X TECHNICAL REPORT DATA ffleae read tn*auctions on ifit reverse btfort complerint) 1. REPORT NO. EPA/600/8-88/048 2. 3. RECIPIENT'S ACCESSION NO. PB88-179528 4. TITLE AND SUBTITLE Health Effects Assessment for n-Pentane 6. REPORT DATE 6. PERFORMING ORGANIZATION CODE 7. AUTHOR(S) I. PERFORMING ORGANIZATION REPORT NO. 9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT NO. 11. CONTRACT/GRANT NO. 12. SPONSORING AGENCY NAME AND ADDRESS Environmental Criteria and Assessment Office Office of Research and Development U.S. Environmental Protection Agency Cincinnati. OH 45268 13. TYPE Of REPORT AND PERIOD COVERED 14. SPONSORING AGENCY CODE EPA/600/22 15. SUPPLEMENTARY NOTES 16. ABSTRACT This report summarizes and evaluates information relevant to a preliminary interim assessment of adverse health effects associated with specific chemicals or compounds. The Office of Emergency and Remedial Response (Superfund) uses these documents in preparing cost-benefit analyses under Executive Order 12991 for decision-making under CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in this document should be considered as preliminary and reflect limited resources allocated to this project. The intent in these assessments is to suggest acceptable exposure levels whenever sufficient data are available. The interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemical(s) addressed. Whenever possible, two categories of values have been estimated for systemic toxicants (toxicants for which cancer is not the endpoint of concern). The first, RfD5 or subchronic reference dose, is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time interval. The RfD is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs for a significant portion of the lifespan. For compounds for which there is sufficient evidence of carcinogen!city, qi*s have been computed, if appropriate, based on oral and inhalation data if available. 7. KEY WORDS AND DOCUMENT ANALYSIS DESCRIPTORS b.IDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Croup DISTRIBUTION STATEMENT Public 19. SECURITY CLASS (This Report I Unclassified 21. NO. Of PAGES 20. SECURITY CLASS (Tha paftj Unclassified 22. PRICE EPA farm 2220.1 (R«T. 4-77) PREVIOUS COITION I* OBSOLETE // ------- EPA/600/8-88/048 July, 1987 HEALTH EFFECTS ASSESSMENT FOR n-PENTANE ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT OFFICE OF RESEARCH AND DEVELOPMENT U.S. ENVIRONMENTAL PROTECTION AGENCY CINCINNATI, OH 4526fa ------- DISCLAIMER This document has been reviewed In accordance with the U.S. Environmental Protection Agency's peer and administrative review policies and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. 11 ------- PREFACE This report summarizes and evaluates Information relevant to a prelimi- nary Interim assessment of adverse health effects associated w'ith n-pentane. All estimates of acceptable Intakes and carcinogenic potency presented 1n this document should be considered as preliminary and reflect limited re- sources allocated to this project. Pertinent toxlcologlc and environmental data were located through on-Hne literature searches of the TOXLINE and the CHEMFATE/DATALOG data bases. The basic literature searched supporting this document Is current up to May, 1986. The Intent In these assessments 1s to suggest acceptable exposure levels for noncardnogens and risk cancer potency estimates for carcinogens whenever sufficient data were available. Values were not derived or larger uncertainty factors were employed when the variable data were limited In scope tending to generate conservative (I.e., protective) estimates. Nevertheless, the Interim values presented reflect the relative degree of hazard or risk associated with exposure to the chemlcal(s) addressed. Whenever possible, two categories of values have been estimated for systemic toxicants (toxicants for which cancer 1s not the endpolnt of concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval (I.e., for an Interval that does not constitute a significant portion of the Hfespan). This type of exposure estimate has not been extensively used, or rigorously defined, as previous risk assessment efforts have been primarily directed towards exposures from toxicants In ambient air or water where lifetime exposure Is assumed. Animal data used for RFD$ estimates generally Include exposures with durations of 30-90 days. Subchronlc human data are rarely available. Reported exposures are usually from chronic occupational exposure situations or from reports of acute accidental exposure. These values are developed for both Inhalation (RfD$j) and oral (RfDgQ) exposures. The