EPA-540/1-86-001 Environmental Protection Agency ^.rice of Emergency and Remedial Response Washington DC 20460 Off'ce of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati OH 45268 Superfund EPA HEALTH EFFECTS ASSESSMENT FOR HEXACHLOROCYCLOPENTADIENE ------- EPA/540/1-86-001 September 1984 HEALTH EFFECTS ASSESSMENT FOR HEXACHLOROCYCLOPENTADIENE U.S. Environmental Protection Agency Office of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati, OH 45268 U.S. Environmental Protection Agency Office of Emergency and Remedial Response Office of Solid Waste and Emergency Response Washington, DC 20460 ------- DISCLAIMER This report has been funded wholly or 1n part by the United States Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse Research Corporation. It has been subject to the Agency's peer and adminis- trative review, and 1t has been approved for publication as an EPA document. Mention of trade names or commercial products does not constitute endorse- ment or recommendation for use. 11 ------- PREFACE This report summarizes and evaluates Information relevant to a prelimi- nary Interim assessment of adverse health effects associated with hexa- chlorocyclopentadlene. All estimates of acceptable Intakes and carcinogenic potency presented 1n this document should be considered as preliminary and reflect limited resources allocated to this project. Pertinent toxlcologlc and environmental data were located through on-Hne literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature searched supporting this document Is current up to September, 1984. Secondary sources of Information have also been relied upon 1n the preparation of this report and represent large-scale health assessment efforts that entail extensive peer and Agency review. The following Office of Health and Environmental Assessment (OHEA) sources have been extensively utilized: U.S. EPA. 1980a. Ambient Water Quality Criteria for Hexachloro- cyclopentadlene. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-055. NTIS PB 81-117667. U.S. EPA. 1984. Health Assessment Document for Hexachlorocyclo- pentadlene. Environmental Criteria and Assessment Office, Cincin- nati, OH. EPA 600/8-84-001F. NTIS PB 85-124915. The Intent 1n these assessments 1s to suggest acceptable exposure levels whenever sufficient data were available. Values were not derived or larger uncertainty factors were employed when the variable data were limited 1n scope tending to generate conservative (I.e., protective) estimates. Never- theless, the Interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemlcal(s) addressed. Whenever possible, two categories of values have been estimated for sys- temic toxicants (toxicants for which cancer 1s not the endpolnt of concern). The first, the AIS or acceptable Intake subchronlc, 1s 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 1n ambient air or water where lifetime exposure 1s assumed. Animal data used for AIS 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. 111 ------- The AIC, acceptable Intake chronic, Is similar 1n concept to the ADI (acceptable dally Intake). 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 (1980b) for a discussion of this concept]. The AIC 1s route specific and estimates acceptable exposure for a given route 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 ranking reportable quanti- ties; the methodology for their development Is explained In U.S. EPA (1983). For compounds for which there Is sufficient evidence of cardnogenldty, AIS and AIC values are not derived. For a discussion of risk assessment methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a process that 1s not characterized by a threshold, any exposure contributes an Increment of risk. Consequently, derivation of AIS and AIC values would be Inappropriate. For carcinogens, q-|*s have been computed based on oral and Inhalation data 1f available. 