methyl cy cl ohexane ------- FINAL 1-8-2013 from renal tubular dilation seen at the end of exposure to "hydrocarbon nephropathy... [that is] characterized by an increase in the incidence of hyaline droplets and of regenerative tubular epithelia in the cortex. " The authors noted that the severity of the lesions associated with methylcyclohexane exposure [was] less severe than [that observed] in male rats [exposed] to gasoline, decalin, [or] jet fuels. No association between testicular tumor incidence and exposure was apparent among male rats 12 months after exposure due to [the] high background incidence of testicular interstitial cell tumors (49/54, 49/55, and 50/52for the control, low-, and high-exposure groups, respectively). The calculated HECs for extrarespiratory effects, assuming a blood:gas partition "3 coefficient of 1, are 0, 268, and 1339 mg/m based on the experiments performed on rats (Kinkead et al., 1985a). Kinkead et al, 1985a Considered together, these data do not clearly identify [NOAEL or LOAEL values] for nonneoplastic effects in male rats exposedfor 1 year to methylcyclohexane via inhalation, with or without a 1-year recovery period (Kinkead et al., 1985a). The induction of renal hyaline droplet-induced nephropathy in male rats is not considered relevant to human exposure (U.S. EPA, 1991c). The observed decreases in body weight (less than 10%) and white blood cell counts are not [clear] adverse effects. Female rat weight was not significantly affected by inhalation exposure to 1607.2 or 8045 mg/m methylcyclohexane for 1 year (Kinkead et al., 1985a). No changes in female rat mortality incidence during the 1-year exposure period were discernable. Differences in the incidences of ovarian cysts (0/11, 4/10, and 1/10 for the control, low-, and high-exposure groups, respectively) [were] not considered biologically significant by the study authors (Kinkead et al., 1985a); however, application of Fisher's exact test (p < 0.05) for this review, determined that the incidence for the low-exposure group was statistically [and] significantly different from the control incidence. [The] mammary gland tumor incidence [of the female rats sacrificed at the end of the exposure period was not reported]. No differences in body weight were seen among the female rat [groups that were allowed a recovery period] (Kinkead et al., 1985a). From these rats, blood was collected from 10 animals/group just prior to sacrifice. Hematology was performed but the clinical chemistry samples were lost. The only statistically significant difference from [the] control values was a decrease in white blood cell counts in the high-exposure group; the authors (Kinkead et al., 1985a) did not consider this effect to be biologically significant. However, this effect was also seen in similarly exposed male rats and the magnitude of the decrease (89% and 67% of control values for the low- and high-exposure groups, respectively) makes the absence of toxicity uncertain. The authors (Kinkead et al., 1985a) did not consider any differences in the incidences of histopathological lesions seen among [the] female rats [that were allowed to recover] (54-55/group) to be statistically significant. Analysis of these data by Fisher's exact test (conducted for this review; p > 0.05) detected a statistically significant increase in the incidence of mammary glandfibroadenoma [in] the high-exposure group (0/47, 12 Methyl cy cl ohexane ------- FINAL 1-8-2013 4/50, and 6/48 in the control, low-, and high-exposure groups, respectively). The incidences of ovarian cysts were not significantly different (6/50, 2/51, and 3/52, respectively). Considered together, these data do not clearly identify [NOAEL or LOAEL values] for nonneoplastic effects in female rats exposedfor 1 year to methylcyclohexane via inhalation, with or without a 1-year recovery period (Kinkead et al., 1985a). The observed decreases in white blood cell counts (high-exposure group at necropsy immediately following exposure) and the increased incidence of ovarian cysts (only significant for [the] low-exposure [group] at the cessation of exposure) provide evidence suggestive of methylcyclohexane-induced toxicity, but were too inconsistently observed to be considered clear evidence of exposure-related adverse effects. Kinkead et al, 1985b No information was provided regarding [the] body weights of female C57BL/6J mice (200/group) exposed to methylcyclohexane for 1 year (Kinkead et al., 1985b). A statistically significant elevation in mortality incidence was apparent [in] mice exposed to 8045 mg/m methylcyclohexane compared [with] controls (9/200, 15/200, and 19/200for the control, low, and high-exposure groups, respectively). The authors did not note any biologically or statistically