RfD (formerly AIC) Is similar In concept and addresses chronic exposure. It Is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs for a significant portion of the Hfespan [see U.S. EPA (1980) for a discussion of this concept]. The RfD 1s route-specific and estimates acceptable exposure for either oral (RfOg) or Inhalation (RfDj) with the Implicit assumption that exposure by other routes 1s Insignificant. Composite scores (CSs) for noncardnogens have also been calculated where data permitted. These values are used for Identifying reportable quantities and the methodology for their development 1s explained 1n U.S. EPA (1983). For compounds for which there Is sufficient evidence of carclnogenldty RfD$ and RfO values are not derived. For a discussion of risk assessment methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a process that Is not characterized by a threshold, any exposure contributes an Increment of risk. For carcinogens, q-j*s have been computed, If appro- priate, based on oral and Inhalation data 1f available. 111 ------- ABSTRACT Data regarding n-pentane were Insufficient for quantitative risk assess- ment. The more relevant route of exposure appears to be by Inhalation. It Is recommended that a complete pharmacoklnetlc profile and subchronlc toxlclty testing be performed. There are no data on the cardnogenlclty, chronic tox1c1ty, or pharmaco- klnetlcs of n-pentane, and subchronlc toxldty experiments are not designed adquately for quantitative assessment of risk. Short-term Inhalation exposure to either n-pentane or n-hexane has produced respiratory tract Irritation In humans and nervous system aberrations 1n both man and experi- mental animals. N-pentane did not Increase the number of revertants In a Salmonella typhlmurlum assay, and had no dominant-lethal effects In mice. A complete pharmacoklnetlcs profile and comprehensive subchronlc toxUHy testing of Inhaled n-pentane are recommended. 1v ------- ACKNOWLEDGEMENTS The Initial draft of this report was prepared by Syracuse Research Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the Technical Project Monitors and John Helms (Office of Toxic Substances) was the Project Officer. The final documents In this series were prepared for the Office of Emergency and Remedial Response, Washington, DC. Scientists from the following U.S. EPA offices provided review comments for this document series: Environmental Criteria and Assessment Office, Cincinnati, OH Carcinogen Assessment Group Office of A1r Quality Planning and Standards Office of Solid Waste Office of Toxic Substances Office of Drinking Water Editorial review for the document series was provided by the following: Judith Olsen and Erma Durden Environmental Criteria and Assessment Office Cincinnati, OH Technical support services for the document series was provided by the following: Bette Zwayer, Jacky Bohanon and K1m Davidson Environmental Criteria and Assessment Office Cincinnati, OH ------- TABLE OF CONTENTS Page 1. ENVIRONMENTAL CHEMISTRY AND FATE. ... 1 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 3 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 4 4. CARCINOGENICITY 7 5. REGULATORY STANDARDS AND CRITERIA 8 6. RECOMMENDATIONS 9 7. REFERENCES 10 v1 ------- LIST OF ABBREVIATIONS CAS Chemical Abstract Service CBI Confidential Business Information ppm Parts per million STEL Short-term exposure level TLV Threshold limit value TWA Time-weighted average vll ------- 1. ENVIRONMENTAL CHEMISTRY AND FATE Selected chemical and physical properties and environmental fate of n-pentane are presented In Table 1-1. In the atmosphere, n-pentane Is expected to occur entirely 1n the vapor phase. The atmospheric half-life listed In Table 1-1 has been calculated based on HO radical reaction rate constants ranging from (3.5H0.13)xlO-12 to 6.55xlO-12 cm3/molecule-sec at 30°C and an ambient HO radical concen- tration of S.OxlO5 molecules/cm3 (Atkinson, 1985). In water, volatilization 1s expected to be a dominant fate process. Based on an experimentally determined value for Henry's Law constant of 1.23 atm-mVmol at 25°C (H1ne and Mookerjee, 1975), the volatilization half-life of n-pentane from a river 1 m deep flowing 1 m/sec with a wind speed of 3 m/sec has been calculated to be 2.5 hours (Lyman et al., 1982). Based on estimated bloconcentratlon factors of 79-220, bloaccumulation 1n aquatic organisms should not be significant. The half-life of n-pentane 1n soil could not be located In the litera- ture searched. Based on the relatively high Henry's Law constant and vapor pressure of n-pentane and assuming moderate adsorption to soil, this compound should rapidly volatilize from both wet and dry soil surfaces. Its residence time In soil 1s expected to be higher than In water. The most probable route of human exposure to n-pentane Is by Inhalation. n-Pentane Is an extremely volatile compound and monitoring data Indicates that It Is a widely occurring atmospheric pollutant (Arnts and Meeks, 1980; Cavanagh et al., 1969; Uno et al., 1985; Altshuller et al., 1971). 