1v ------- ABSTRACT In order to place the risk assessment evaluation 1n proper context, refer to the preface of this document. The preface outlines limitations applicable to all documents of this series as well as the appropriate Inter- pretation and use of the quantitative estimates presented. Subchronlc oral exposure data are limited. Ninety day exposures of rats and mice Indicated that rats are more sensitive to HEX toxldty than mice. Both species showed lesions of the forestomach at their respective LOAELs. Using the rat data, an AIS for oral exposure of 4.9 mg/day 1s estimated. In the absence of chronic oral exposure data, an AIC of 0.49 mg/day for the oral route 1s eslmtated by applying an additional uncertainty factor of 10 to the AIS. Subchronlc Inhalation data are also limited. Rats and monkeys have been tested for periods up to 14 weeks. Using the monkey data, an Inhalation AIS of 0.2 mg/day 1s estimated. Chronic Inhalation evaluations of HEX have been conducted 1n guinea pigs, rabbits, rats and mice. Data are of limited use, except for the rat, because of Incomplete reporting of results and questions concerning the purity of the compound. However, the data are adequate to raise questions concerning interspecles differences in sensitivity to this compound. An Inhalation AIC of 0.0046 mg/day 1s estimated based on the rat data of Clark et al. (1982a). This estimate is lower than an estimate which could be derived from the TLV. Despite questions concerning available data, the Incorporation of uncertainty factors should provide an adequate margin of safety. These estimates should be reviewed when more complete data are available. A CS of 62 was calculated based on mortality in mice exposed to 1.7 mg/m3, 7 hours/day, 5 days/week, for as many as 150 treatments. ------- 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. Or. Christopher DeRosa and Karen Blackburn were the Technical Project Monitors and Helen Ball was^the Project Officer. The final documents 1n 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 Air 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: Judith Olsen and Erma Durden Environmental Criteria and Assessment Office Cincinnati, OH Technical support services for the document series was provided by: Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon Environmental Criteria and Assessment Office Cincinnati, OH v1 ------- TABLE OF CONTENTS 1. ENVIRONMENTAL CHEMISTRY AND FATE 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . 2.1. 2.2. 2.3. ORAL INHALATION CONCLUSIONS REGARDING HEX ABSORPTION RATES 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. 3.2. 3.3. 3.4. SUBCHRONIC 3.1.1. Oral 3.1.2. Inhalation CHRONIC 3.2.1. Oral 3.2.2. Inhalation TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . 3.3.1. Oral 3.3.2. Inhalation TOXICANT INTERACTIONS 4. CARCINOGENICITY 4.1. 4.2. 4.3. 4.4. HUMAN DATA BIOASSAYS OTHER RELEVANT DATA 4.3.1. MutagenlcHy WEIGHT OF EVIDENCE 5. REGULATORY STANDARDS AND CRITERIA 5.1. 5.2. 5.3. 5.4. 5.5. 5.6. 5.7. OCCUPATIONAL STANDARDS TRANSPORTATION REGULATIONS SOLID WASTE REGULATIONS FOOD TOLERANCES WATER REGULATIONS AIR REGULATIONS OTHER REGULATIONS Page 1 8 . . . 8 . . . 8 8 . . . 9 . . . 9 . . . 9 . . . 9 . . 11 . . . 11 11 . . . 12 . . . 12 . . . 13 . . . 13 . . . 15 . . . 15 . . . 15 . . . 15 , , . 15 . . . 17 . . . 19 . . . 19 . . . 19 . . . 19 . . . 20 . . . 20 . . . 20 . . . 20 V11 ------- TABLE OF CONTENTS (cont.) 6. RISK ASSESSMENT 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 6.1.1. Oral 6.1.2. Inhalation 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 6.2.1. Oral 6.2.2. Inhalation Page 22 22 22 22 23 23 23 6.3. CARCINOGENIC POTENCY (q-|*) 25 7. REFERENCES 26 APPENDIX: Summary Table for Hexachlorocyclopentadlene 35 V111 ------- LIST OF ABBREVIATIONS ADI Acceptable dally Intake AIC Acceptable Intake chronic AIS Acceptable Intake subchronlc BCF file-concentration factor bw Body weight CS Composite score DNA Deoxyr1bonucle1c add PEL Frank-effect level GC/MS Gas chromatography/mass spectrometry 105 Dose lethal to 5% of recipients LOAEL Lowest-observed-adverse-effect level LOEL Lowest-observed-effect level MED Minimum effective dose NOAEL No-observed-adverse-effect level NOEL No-observed-effect level ppb Parts per billion ppm Parts per million RQ Reportable quantity RVd Dose-rating value » RVe Effect-rating value SMR Standardized mortality ratio STEL Short-term exposure limit TLV Threshold limit value TWA Time-weighted average 1x ------- 1. ENVIRONMENTAL CHEMISTRY AND FATE Hexachlorocyclopentadlene (HEX) Is the most commonly used name for the compound that 1s designated 