significant differences in histopathology among the [exposure groups at the end of the study] (Kinkead et al., 1985b); similarly, no differences were detected [using] data analysis by Fisher's exact test (conductedfor this review; p>0.05). No significant differences among the incidences of uterine cysts were apparent (18/29, 16/35, and 14/39 for the control, low-, and high-exposure groups, respectively). Spleen lesion incidence was not reported. The FEL [frank effect level] for female mice exposed to methylcyclohexane for 1 year is 8045 mg/m , based on increased mortality. For mice allowed to recover for 1 year after inhalation exposure to methylcyclohexane (161-171/group), insufficient data precluded [the] estimation of [the] mortality incidence during the recovery period, and no data were provided regarding individual or group body weights (Kinkead et al., 1985b). The authors did not consider any of the differences in [histopathological incidences] to be statistically or biologically significant. However, analysis of the lesion data provided in the report by Fisher's exact test (performed for this review; p < 0.05) detected statistically significant increases in the incidences of multiple uterine cysts at both concentrations (10/164, 23/158, and 23/152for the control, low-, and high-exposure groups, respectively) and spleen hematopoiesis only [at] the low concentration (22/164, 34/150, and 23/154 in the control, low-, and high-dose groups respectively). These two effects are suggestive evidence of methylcyclohexane-induced toxicity; they are not, however, [clear] adverse treatment-related effects because they are common lesions in aged mice and were only seen in the recovery animals. 13 Methyl cy cl ohexane ------- FINAL 1-8-2013 The calculated HECs for extrarespiratory effects, assuming a blood:gas partition coefficient of 1, are 0, 268, and 1339 mg/m3 for experiments performed on mice (Kinkead et al., 1985b). The dose-related mortality observed in the treated mice at all levels of exposure precludes the identification of NOAEL or LOAEL values. Deficiencies in the reporting of the mouse data, which were allowed a recovery period following exposure, precludes the identification of NOAEL or LOAEL values, as well. Kinkead et al, 1985c [Male Golden Syrian hamsters exposed] to either 1607.2 or 8045 mg/m methylcyclohexane for 1 year [showed evidence of] reduced weight gain (Kinkead et al., 1985c). Hamsters were 12 weeks of age at the onset of exposure, and body weight peaked in the first 2-4 weeks of exposure [in] all [groups of hamsters]. After the first month of exposure, body weights [of] the low- and high-exposure groups were approximately 5 and 10% less, respectively, than control body weight. From the [second] through the [twelfth] month of exposure, [the] body weights [of] all exposure groups were 10-18% lower [than the control group]. The authors did not provide a statistical evaluation of these [effects on] body weight. For all animal groups, water was freely available at all times and food was available only during nonexposure periods; therefore, decreased palatability is unlikely to be a direct cause of the observed weight loss. No changes in [the incidence of] male hamster mortality during the 1-year exposure period were discernable. The authors (Kinkead et al., 1985c) did not consider any of [the] differences in [the incidences of lesions] among [the] male hamsters to be biologically or statistically significant. Likewise, analysis of the data provided in the report by Fisher's exact test (performed for this review) found no statistically significant differences. The calculated HECs for extrarespiratory effects, assuming a blood:gas partition "3 coefficient of 1, are 0, 268, and 1339 mg/m for experiments performed on hamsters (Kinkead et al., 1985c). Neither NOAEL nor LOAEL values were identified in hamsters by Kinkead et al. (1985c). While there appears to be an effect on body weight, which decreased by more than 10% starting 1 month after exposure began, as reported by the study authors, the data reporting is not sufficient for statistical analysis. Additionally, while it may be presumed that this effect was caused by the palatability of the feed, no data to support or discredit this assumption were identified. Kinkead et al, 1985d All beagle dogs (4/sex/group) [that were] exposed by inhalation to methylcyclohexane for 1 year survived until 5 years postexposure (Kinkead et al., 1985d). No sacrifices had been scheduled [to occur at] the cessation of exposure. No canine body weight data were provided. Blood was sampled every 2 weeks during exposure and every 6 months after cessation of exposure. The only blood parameter to exhibit a statistically significant change during exposure was serum alanine