0097h -1- 01/26/87 ------- TABLE 1-1 Selected Chemical and Physical Properties and Environmental Fate of n-Pentane CAS number: Chemical class: Molecular weight: Vapor pressure: Hater solubility: Log octanol/water partition coefficient: Bloconcentratlon factor: Soil adsorption coefficient: Half-life In A1r: Water: Soil: 109-66-0 aliphatic hydrocarbon 72.15 513 mm Hg at 25°C 38.5 mg/l at 25°C 3.39 79-220 (estimated) 590 (estimated) 2-3 days (estimated) hours (estimated) not available Mackay and Shu1, 1981 Mackay and Shul, 1981 Hansch and Leo, 1985 Lyman et al., 1982 Lyman et al., 1982 0097h -2- 10/07/86 ------- 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS Pertinent data regarding the absorption of n-pentane after oral or Inhalation exposure could not be located In the available literature. 0097h -3- 10/07/86 ------- 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS Data regarding the oral toxldty of n-pentane are limited to a single 28-day experiment In rats. American Petroleum Institute (1985) administered n-pentane by gavage at 0, 0.5 or 2.0 g/kg 5 days/week for 4 weeks to groups of 10 male F344 rats. Control rats received saline only. Parameters of toxlclty evaluated Included twice dally observation for mortality and clinical signs of toxldty, terminal body weights and gross and microscopic appearance of the kidneys. Mortality occurred In 40% of high-dose rats and 20% of low-dose rats. Terminal body weights of both treated groups were significantly less than controls (p<0.05). Absolute kidney weights were lower In both treated groups (p<0.05) than In controls. The Mstopathologl- cal appearances of the kidneys was not remarkable. This study Is Inadequate for use 1n risk assessment. Data regarding the toxldty of n-pentane after Inhalation exposure are limited. Gaultler et al. (1973) found polyneuropathy 1n five employees exposed by Inhalation to a solvent mixture consisting of 554 n-hexane, 14% n-heptane and 80% pentane. Duration of exposure and exposure concentration were not specified. Affected workers had anorexia, paresthesla, symmetrical muscle failure, asthemla, peripheral nerve damage and signs of denervatlon In the legs. Patty and Yant (1929) found no symptoms of neuromuscular dis- order In human volunteers exposed to 5000 ppm (-14,750 mg/m3) n-pentane for 10 minutes. Ten minutes exposure to 5000 ppm (-17,200 mg/m3) n-hexane, however, was associated with marked vertigo. Male rats were exposed to -3000 ppm (8850 mg/m3) >99X pure n-pentane, 12 hours/day for 16 weeks, for study of nerve conduction velocities and distal (tall) latency to electrical stimulation (Takeuchl et al., 1980, 0097h 4- 01/26/87 ------- 1981). One rat was sacrificed at the end of 16 weeks, and light and electron microscopy was performed on the gastrocnemlus and soleus muscles, the dorsal trunk of the tall nerve and the tibia! nerve. N-pentane had no effect on measures of nerve conduction, body weights or distal latencies. There was slight swelling of the mitochondria and the sarcoplasmlc retlcu- lum, and minor dilation of the myofllaments of these muscles. Since the tissues of only one rat were studied microscopically, and the nerve conduc- tion data do not suggest adverse effects, the data of Takeuchl et al. (1980, 1981) are Inadequate for quantitative risk assessment. Administration of 3000 ppm (-10,300 mg/m3) n-hexane, on the same treatment schedule, resulted In severe decreases In body weight gain and nerve conduction velocity, and Increases In distal latency (Takeuchl et al., 1980, 1981). Treated rats had clinical signs of neuropathy. Microscopic examination of tissues from two n-hexane .exposed rats revealed myelln damage, denervated neuromuscular Junctions, muscle structure Irregularities and axonal degeneration. IIT (1985) exposed rats to 1000 ppm (-2650 mg/m3) and 4500 ppm (-12,000 mg/m3) of a 50:50 mixture of n-butane and n-pentane, 6 hours/day, 5 days/week for 13 weeks. Exposure was associated with a transient hunched appearance, tremors and a nonconcentratlon related Inhibition 1n body weight gain, which was reversible 1n males. There were no treatment-related changes on gross necropsy observations, renal