1,2,3,4,5,5'-hexachloro-l,3-cyclopentad1ene by the International Union of Pure and Applied Chemistry system (IUPAC). Table 1-1 cites the IUPAC name and synonyms, the Chemical Abstract number and molecular and structural formulas for HEX. Hexachlorocyclopentadlene 1s a nonflammable liquid with a characteristic pungent, musty odor; the pure compound 1s light lemon-yellow. Table 1-2 presents the physical properties and constants for HEX. Commercial HEX has various purities depending upon the route of synthe- sis. HEX 1s a highly reactive dlene that readily undergoes addition and substitution reactions and also participates In 01els-Alder reaction of HEX with a compound containing a nonconjugated double bond consisting of 1:1 adducts containing a hexachloroblcyclo (2,2,1) heptene structure; the monene derived part of the adduct 1s nearly always In the endo position. Figure 1-1 Illustrates synthetic pathways to various chlorinated pesticides for which HEX 1s a precursor. HEX may be present 1n these pesticides as a contaminant. HEX 1s released Into the environment during Its manufacture and during the manufacture of products requiring HEX. Limited monitoring data from production sites Indicated that HEX was present at 18 mg/8, 1n the aqueous discharge from the Memphis pesticide plant (U.S. EPA, 1984). In May 1977, HEX was also detected at 0.17 mg/8. 1n the aqueous dis- charge and at 56 ppb 1n air samples collected from a waste site 1n Montague, MI (U.S. EPA, 1984). At a waste site In Hardeman County, TN, HEX has been shown to be emitted Into the air, groundwater, wastewater and drinking water (Clark et al., 1982b). Indoor air concentrations of HEX In houses with contaminated groundwater supplies ranged from 0.06-0.10 yg/m3. -1- ------- TABLE 1-1 Identity of Hexachlorocyclopentadlene* Identifying Characteristic Name/Number/Structure IUPAC Name: Trade Names: Synonyms: CAS Number CIS Accession Number: Molecular Formula: Molecular Structure: l,2,3,4,5,5'-Hexachloro-l,3-cyclopentad1ene C56; HRS 1655; Graphlox Hexachlorocyclopentadlene Perchlorocyclopentadlene HEX HCPD HCCP HCCPO C-56 HRS 1655 Graphlox 77-47-4 7800117 Cl Cl Cl Cl Cl Cl *Source: Stevens, 1979 -2- ------- TABLE 1-2 Physical Properties of Hexachlorocyclopentadlene Property Value/Description Reference Molecular Weight: Physical Form (25°C) Odor: Electronic Absorption Maximum (In 50% acetonltr He-water) Solubility Water (mg/l): Organic Solvents: Vapor Density (air = 1) Vapor Pressure (mmHg, °C): Specific Gravity: Melting Point (°C): Boiling Point (°C): Octanol/Water Partition Coefficient (log P) (measured): (estimated): Latent Heat of Vaporiza- tion Henry's Law Constant (atm-mVmole) 272.79 Stevens, 1979 Pale yellow liquid Hawley, 1977; Irish, 1963 Pungent Hawley, 1977; Irish, 1963 322 nm 2.1 (25°C) 0.805 (25°C) 1.8 (28°C) Mlsdble (Hexane) 9.4 0.08 (25°C) 0.975 (62°C) 1.717 (15°C) 1.710 (20°C) 1.7019 (25°C) -9.6 -11.34 239 @ 753 mm Hg 234 5.04±0.04 5.51 176.6 J/g 2.7xlO'2 Wolfe et a!., 1982 Oal Monte and Yu, 1977 Lu et al., 1975 Wolfe et al., 1982 Bell et al., 1978 Verschueren, 1977 Irish, 1963 Stevens, 1979 Hawley, 1977 Stevens, 1979 Weast and Astle, 1980 Hawley, 1977 Stevens, 1979 Hawley, 1977; Stevens, 1979 Irish, 1963 Wolfe et al., 1982 Wolfe et al., 1982 Stevens, 1979 Atallah et al., 1980; Wolfe et al., 1982 -3- ------- OlIlMlN •«ei|. M>» CM twiin •MM IN co«o» c«i% Ol 1O|C"| • IIN ton " Mini FIGURE 1-1 Synthesis of Chlorinated Cyclodlene Pesticides from Hexachlorocyclopentadlene Source: U.S. EPA. 1984 ------- Published reports, environmental releases and physlochemlcal properties of HEX Imply that it will be present mainly In the aquatic compartment and associated with bottom sediments and organic matter. Relatively much lower concentrations will be found 1n the soil and air compartments. A1r levels 1n areas near previous dump sites have been shown to be high. High concen- trations of HEX have been recorded 1n wastewater and, 1n two Incidences, have Increased the ambient HEX levels Inside treatment facilities above the ACGIH TWA. Little relevant Information Is available to predict the fate of HEX 1n air. Its tropospherlc residence time was estimated by CupHt (1980) to be ~5 hours based upon rates of reaction with hydroxyl radicals and ozone. The respective