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Hexane, All IsomersCAS Registry Number:n-Hexane: 110-54-3Other 4 IsomersPrepared byBernard J. Kadlubar, M.S.Jong-Song Lee, Ph.D.Toxicology DivisionDevelopment Support DocumentFinal, August 16, 2017TEXAS COMMISSION ON ENVIRONMENTAL QUALITY

Hexane, All IsomersPage iDSD HistoryEffective DateReasonOctober 15, 2007Original n-Hexane DSD posted as finalSeptember 14, 2015The odor-based value was withdrawn because n-hexane does not have apungent, disagreeable odor (TCEQ 2015b).July 8, 2016Public request for toxicity information on isomers of n-hexaneSeptember 2, 2016Public request for toxicity information on n-hexaneDecember 30, 2016Hexane, All Isomers DSD proposed for public commentAugust 16, 2017Hexane, All Isomers DSD posted as final

Hexane, All IsomersPage iiTABLE OF CONTENTSDSD HISTORY. ITABLE OF CONTENTS . IILIST OF TABLES . IIIACRONYMS AND ABBREVIATIONS . VCHAPTER 1 SUMMARY TABLES . 1CHAPTER 2 MAJOR USES OR SOURCES . 5CHAPTER 3 ACUTE EVALUATION . 63.1 PHYSICAL/CHEMICAL PROPERTIES . 63.2 HEALTH-BASED ACUTE REV AND ESL . 63.2.1 Key Animal Study (Glowa 1991) . 73.2.2 Supporting Studies. Swann et al. (1974) Animal Study . Patty and Yant (1929) Human Study . Rebert and Sorenson (1983, as cited in ATSDR 1999) Animal Study . Other Animal Studies . 93.2.3 Reproductive/Developmental Toxicity Studies . Mast el at. (1987) Animal Study . Mast et al. (1988) Animal Study . Litton Bionetics (1979) Animal Study . Bus et al. (1979) Animal Study . Neeper-Bradley (1989a,b) Animal Studies . Daughtrey et al. (1992, 1994) Two-Generation Reproductive Study . Summary of Reproductive/Developmental Studies . 123.2.4 Mode of Action (MOA) Analysis and Dose Metric . 133.2.5 POD and Critical Effect . 143.2.6 Dosimetric Adjustments . Exposure Duration Adjustments . Default Dosimetry Adjustments from Animal-to-Human Exposure . 143.2.7 Adjustments of the PODHEC . 153.2.8 Health-Based 1-h Acute ReV and acuteESL. 153.3 HEALTH-BASED ACUTE 24-HOUR REV. 163.3.1 Dosimetric Adjustments . Exposure Duration Adjustments . Default Dosimetry Adjustments from Animal-to-Human Exposure . 173.3.2 Adjustments of the PODHEC . 173.3.3 Health-Based 24-h Acute ReV. 173.4 WELFARE-BASED ACUTE ESLS . 183.4.1 Odor Perception. 183.4.2 Vegetation Effects . 183.5 SHORT-TERM ESLS AND VALUES FOR AIR MONITORING DATA EVALUATIONS. 19