hlstopathology or organ weights. Lazarew (1929) found that 2-hour exposure to 200-300 mg/l (200-300 g/m3) n-pentane caused mice to lay on their sides, whereas only 100 mg/i (100 g/m3) n-hexane for 2 hours was needed for the same effect. Swann et 0097h -5- 01/26/87 ------- al. (1974) observed no anesthesia In mice exposed for 5 minutes to <16,000 ppm (-47,200 mg/m3) n-pentane. At 32,000 ppm (-94,400 mg/m3), light anesthesia was observed during recovery, and at higher concentrations there were signs of respiratory Irritation and deep anesthesia. NIOSH (1977) concluded that, within the alkane series C5-C8, physiological potency Increases as chain length Increases. Epstein et al. (1982) studied the potential dominant-lethal effects of n-pentane, collected as fractions of partlculate atmospheric pollutants In 9-60X ether, In mice. Before mating, between seven and nine male mice were Injected once 1ntraper1toneally with between 48 and 666 mg/kg of one of the pentane fractions. Females were sacrificed 13 days after the midweek of their presumed mating, and autopsled. Treatment had no effect on early fetal deaths or prelmplantatlon losses. There are no data on the Interactive effects of n-pentane with other toxicants. CBI data Indicate that concentrations of >10% n-propane, n-butane, Isobutane or Isopentane sensitized dog hearts to the effects of exogenous eplnephrlne. 0097h -6- 01/26/87 ------- 4. CARCINOGENICITY Pertinent data regarding the carclnogenldty of n-pentane, by any route of exposure, could not be located 1n the available literature. The CBI files contained the results of an unpublished mutagenlclty study 1n which n-pentane did not Increase the number of revertants In six strains of Salmonella typh1mur1um. with or without metabolic activation. NIOSH (1977) stated that C5-C8 alkanes probably do not have carcinogenic or mutagenlc activity because they are not chemically related to compounds that express such activity. N-pentane should be considered a U.S. EPA Group D (U.S. EPA, 1986), or IARC Group 3 compound 1n terms of the available evidence of carcinogenic potential. These classifications are for compounds with Inadequate animal evidence of carclnogenldty, and no human data. 0097h -7- 03/23/87 ------- 5. REGULATORY STANDARDS AND CRITERIA NIOSH (1977) recommended a TWA occupational standard for n-pentane exposure of 350 rag/m3 and a 15-mlnute celling concentration limit of 1800 mg/m3. These levels were determined by analogy to n-hexane, which produces polyneuropathy at levels <1800 mg/m3. NIOSH (1977) did not clearly Indicate how the standard was developed based on these data. Because workers are typically exposed to mixtures of alkanes, and because data on the metabolism of Individual alkanes are Incomplete,, NIOSH (1977) recommended the same standard for all alkanes. ACGIH (1985) adopted a TWA of 600 ppm (-1800 mg/m3) and a STEL of 750 ppm (-2250 mg/m3) for n-pentane. ACGIH (1986) proposed that the TLV and the STEL should provide a margin of safety for narcotic and Irritant effects. They did not rule out the possibility of polyneuropathy after chronic exposure based on the report by Gaultler et al. (1973), but stated that the effect would occur for n-pentane at higher exposure levels than for n-hexane. The workplace standard of 350 mg/m3 (NIOSH, 1977), based primarily on n-hexane exposure data, was therefore considered unneccesarlly conservative for n-pentane. The OSHA (1985) occupational standard Is 1000 ppm (-2950 mg/m3) for an 8-hour workday. 0097h -8- 10/07/86 ------- 6. RECOMMENDATIONS Because n-pentane exists In the atmosphere completely In the vapor phase (Atkinson, 1985), and volatilization from both water (Hlne and Mookerjee, 1975) and soil 1s apparently rapid, 1t Is likely that the more relevant route of exposure for humans Is by Inhalation. Limited evidence suggests that the major toxic effects of Inhaled short-chain alkanes Involve the nervous system (Gaultler et al., 1973; Takeuchl et a!., 1980, 1981; IIT, 1985; Lazarew, 1929), although there have been few assessments of other endpolnts. Both acutely and subchronlcally, n-hexane was found to be consistently more toxic than n-pentane (NIOSH, 1977) at equlmolar concentrations, so that risk assessment by analogy 1s not recommended. The ACGIH (1986) TLV appears to be too weak a basis for quantitative risk assessment. Assays for reverse mutations (C8I files) and dominant-lethal effects (Epstein et al., 1982), as well as the chemical structure of n-pentane (NIOSH, 1977), all suggest that It Is not a carcinogenic or mutagenlc threat. It 1s recommended that a complete pharmacoklnetlc profile of Inhaled n-pentane In experimental animals be conducted. Results of acute toxldty testing In a relevant species should be a guideline for the development of a multi-concentration subchronlc test. Although gross disruption In nervous system activity Is consistently found at higher concentrations, H Is Important to establish whether lower concentrations Interfere with more subtle measures of behavioral performance. Hematologlcal, blood biochemical and hlstopathologlcal parameters should also be assessed at all concentra- tions 1n a subchronlc study. 