reaction rates were theoretically estimated to be 59xlO~12 and 8xlO~18 cm3 molecule'1 sec"1. Atmospheric photolysis of HEX was rated as probable, since HEX has a chromophore that absorbs light 1n the solar spectral and 1s known to photolyze 1n aqueous media. CupHt (1980) listed the theoretical degradation products as CUCO, dlacylchloMdes, ketones, and free Cl radical, all of which would be likely to react with other elements and compounds. In the event of release Into shallow or flowing bodies of water, degra- datlve processes such as photolysis, hydrolysis and blodegradatlon, as well as transport processes Involving volatlzatlon and other physical loss mecha- nisms, are expected to be prominent 1n HEX dissipation. Under a variety of sunlight conditions, 1n both distilled and natural waters of 1-4 cm depth, phototransformatlon half-life was <10 minutes. Addition of sediments to distilled water containing HEX had little effect on the phototransformatlon rate constant of HEX at this latitude on cloudless -5- ------- days (averaged over both light and dark periods for a year) that was 3.9 hour"1, corresponding to a half-life of 10.7 minutes (Zepp et al., 1979; Wolfe et al., 1982). Studies of the hydrolysis of HEX Indicate that at 25-30°C and In the environmental pH range of 5-9, a hydrolytlc half-life of -3-11 days Is observed (Wolfe et al., 1982). Hydrolysis 1s much slower than photolysis, but may be a significant load-reducing process 1n waters where photolysis and physical transport processes are not Important (I.e., 1n deep, nonflow- 1ng waters). Wolfe et al. (1982) found hydrolysis of HEX to be Independent of pH over a range of 3-10. With a variation 1n temperature, these rates changed somewhat. HEX 1s not expected to be oxidized under ordinary environmental condi- tions. Based on an estimated first order oxidation rate constant, a com- puter simulation predicted that HEX would not be oxidized 1n the simulated river, pond or eutrophlc lake. Tabak et al. (1981) stated that HEX 1s blodegraded fairly rapidly 1n a static laboratory culture. Upon release onto soil, HEX 1s likely to adsorb strongly to any organic matter or humans present (Kenaga and Goring, 1980; Weber, 1979). With time, HEX concentrations should decrease as populations of soil microorganisms better adapted to metabolize HEX increase (Rieck, 1977a,b,c; Thuma et al., 1978). The log octanol/water partition coefficient (log P) of HEX has been experimentally determined to be 5.04 (Wolfe et al., 1982) and 5.51 (Velth et al., 1979), which indicates a substantial potential for bloconcentration, bioaccumulation and biomagification. Actual determinations of bioconcentra- -6- ------- tlon and bloaccumulatlon In several aquatic organisms Indicate that HEX does accumulate to a great extent (Podowski and Khan, 1979; VeHh et al., 1979; Spehar et al., 1979). VeHh et al. (1979) determined the BCF for HEX to be 29 In the fathead minnow, P^. promelas. Spehar et al. (1979) conducted a 30-day early-Hfe stage, flowthrough toxldty test at 25°C with the fathead minnow. HEX residues 1n the fish after 30 days of continuous exposure to HEX were <0.1 mg/kg for all concentrations tested (0.78-9.1 vg/8. 1n water). In two other studies (Velslcol Chemical Corporation, 1978; Bennett, 1982), HEX was not detected 1n any of the fish tissue samples analyzed by GC/MS. The fate and transport of HEX 1n the atmosphere are not well documented, but available Information suggests that the compound does not persist. In water, HEX 1s likely to dissipate rapidly by means of photolysis, hydrolysis and blodegradatlon. B1odegradat1on may also be a significant process 1n certain waters, although the evidence 1s weak. HEX 1s known to volatilize from water; however, It 1s possible that volatilization Is limited by diffu- sion, particularly 1n waters that are not well mixed, and by sorptlon on sediments. The fate and transport of HEX 1n soils are affected by Us strong tendency to adsorb onto organic matter. HEX 1s predicted to be relatively Immobile 1n soil based on Us high log P value. Volatilization, which 1s likely to occur primarily at the soil surface, Is Inversely related to the organic matter levels and water-holding capacity of the soil. Leaching of HEX by groundwater should be