Hexane, All IsomersPage iii3.5.1 n-Hexane . 193.5.2 Other hexane Isomers. 193.6 ACUTE INHALATION OBSERVED ADVERSE EFFECT LEVELS (IOAELS) . 19CHAPTER 4 CHRONIC EVALUATION . 204.1 PHYSICAL/CHEMICAL PROPERTIES . 204.2 HEALTH-BASED TOXICITY FACTORS. 204.2.1 Key Studies. Chang et al (1993) Human Study . Miyagaki (1967) Animal Study . 214.2.2 Supporting Studies. 214.2.3 Mode-of-Action (MOA) Analysis and Dose Metric . 234.2.4 Critical Effect and POD . 234.2.5 Dosimetric Adjustments . Exposure Duration Adjustments . 234.2.6 Adjustments of the PODHEC . 244.2.7 Health-Based Chronic ReV and chronicESLthreshold(nc) . 244.3 CARCINOGENIC POTENTIAL . 254.4 WELFARE-BASED CHRONIC ESL . 264.5 LONG-TERM ESL AND VALUES FOR AIR MONITORING DATA EVALUATIONS . 264.5.1 n-Hexane . 264.5.2 Other hexane Isomers. 264.6 CHRONIC INHALATION OBSERVED ADVERSE EFFECT LEVELS (IOAELS) . 26CHAPTER 5 REFERENCES . 275.1 REFERENCES CITED IN DSD . 275.2 REFERENCES OF OTHER STUDIES REVIEWED BY THE TD . 30APPENDIX DETERMINATION OF CHRONIC PODHEC FOR LOAELS . 32A.1 POD FOR LOAEL FROM THE CHANG ET AL. (1993) STUDY . 32A.1.1 Exposure Duration Adjustments . 32A.2 POD FOR LOAEL FROM THE MIYAGAKI (1967) STUDY . 32A.2.1 Exposure Duration Adjustments . 32A.2.2 Default Dosimetry Adjustments from Animal-to-Human Exposure . 32LIST OF TABLESTable 1. Acute Health and Welfare-Based Screening Values for Hexane, All Isomers . 2Table 2. Chronic Health and Welfare-Based Screening Values for Hexane, All Isomers . 3Table 3. Chemical and Physical Data. 4Table 4. Isomers of Hexane and CAS No. . 5Table 5 Summary of Reproductive/Developmental Animal Inhalation Studies . 12Table 6. Summary of 1-h Acute ReV and acuteESL for n-Hexane . 16Table 7. Summary of 24-h Acute ReV . 18

Hexane, All IsomersPage ivTable 8. Summary of Supporting Subchronic/Chronic Inhalation Studies of n-Hexane . 22Table 9. Derivation of the Chronic ReV and chronicESLthreshold(nc) . 25

Hexane, All IsomersPage vAcronyms and AbbreviationsAcronyms andAbbreviationsDefinitionAMCVair monitoring comparison valueodegrees CelsiusCCNScentral nervous systemdday(s)DSDdevelopment support documentESLeffects screening levelacuteESLacute health-based effects screening level for chemicals meetingminimum database requirementsacuteESLodoracute odor-based effects screening levelacuteESLvegacute vegetation-based effects screening levelchroniceESLgenericchronic health-based effects screening level for chemicals not meetingminimum database requirementschronicESLthreshold(c)chronic health-based Effects Screening Level for threshold doseresponse cancer effectchronicESLthreshold(nc)chronic health-based Effects Screening Level for threshold doseresponse noncancer effectschronicESLnonthreshold(c)chronic health-based Effects Screening Level for nonthreshold doseresponse cancer effectschronicESLnonthreshold(nc)chronic health-based Effects Screening Level for nonthreshold doseresponse noncancer effectschronicESLvegchronic vegetation-based effects screening levelhhour(s)Hb/gblood:gas partition coefficient(Hb/g)Ablood:gas partition coefficient, animal(Hb/g)Hblood:gas partition coefficient, humanmm Hgmillimeters of mercuryHEChuman equivalent concentration

Hexane, All IsomersPage viAcronyms andAbbreviationsDefinitionHQhazard quotientHSDBHazardous Substance Data BankIARCInternational Agency for Research on CancerIOAELinhalation observed adverse effect levelacuteacute inhalation observed adverse effect levelIOAELsubacuteIOAELsubacute inhalation observed adverse effect levelchronicIOAEL(nc)chronic inhalation observed adverse effect level (noncancer effects)chronicIOAEL(c)chronic inhalation observed adverse effect level (cancer ect-levelMWmolecular weightµgmicrogramµg/m3micrograms per cubic meter of airmgmilligramsmg/m3milligrams per cubic meter of airminminute(s)MOAmode of anization for Economic Cooperation and DevelopmentPODpoint of departurePODADJpoint of departure adjusted for exposure durationPODHECpoint of departure adjusted for human equivalent concentrationppbparts per billionppmparts per millionReVreference valueAcute ReVacute (e.g., 1-hour) health-based reference value for chemicalsmeeting minimum database requirements