aminotransferase: transient increases (week 7 [and weeks 39-43]) seen in the 8045 mg/m3 group were attributed to 1 dog, and changes [in] the 1607.2 mg/m [group] were attributed to 2 animals (only [observed in weeks 39-43]). The authors did not consider any [of the observed] lesions in the 14 Methyl cy cl ohexane ------- FINAL 1-8-2013 dogs to be biologically or statistically significant. Analysis of the data provided by Fisher's exact test (performedfor this review) found no statistically significant differences between [the] control and exposed animals. The calculated HECs for the extrarespiratory effects, assuming a blood:gas partition "3 coefficient of 1, are 0, 268, and 1339 mg/m for experiments performed on dogs (Kinkead et al., 1985d). Kinkead et al, 1985d [Due to] the small numbers of dogs used and the long postobservation period prior to their histopathologic examination, this study design is not suitable for [the] determination of a NOAEL for male or female dogs. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) Several studies were identified regarding the genotoxicity of methylcyclohexane (see Table 4A). 15 Methyl cy cl ohexane ------- FINAL 1-8-2013 Table 4A. Summary of Methylcyclohexane Genotoxicity Endpoint Test System Dose Concentration" Resultsb Comments References Without With Activation Activation Genotoxicity studies in prokaryotic organisms Reverse mutation NA SOS repair induction NA Genotoxicity studies in nonmammalian eukaryotic organisms Mutation NA Recombination induction NA Chromosomal aberration NA Chromosomal malsegregation NA Mitotic arrest NA Genotoxicity studies in mammalian cells—in vitro Mutation NA Chromosomal aberrations NA Sister chromatid exchange (SCE) NA DNA damage NA DNA adducts NA Genotoxicity studies in mammals—in vivo Chromosomal aberrations NA Sister chromatid exchange (SCE) NA DNA damage NA DNA adducts NA Mouse biochemical or visible specific locus test NA Dominant lethal NA Genotoxicity studies in subcellular systems DNA binding NA aLowest effective dose for positive results or highest dose tested for negative results. bNA = not applicable. 16 Methyl cy cl ohexane ------- FINAL 1-8-2013 Table 4B. Other Studies Test Materials and Methods" Results Conclusions References Acute studies 4 rabbits (unspecified strain and sex), exposed to 59,900 mg/m3 vapor for 70 min; 28,750 or 30,550 mg/m3 for 6 hr/d, 5 d/wk for 2 wk; 11,350 mg/m3 for 3 wk; or 21,900 mg/m3 for 4 wk 100% mortality in animals exposed to 59,900 mg/m3 vapor for 70 min or 30,550 mg/m3 for 2 wk; decreased body weight, lethargy, and decreased coordination at 28,750 mg/m3 for 2 wk; slight lethargy at 21,900 mg/m3 for 4 wk; minor liver and kidney effects at 11,350 mg/m3 for 3 wk Systemic toxicity; severity of effects correlated with increasing exposure Treon etal., 1943b Mice (unreported number, strain and sex), exposed to 30,000, 40,000, or 50,000 mg/m3 for 2 hr Prostration at 30,000-40,000 mg/m3; mortality at 40,000-50,000 mg/m3 Systemic toxicity resulting in mortality at high doses Lazarew, 1929, as cited in U.S. EPA, 2005 Mice and rabbits (number, strain, and sex not available) for 4 hr LD50 determined to be 40,000 mg/m3 in mice and 60,000 mg/m3 in rabbits Systemic toxicity resulting in mortality at high doses Shell Chemical Co., 1999, as cited in U.S. EPA, 2005 aExposure values from acute animal studies are not adjusted to continuous exposure or converted to HEC. Acute Studies Studies investigating the acute effects of methylcyclohexane exposure were reviewed in the 2005 PPRTV on methylcyclohexane (U.S. EPA, 2005; see Table 4B). The text below is quoted directly from the PPRTV as denoted by the italicized and indented text, with changes to the text within the quotes indicated in brackets. No additional literature was identified. ... Treon et al. (1943b) also exposed groups of 4 rabbits to 59.9 mg/L (59,900 mg/m3) methylcyclohexane for 70 minutes, 28.75 or 39.55 mg/L (28,750 or 30,550 mg/m3) for 6 hours/day, 5 days/week for 2 weeks, 11.35 mg/L (11,350 mg/m3) for 3 weeks, or 21.90 mg/L (21,900 mg/m3) for 4 weeks. The same endpoints were measured as in the 10-week experiment (for these concentrations, histology was reported only for [the 11,350 mg/m3 group]). At [concentrations of] 59,900 and 39,550 mg/m , all rabbits died; they exhibited increased [body] temperature, decreased body weight, convulsions, narcosis, labored breathing, salivation, and conjunctival congestion. No mortalities were seen at [the] lower doses. Exposure to 28,750 mg/m3 caused decreased body weight, lethargy, and impaired coordination, while exposure to 21,900 mg/m produced only slight lethargy. At 11,350 mg/m3, microscopic analysis [revealed] "barely demonstrable " liver and kidney [injuries]. The acute exposure portion