very limited, and chemical hydrolysis and mlcroblal metabolism are expected to reduce environmental levels. HEX Is metabolized by a number of soil microorganisms. HEX may be found In areas where there was no HEX production or usage, because It may be present as a contaminant In products made from It. -7- ------- 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2.1. ORAL Absorption rates have not been calculated for HEX. Dorough (1979) studied the oral absorption of HEX 1n male and female Sprague-Dawley rats and mice. Although absorption was shown by the presence of the radlolabeled compound 1n the feces (72%) and urine (14%), the rates were not calculated. In a study by Yu and Atallah (1981), male and female Sprague-Dawley rats (240-350 g) were given a single dose of 3 or 6 mg/kg 14C-HEX 1n 0.5 ms, corn oil by oral gavage. Radioactivity appeared 1n the blood within 30 minutes, reached a maximum value at 4 hours, and then gradually decreased. The excretion levels were near the values of Dorough (1979). 2.2. INHALATION Dorough (1980) studied the absorption and fate of Inhaled HEX 1n female Sprague-Dawley rats (175-250 g). Animals were exposed to vapors of 14C-HEX over a 1-hour period to achieve doses of -24 vg/kg bw. The radlolabel was recovered 1n the feces and urine; however, no absorption rates were calculated. 2.3. CONCLUSIONS REGARDING HEX ABSORPTION RATES From the data reviewed 1n the pharmacok1net1c studies of HEX, the fol- lowing points can be made regarding the fate of HEX 1n biological systems: HEX reacts with biological tissues and macromolecules at the point of administration as Indicated by the high concentration of HEX equivalents 1n the lung and trachea following Inhalation exposure. HEX 1s not readily absorbed through the gastrointestinal tract as Indicated by the following: the 2- to 3-fold higher fecal elimination of HEX equivalents following oral administration as compared with Intravenous or Inhalation administration, and the reactivity of HEX with the gastrointestinal contents as Indi- cated by the fact that no unchanged HEX 1s excreted following oral administration. -8- ------- 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. In a range-finding study, Litton B1onet1cs Inc. (1978a) determined the oral LD_ of HEX 1n Charles River CD-I rats to be 76 mg/kg. However, when the LD5 was administered to rats for 5 consecutive days, all 24 animals died. In a comparable range-finding study 1n Fischer 344 rats (SRI, 1980b) no mortality was reported at doses of 25, 50 or 100 mg/kg when given 12 doses 1n 16 days. The subchronlc toxldty of HEX 1s summarized 1n Table 3-1. In the oral dose studies (Abdo et al., 1984), dose levels of 19, 38, 75, 150 and 300 mg/kg HEX (94.3-97.4% pure) in corn oil were administered by gavage to groups of 10 male and 10 female mice. Doses were administered 5 days/week for 13 weeks. At the highest dose level (300 mg/kg), all male mice died by day 8 and 3 females died by day 14. In female mice, the liver was enlarged. Dose levels of >38 mg/kg HEX. caused lesions in the forestomach, including ulceration in both males and females. At doses of >75 mg/kg, toxic nephro- sis was seen In females. In the rat portion of this study, doses of 10, 19, 38, 75 and 150 mg/kg HEX were administered. Mortality and toxic nephrosls were noted In both males and females at doses of >38 mg/kg. The male rats treated at 19 mg/kg dose level did not show any highly abnormal effects, while females exhibited lesions of the forestomach. Such lesions were observed In male rats at the >38 mg/kg dose levels. There was a dose- related depression of body weight gain relative to the controls. The NOAEL for rats was selected to be the 10 mg/kg level. 