Hexane, All IsomersPage viiAcronyms andAbbreviationsDefinitionAcute ReV-24hracute 24-hour health-based reference value for chemicals meetingminimum database requirementsChronic ReVthreshold(nc)chronic health-based reference value for threshold dose responsenoncancer effectsRGDRregional gas dose ratioRPFrelative potency factorSDSprague-Dawley ratsTCEQTexas Commission on Environmental QualityTDToxicology DivisionUFuncertainty factorUFHinterindividual or intraspecies human uncertainty factorUFAanimal to human uncertainty factorUFSubsubchronic to chronic exposure uncertainty factorUFLLOAEL to NOAEL uncertainty factorUFDincomplete database uncertainty factorUSEPAUnited States Environmental Protection Agencywkweek(s)yryear(s)

Hexane, All IsomersPage 1Chapter 1 Summary TablesTable 1 and Table 2 provide a summary of health- and welfare-based values from an acute andchronic evaluation of n-hexane and all isomers, respectively, for use in air permitting and airmonitoring. Please refer to Section 1.6.2 of the TCEQ Guidelines to Develop Toxicity Factors(TCEQ 2015a) for an explanation of reference values (ReVs) and effects screening levels (ESLs)used for review of ambient air monitoring data and air permitting. Table 3 provides summaryinformation on physical/chemical data for n-hexane).

Hexane, All IsomersPage 2Table 1. Acute Health and Welfare-Based Screening Values for Hexane, All IsomersScreening Level DurationTypeAcute ReVValue 2(ppb)Usage Flags Surrogated/RPFCritical Effect(s)Notes19,0005,500MA--Neuroendocrine effects inrats.Applicable to n-hexane and 4isomers.Acute ReV-24hr 24 h19,0005,500MA--Reduction in fetal bodyweight in rats.Applicable to n-hexane and 4isomers; used for the evaluationof 24-h air monitoring data.acute1,600PS,D--Neuroendocrine effects inrats.Applicable to n-hexane and 4isomers.acute1hValue 1(µg/m3)ESL a1h5,600IOAEL20 h3,500,000 1,000,000 Nnone --Reduction in fetal bodyweight in ------------Gasoline-like odor, not pungentor disagreeable.acuteESLveg--------------No data found.Bold values used for air permit reviews.aBased on the acute 1-h ReV multiplied by 0.3 (i.e., HQ 0.3) to account for cumulative and aggregate risk during the air permit review.Usage:Flags:P Used in Air PermittingA AMCV reportM Used to Evaluate Air Monitoring DataS ESL Summary ReportR Used to Calculate Remediation Cleanup LevelsD ESL Detail ReportN Usage Not Defined

Hexane, All IsomersPage 3Table 2. Chronic Health and Welfare-Based Screening Values for Hexane, All IsomersScreening Level Type Duration Value 1 Value 2 Usage Flags Surrogated/(µg/m3) (ppb)RPFCritical Effect(s)NotesChronic ReVthreshold(nc) 70 yr670190MA--Peripheral neuropathy inoccupational workers from anoffset printing factory.Applicable to n-hexane and 4isomers.chronic57PS,D--Same as above.Applicable to n-hexane and4 isomers.ESLthreshold(nc) a70 yr200chronicIOAEL(nc)70 yr460,000 130,000 Nnone--Same as uate information toassess carcinogenic nadequate information toassess carcinogenic Lveg--------------No data found.chronicESLanimal--------------No data found.Bold values used for air permit reviewsaBased on the chronic ReV multiplied by 0.3 (i.e., HQ 0.3) to account for cumulative and aggregate risk during the air permit review.Usage:Flags:P Used in Air PermittingA AMCV reportM Used to Evaluate Air Monitoring DataS ESL Summary ReportR Used to Calculate Remediation Cleanup LevelsD ESL Detail ReportN Usage Not Defined