of this experiment (Treon et al., 1943a) is consistent with other acute inhalation studies. Exposure ...to methylcyclohexane for 2 hours resulted in prostration [in mice exposed to] 7500-10,000ppm (30,000 and 40,000 mg/m3 [ respectively]) 17 Methyl cy cl ohexane ------- FINAL 1-8-2013 5 and death [in mice exposed to] 10,000-12,500 ppm (40,000 and 50,000 mg/m [, respectively]) (Lazarew, 1929). Shell Chemical Co. (1999) reported 4-hour LC50 values of 10,000 ppm (40,000 mg/m3)[for] mice and 15,000 ppm [for] rabbits (60,000 mg/m3). DERIVATION OF PROVISIONAL VALUES Tables 5 and 6 present a summary of the noncancer and cancer reference values, respectively. IRIS data are indicated in the table, if available. Table 5. Summary of Noncancer Reference Values for Methylcyclohexane (CASRN 108-87-2) Toxicity Type (units) Critical p-Reference Principal Species/Sex Effect Value POD Method POD UFC Study Subchronic p-RfD (mg/kg-d) NDr Chronic p-RfD (mg/kg-d) NDr Subchronic p-RfC (mg/m3) NDr Chronic p-RfC (mg/m3) NDr NDr = not determined. Table 6. Summary of Cancer Values for Methylcyclohexane (CASRN 108-87-2) Toxicity Type Species/Sex Tumor Type Cancer Value Principal Study p-OSF NDr p-IUR NDr NDr = not determined. DERIVATION OF ORAL REFERENCE DOSES No acceptable studies for the derivation of provisional oral references doses for oral exposure to methylcyclohexane were identified. Derivation of Subchronic Provisional RfD (Subchronic p-RfD) A subchronic p-RfD cannot be derived for methylcyclohexane because no subchronic oral data were identified. 18 Methyl cy cl ohexane ------- FINAL 1-8-2013 Derivation of Chronic Provisional RfD (Chronic p-RfD) A chronic p-RfD cannot be derived for methylcyclohexane because no chronic oral data were identified. DERIVATION OF INHALATION REFERENCE DOSES There is only one inhalation study in the available databases (Kinkead et al., 1985). Data from all four portions of this study are inadequate for the derivation of provisional inhalation estimates for inhalation exposure to methylcyclohexane. Derivation of Subchronic Provisional RfC (Subchronic p-RfC) A subchronic p-RfC cannot be derived for methylcyclohexane because no subchronic inhalation dose-response data were identified. Derivation of Chronic Provisional RfC (Chronic p-RfC) A chronic p-RfC cannot be derived for methylcyclohexane because no adequate chronic inhalation data were identified. Justification Analysis of the current available literature concurs with the analysis presented in the previous PPRTV (U.S. EPA, 2005). Limitations in the available data preclude the development of both cancer and noncancer toxicity values. Text quoted directly from the previous PPRTV is denoted by the italicized and indented text, with changes to the text within the quotes indicated in brackets. No adequate studies were found [in regards to] human inhalation exposure to methylcyclohexane. Furthermore, no unequivocal NOAELs or LOAELs could be identifiedfrom the available animal inhalation studies. The highest concentration of methylcyclohexane tested in rabbits by Treon et al. (1943b), [which was a concentration of} 4570 mg/m3 [administered] for 10 weeks, was determined to be] a NOAEL... [however, this] study is limited by the small group size, the allowance of a recovery period prior to sacrifice, and reporting deficiencies that fail to indicate whether or not comprehensive [histopathological examinations were] performed. Additionally, deficiencies in the methods, data reporting, and analysis sections of the Kinkead et al. (1985a,b,c,d) study, which is also reported by the American Petroleum Institute (1985) and the Air Force Medical Research Lab (1985), are sufficient to similarly preclude the use of this study for the derivation of a p-RfC. Examples of these deficiencies include: • The pathologies of the animals that died were grouped together with animals scheduled for sacrifice at the end of the exposure. • Data were often missing for some group members. • Small numbers of animals were used in each group. • While hematology was performed on animals sacrificed immediately after exposure, the clinical chemistry samples were lost. 19 Methyl cy cl ohexane ------- FINAL 1-8-2013 Data obtained from hamsters, rats, mice, and dogs that were presented by Kinkead et al. (1985a,b,d) are not sufficient to clearly identify NOAEL or LOAEL values for effects due to methylcyclohexane exposure in male or female rats, with or without a year of recovery period. ALTERNATIVE METHODS An attempt was made to identify a surrogate chemical whose toxicity value could be used to predict the toxicity of methylcyclohexane (details regarding searches and methods are presented in Wang et al. [2012]). Several public databases including DSS Tox and ChemID Plus were searched. Several