0097h -9- 01/26/87 ------- 7. REFERENCES ACGJH (American Conference of Governmental Industrial Hyglenlsts). 1985. TLVs: Threshold limit values for chemical substances 1n the work environment adopted by ACGIH with Intended changes for 1985-1986. Cincinnati. OH. p. 26. ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. p. 463. Altshuller, A.P., W.A. Lonneman, F.D. Sutterfleld and S.L. Kopczynskl. 1971. Hydrocarbon composition of the atmosphere of the Los Angeles basin -- 1967. Environ, Scl. Technol. 5: 1009-1016. American Petroleum Institute. 1985. Four-week oral nephrotoxldty study 1n male F344 rats. OTS submission Microfiche #FYI-AY-1284-0280, Addendum #2. Arnts, R.R. and S.A. Weeks. 1980. Blogenlc hydrocarbon contribution to the ambient air of selected areas. U.S. EPA, Research Triangle Park, NC. EPA 600/3-80-023. Atkinson, R. 1985. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with organic compounds under atmospheric conditions: Chem. Rev. 85: 83. 0097H -10- 01/26/87 ------- Cavanaugh, L.A., C.F. Schadt and E. Robinson. 1969. Atmospheric hydro- carbon and carbon monoxide measurements at Point Barrow, Alaska. Environ. Sc1. Technol. 3: 251-257. Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop. 1982. Detec- tion of chemical mutagens by the dominant lethal assay In the mouse. Toxlcol. Appl. Pharmacol. 23: 288-325. Gaultler, M., G. Rancurel, C. Plra and M.L. Ethymloc. 1973. Polyneurltls and aliphatic hydrocarbons. J. Environ. Toxlcol. 6: 294-296. (Fre.) (Cited In NIOSH, 1977) Hansch, C. and A.J. Leo. 1985. MedChem Project Issue No. 26, Pomona College, Claremont, CA. H1ne, J. and P.K. Mookerjee. 1975. The Intrinsic hydrophlUc character of organic compounds, correlations 1n terms of structural contributions. J. Org. Chem. 40: 292-298. IIF (Illinois Institute of Technology). 1985. Research Institute. Thirteen-week Inhalation toxldty study of C4/C5 hydrocarbon blands 1n rats. 89 p, Lazarew, N.W. 1929. On the toxUHy of various hydrocarbon vapors. Arch. Exp. Path. Pheumakol. 143: 223-233. (Ger.) (Cited 1n NIOSH, 1977) 0097h -11- 01/26/87 ------- Lyman, W.J., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical Property Estimation Methods. McGraw-Hill Book Co., New York. p. 4-9, 5-5, 15-13, 15-21. Mackay, D. and W.Y. Sh1u. 1981. A critical review of Henry's Law Constants for chemicals of environmental Interest. J. Phys. Chem. Ref. Data. 19: 1175-1199. NIOSH (National Institute for Occupational Safety and Health). 1977. Criteria for a Recommended Stardard...Occupational Exposure to Alkanes. U.S. OHEW, PHS, COC, Rockvllle, MO. OSHA (Occupational Safety and Health Administration). 1985. Safety and Health Standards. Code of Federal Regulations. 29: 1910.1000. Patty, F.A. and W.P. Yant. 1929. Report of Investigators — Olor Intensity and symptoms produced by commercial propane, butane, pentane, hexane and heptane vapor, No. 29-79. U.S. Dept. of Commerce, Bure-au of Mines. 10 p. (Cited 1n NIOSH, 1977) Swann, H.E., Jr., B.K. Kwon, G.K. Hogan and W.M. SnelUngs. 1974. Acute Inhalation toxicology of volatile hydrocarbons. Am. Ind. Hyg. Assoc. J. 35(9): 511-518. Takeuchl, Y., Y. Ono, N. Hlsanaga, J. KHoh and Y. Suglura. 1980. A comparative study on the neurotoxldty of n-pentane, n-hexane, and n-heptane 1n the rat. Br. J. Ind. Med. 37(3): 241-247. 0097h -12- 01/26/87 ------- Takeuchl, Y., Y. Ono, N. Hisanaga, J. Kltoh and Y. Suglura. 1981. A comparative study of the tox1c1ty of n-pentane, n-hexane and n-heptane to the peripheral nerve of the rat. Clln. Toxlcol. 18(12): 1395-1402. Uno, I., S. Wakamatsu, R.A. Wadden, S. Konno and H. Koshlo. 1985. Evalua- tion of hydrocarbon reactivity In urban air. Atmos. Environ. 19: 1283-1293. U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of Health Effect Assessment Chapters of the Consent Decree Water Criteria Documents. Federal Register. -45(231): 49347-49357. U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter- minations Based on Chronic ToxIcHy Data. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. 0097h -13- 08/03/87 ------- |