Hexane, All IsomersPage 4Table 3. Chemical and Physical DataParameterMolecular FormulaValueC6H14Chemical StructureReferenceChemfinder 2004ChemSpider 2016Molecular Weight86.1766TRRP 2006Physical StateLiquidTRRP 2006ColorColorlessChemfinder 2004OdorGasoline typeChemfinder 2004CAS Registry Number110-54-3TRRP 2006Synonymsn-Hexane, Hexane/mixed isomers,Hexanes, dipropyl, gettysolve-b,Hex, Hexyl hydride, Normalhexane, skellysolve BChemfinder 2004Solubility in water, mg/L13.0 mg/LTRRP 2006Log Pow or Kow3.9Chemfinder 2004Vapor Pressure153 mm Hg at 25 CHSDB 2005Relative Vapor Density0.2 cm2/sTRRP 2006Density0.67 at 25 CHSDB 2005Melting Point-95 C to -100 CChemfinder 2004Boiling Point69 CChemfinder 2004Conversion Factors1 µg/m3 0.284 ppb1 ppb 3.52 µg/m3Toxicology Division

Hexane, All IsomersPage 5Chapter 2 Major Uses or Sourcesn-Hexane and other isomers (hexanes) are all colorless volatile liquids at room temperature,odorless when pure, low solubility in water, and with boiling points between 50 and 70 C.Hexanes are used in the formulation of glue for shoes, leather products, and roofing. There are5 isomers of hexane including n-hexane, 2- and 3-methylpentane, 2,2- and 2,3-dimethylbutane(Table 4).Table 4. Isomers of Hexane and CAS No.Isomer NameCAS lbutane75-83-2Chemical Structuren-Hexane (hexane) is a solvent that has many uses in the chemical and food industries, either inpure form or as a component of the commercial hexane mixture. Highly purified hexane isprimarily used as a reagent for chemical or chromatographic separations. Commercial hexane isa mixture that contains approximately 52% hexane; the remaining balance is made up ofvarying amounts of structural isomers and related chemicals, such as methylpentane andmethylcyclopentane. Mixtures containing hexane are also used in the extraction of edible fatsand oils in the food industry, as cleaning agents in textile and furniture manufacturing, and inthe printing industry. Hexane is the solvent base for many commercial products, such as glues,cements, paint thinners, and degreasers. The chemical is a minor constituent of crude oil and

Hexane, All IsomersPage 6natural gas and, therefore, represents a variable proportion of different petroleum distillates.For example, hexane comprises about 11.6% of unleaded gasoline and about 2% of JP-4aviation fuel (ATSDR, 1993b, 1999, USEPA 2005).The most probable route of human exposure to hexane is by inhalation. Individuals are mostlikely to be exposed to hexane in the workplace; however, monitoring data indicate that hexaneis a widely occurring atmospheric pollutant. Exposure from contact with vapors or emissionsfrom heating and motor fuels refined from petroleum products is the most widespread form oflow-level exposure for the general population. Most hexane in these fuels is oxidized, ordestroyed, as part of the combustion process to provide heat or drive internal combustionengines. Small amounts of hexane, along with other petroleum compounds, volatilize to theatmosphere during handling, storage in fuel tanks, or through incomplete combustion. Recentresearch suggests that certain fungi may be able to produce hexane. These fungi may becommon in older buildings, and in some parts of the country may provide exposures frompreviously unsuspected indoor sources (ATSDR 1993a, 1999, NSC 2003).In Texas, the highest reported 1-hour (h) concentration (from 1996 through 2016) of n-hexanewas 380.2 ppb collected from an automated gas chromatograph (AutoGC) sample at anambient air monitoring site at the Decatur Thompson monitoring site in Dallas in 2013. Thehighest represented annual concentration of n-hexane was 1.4 ppb measured at the Clintonmonitoring site in Houston in 1998. The highest 24-h n-hexane value collected from a canistersample from 1995 to 2015 was 690.7 ppb at the Beaumont Downtown monitor in 1996. Thehighest represented annual concentration of n-hexane was 13.4 ppb measured at theBeaumont Downtown in 1996.Chapter 3 Acute Evaluation3.1 Physical/Chemical PropertiesThe main chemical and physical properties of n-hexane are summarized in Table 3. Chemicaland physical properties for other hexane isomers are similar to n-hexane.3.2 Health-Based Acute ReV and ESLInhalation of n-hexane usually causes eye, nose, throat and respiratory irritation, which arerapidly reversible when exposure is discontinued. Acute effects are considered similar to that ofother saturated aliphatic hydrocarbons of similar length (C3-C8 alkanes) (EU 2003). However,there is a direct relationship between aliphatic carbon chain length and the potency of alkanesfor effects such as lethality, anesthetic activity, physiological response, respiratory irritation,and neurological toxicity (i.e., as chain length increases up to C10, toxicity increases) (Patty andYant 1929, Glowa 1991, Swann et al. 1974, Lammers et al. 2011). One reason is, as carbon chain