closely related structural analogs were found, including methylcyclooctane (87% similarity) and ethylcyclohexane (86% similarity). However, no repeat-dose toxicity information was available for any of the potential surrogates and commonality in endpoints and/or toxic effects could not be identified. CANCER WOE DESCRIPTOR No human or suitable animal data on the carcinogenicity of methylcyclohexane were identified. U.S. EPA (2011) has not classified the carcinogenic potential of methylcyclohexane, and no other agencies have reviewed or classified the carcinogenic potential of this chemical (IARC, 2011; NTP, 2005; CalEPA, 2008). Furthermore, no studies regarding the genotoxicity of methylcyclohexane were identified. Thus, the cancer WOE descriptor for methylcyclohexane is "inadequate information to assess carcinogenic potentiaF (see Table 7). Table 7. Cancer WOE Descriptor for Methylcyclohexane Possible WOE Descriptor Designation Route of Entry Comments "Carcinogenic to Humans " NA NA There are no human data available. "Likely to Be Carcinogenic to Humans " NA NA There is not enough evidence to support this statement. "Suggestive Evidence of Carcinogenic Potential" NA NA There is not enough evidence to support this statement. "Inadequate Information to Assess Carcinogenic Potential" Selected Both No evidence of treatment-related carcinogenicity in humans or animals is available for methylcyclohexane. "Not Likely to Be Carcinogenic to Humans " NA NA There is not enough evidence to support this statement. 20 Methyl cy cl ohexane ------- FINAL 1-8-2013 APPENDIX A. PROVISIONAL SCREENING VALUES No screening values are presented. 21 Methyl cy cl ohexane ------- FINAL 1-8-2013 APPENDIX B. DATA TABLES No data tables are presented. 22 Methyl cy cl ohexane ------- FINAL 1-8-2013 APPENDIX C. BMD OUTPUTS No BMD outputs are presented. 23 Methyl cy cl ohexane ------- FINAL 1-8-2013 APPENDIX D. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). (2008) Threshold limit values for chemical substances and physical agents and biological exposure indices. ACGIH, Cincinnati, OH. As cited in HSDB (Hazardous Substances Data Bank). Available online at http://toxnet.nlm.nih.eov/cgi-bin/sis/htmlgen7HSDB. Accessed on January 25, 2011. 594308. Agnesi, R; Valentini, F; Mastrangelo, G. (1997) Risk of spontaneous abortion and maternal exposure to organic solvents in the shoe industry. Int Arch Occup Environ Health 69:311-316. Available online at http://dx.doi.org/10.1007/s00420005Q153. Accessed on January 25, 2011. 677518. Air Force Medical Research Lab. (1985) Chronic inhalation exposure of experimental animals to methylcyclohexane with cover letter dated 082685. U.S. Environmental Protection Agency, Washington, DC; Report No. 408589005; NTIS No. OTS0511483. 677200. American Petroleum Institute. (1985) Twelve-month chronic inhalation exposures to methylcyclohexane. U.S. Environmental Protection Agency, Washington, DC; Report No. 878216027; NTIS No. OTS0206798. 677169. ATSDR (Agency for Toxic Substances and Disease Registry). (2010) Toxicological profile information sheet. U.S. Department of Health and Human Services, Public Health Service. Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed on January 25, 2011. 595415. CalEPA (California Environmental Protection Agency). (2008) All OEHHA acute, 8-hour and chronic reference exposure levels (chRELs) as on December 18, 2008. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/air/allrels.html. Accessed on January 25, 2011. 595416. CalEPA (California Environmental Protection Agency). (2009) OEHHA toxicity criteria database. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/riskAChemicalDB/index.asp. Accessed on January 25, 2011. 595417. ChemlDplus. (2011) Methylcyclohexane. National Library of Medicine, Bethesda, MD. Available online at http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.isp. Accessed on January, 25,2011. HSDB (Hazardous Substances Data Bank). (2011) Methylcyclohexane. National Library of Medicine, National Toxicology Program, Bethesda, MD. Available online at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7HSDB. Accessed on January 25, 2011. IARC (International Agency for Research on Cancer). (2011) IARC monographs on the evaluation of carcinogenic risks to humans. Lyon, France: IARC. Available online at http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. 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Available online at http://www.sciencedirect.eom/science/article/pii/S0273230012000323. 1239453 WHO (World Health Organization). (2011) Online catalogs for the Environmental Health Criteria series. Available online at http://www.who.int/ipcs/publications/ehc/en/. Accessed January 25, 2011. 595424. 26 Methyl cy cl ohexane ------- |