Hexane, All IsomersPage 7length of alkanes increases and the potency increases, the higher number of carbon atoms inaliphatic hydrocarbons have higher uptake rates (Dahl et al. 1988, McKee et al. 2006, Lammerset al. 2011). Furthermore, elimination of low-molecular-weight hydrocarbons is predominantlyby exhalation and very rapid whereas elimination of molecules of greater molecular weights ismore likely to involve metabolism and urinary excretion, increasing elimination half times froma few minutes (min) to approximately 2 h (Lammers et al. 2011). Studies of the comparativeinhalation toxicities of the saturated hydrocarbons showed that straight-chain alkanes are moretoxic than their branched isomers (Lazarew 1929, as cited in Carreón T. 2005).3.2.1 Key Animal Study (Glowa 1991)Glowa (1991) examined the ability of individual n-alkanes (C5-C8) including n-hexane to impairperformance (neurobehavioral effects) and to stimulate the hypothalamic-pituitary-adrenal(HPA) axis (neuroendocrine effects) in adult male CD-1 mice (35-40 grams).For neurobehavioral effects assessment, impaired performance was assessed by studyingoperant response maintained under a fixed interval 60-second schedule of milk presentation. Inthe presence of flashing green lights, the first response to occur after the elapse of a 60-secondinterval produced milk. Eight mice were studied. Individual concentration-effect functions wereobtained by comparing pre-exposure (control) levels of response to response after 30-min ofexposure of incrementally increased hexane concentrations. Recovery was determined 30 minfollowing removal from exposure. Concentration was increased from 100 ppm (nominalconcentrations) until the response was abolished. The results showed that concentrations lessthan 3,000 ppm had no effect. Concentrations of 5,600 ppm n-hexane decreased the rate ofresponse in a concentration-related manner with decreased rate of response of slightly lessthan 50% at 5,600 ppm, about 80% at 8,000 ppm, and completely abolishing it (100%) at 17,000ppm. Response recovered fully 30 min following ceasing exposure to 17,000 ppm n-hexane.Mean concentrations ( standard deviation) resulting in a 50% and 10% rate of responsedecreasing potency (EC50 and EC10) were 7,051 3,138 and 4,537 3,490 ppm, respectively.The level of 3,000 and 4,537 ppm (EC10) can be considered a 30-min no-observed-adverseeffect-level (NOAEL) and minimal lowest-observed-adverse-effect-level (NOAEL), respectively,for transient behavioral impairment.For neuroendocrine effects assessment, the effect on HPA axis activation was studied bymeasuring adrenocortocotropin (ACTH) levels following exposure of mice (6 mice perconcentration) to n-hexane (100 to 10,000 ppm) for 30 min. Immediately after exposureceased, animals were sacrificed and the ACTH levels in serum were measured. ACTH levels werethe same from 100 to 1,000 ppm compared to the control. ACTH levels increased sharplyapproximately 1,400% and 1,700% of control at 3,000 and 10,000 ppm, respectively. The levelsof 1,000 and 3,000 ppm may be considered a 30-min NOAEL and LOAEL, respectively, for HPA

Hexane, All IsomersPage 8activation. However, no statistical analyses were performed and thus, statistical significance isunknown. Without knowing the biological significance of the neuroendocrine effects asmeasured by HPA activation, or the statistical significance of the effects, we could notdetermine if the effects were adverse. Nevertheless, the 30-min NOAEL of 1,000 ppm forneuroendocrine effects was conservatively used as point of departure (POD) to develop the 1-hacute ReV for n-hexane.3.2.2 Supporting Studies3.2.2.1 Swann et al. (1974) Animal StudySwann et al. (1974) studied the respiratory tract irritation properties of n-hexane in male Swissmice (25 g). Four animals were exposed head-only for 5 min at each of the followingconcentrations of n-hexane: 1,000, 2,000, 4,000, 8,000, 16,000, 32,000, and 64,000 ppm(nominal concentrations). The respiratory rate, depth, and configuration were counted andrecorded for 15-second intervals while the animals were inhaling n-hexane. Concentrations upto 8,000 ppm produced no anesthesia. At 16,000 ppm, mice experienced some periodic bodymovement during exposure. Some slight anesthesia occurred during the recovery period. At32,000 ppm, mice experienced respiratory irregularity during exposure with deeper anesthesiaand increased expiratory effect. At 64,000 ppm, all mice stopped breathing within 4.5 min ofthe onset of exposure. A NOAEL and LOAEL of 8,000 and 16,000 ppm, respectively, for irritationwere identified from this study. Since the exposure duration was only 5 min, the NOAEL wasnot used as a POD to develop the acute toxicity values. Patty and Yant (1929) Human StudyIn a human inhalation study, no symptoms were experienced by three to six volunteers exposedto 2,000 ppm hexane for 10 min, but dizziness and a sense of giddiness were experienced at5,000 ppm (Patty and Yant 1929). This study is rather dated and focused on a limited number ofparameters to examine the warning properties of C3-C7 alkanes, evaluated only 3-6 subjects,study results were not well reported, and exposure was for only 10 min. Thus, the NOAEL of2,000 ppm identified from this study was not used as the POD to derive the acute ReV andacuteESL for n-hexane. Rebert and Sorenson (1983, as cited in ATSDR 1999) Animal StudyIn a subacute study by Rebert and Sorenson (1983, as cited in ATSDR 1999), the body weights ofmale Fischer 344 rats exposed to 1,500 ppm n-hexane 24 h/day (d), 5 d/week (wk) were 11%below those of control rats within 2 wk. Statistical significance was not reported. The level of1,500 ppm can be considered a free-standing LOAEL for decrease in body weight gain. Since thestudy was for subacute exposure (24 h/d), even if a 1-h LOAEL adjusted from a single 24-hexposure were deemed appropriate in this case (the duration of actual exposure was 100 h),

Hexane, All IsomersPage 9the LOAEL from this subacute study would be much higher so was not used as POD to developthe acute ReV. Other Animal StudiesIn another study, a NOAEL of 500 ppm was reported after a 5-min inhalation exposure in anunidentified test species (Wayne and Orcutt 1960). Iba and Bird (2007) reported that ratsexposed to 1,000 ppm for 6 h experienced no adverse health effects when compared to othertreatment groups. This study did not clearly identify a NOAEL for hexane exposure as thepurpose of the study was to examine the effects of co-exposure of rats to hexane and the 1,3butadiene metabolite, 3-butene-1,2-diol. However, the findings of the Iba and Bird (2007) studyadd further evidence to the relatively nontoxic nature of hexane. The NOAEL is likely to be atleast 1,000 ppm for exposure to hexane alone.3.2.3 Reproductive/Developmental Toxicity StudiesNo information is available on the reproductive or developmental effects of hexane in humans

CAS Registry Number: n-Hexane: 110-54-3 Other 4 Isomers Prepared by Bernard J. Kadlubar, M.S. Jong-Song Lee, Ph.D. Toxicology Division Development Support Document Final, August 16, 2017 . Hexane, All Isomers Page i DSD Hi