3.1.2. Inhalation. Rand et al. (1982) and Alexander et al. (1980) performed inhalation studies 1n rats and monkeys. Groups of 40 male and 40 female Sprague-Dawley rats weighing 160-226 g, or groups of 12 cynomolgus -9- ------- TABLE 3-1 Subchronlc Toxlclty of HEX o i Study Species 90-Day rat Feeding 90-Day mouse Feeding 14 -Week rat Inhalation Toxlclty 14 -Week monkey Inhalation Toxlclty Dose 10, 19, 38, 75, 150 or 300 mg/kg (by gavage) 19, 38, 75, 150 or 300 mg/kg (by gavage) 0.01, 0.05 and 0.2 ppm (5 days/week) 0.01, 0.05 and 0.2 ppm (5 days/week) Results NOAEL LOEL NOAEL LOEL NOAEL LOEL NOAEL LOEL - 10 mg/kg - 19 mg/kg - 19 mg/kg - 38 mg/kg - 0.2 ppm - NE - 0.2 ppm - NE Effects at LOEL or Lowest Dose Lesions of forestomach In female rats at 19 mg/kg Lesions of forestomach In both sexes at 38 mg/kg No statistically significant effects No effects noted Reference Abdo et al 1984b Abdo et al 1984 Rand et al 1982 * t * » * t Alexander et al., 1980 NE = Not established ------- monkeys weighing 1.5-2.5 kg (average 2.0 kg), were exposed to HEX, 6 hours/ day, 5 days/week, for 14 weeks. Levels of exposure were 0, 0.01, 0.05 and 0.20 ppm HEX. In monkeys, there were no mortalities, adverse clinical signs, weight gain changes, pulmonary function changes, eye lesions, hemato- loglc changes, clinical chemistry abnormalities or hlstopathologlc abnormal- ities at any dose level tested. Male rats 1n this study (Rand et al., 1982) had a transient appearance of dark-red eyes at 0.05 and 0.2 ppm HEX. At 12 weeks, there were marginal, but not statistically significant, Increases 1n hemoglobin concentration and erythrocyte count In 0.01 ppm males, 0.05 ppm females and 0.20 ppm males and females. There were no treatment-related abnormalities 1n gross pathology or hlstopathology. 3.2. CHRONIC 3.2.1. Oral. The chronic oral toxldty of HEX has not been determined. The longest oral study to date was the previously reviewed work of Abdo et al. (1984). 3.2.2. Inhalation. Treon et al. (1955) exposed guinea pigs, rabbits, rats and mice to a concentration of 0.33 ppm for 7 hours/day, 5 days/week for 25-30 exposures. Guinea pigs survived 30 exposures; however, rats and mice did not survive 5 exposures, and 4/6 rabbits did not survive 30 exposures. Using a lower concentration (0.15 ppm HEX), guinea pigs, rabbits and rats survived 150 7-hour exposure periods. This level was too high for a chronic level study 1n mice since 4/5 animals did not survive. Slight renal and hepatic degeneration was noted In all species; mice, rats and guinea pigs also developed lesions 1n the lungs. -11- ------- A 30-week chronic Inhalation study of technical grade HEX (96%) 1n rats was conducted by Shell Toxicology Laboratory (Clark et al., 1982a). Four groups of 8 male and 8 female Wlstar Albino rats were exposed to HEX at nominal concentrations of 0, 0.05, 0.1 and 0.5 ppm for 6 hours/day, 5 days/ week, for 30 weeks and were observed for a 14-week recovery period without HEX exposure. At the highest dose level, 4 males and 2 females died. In males, there was depressed body weight gain 1n the 0.5 ppm group relative to controls beginning at 7 weeks of exposure and persisting throughout the remainder of the study. Females 1n the medium and high dose groups had lower body weights at the end of the recovery period as compared with controls. At 0.5 ppm, pulmonary degenerative changes were noted 1n both sexes although the males were affected more severely. At the highest dose, there were mild degenerative changes 1n the Hver and kidneys at 30 weeks 1n a few rats and kidney weights were significantly Increased 1n the females. After 30 weeks of study, there was no biologically significant toxlclty noted 1n animals exposed to concentrations of 0.05 or 0.1 ppm HEX (Clark et al., 1982a). A chronic Inhalation study has been scheduled by the National Toxicology Program (Abdo, 1983). 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 3.3.1. Oral. The teratogenlc potential of HEX was evaluated In pregnant Charles River CD rats that were administered HEX (98.25%) by gastric Intuba- tion 1n corn oil at dose levels of 3, 10 and 30 mg/kg/day from days 6-15 of gestation. A control group received the vehicle (corn oil) at a dose volume of 10 ma/kg/day. Survival was 100%, and there was no difference In mean maternal body weight gain between dosed groups and controls. There were no differences 1n the mean number of Implantations, corpora lutea, live -12- ------- fetuses, mean fetal body weights or male/female sex ratios among any of the groups; and there were no statistical differences In malformation or devel- opmental variations compared with the controls when external, soft tissue and skeletal examinations were performed (IRDC, 1978). Murray et al. (1980) evaluated the teratogenlc potential of HEX (98%) 1n CF-1 mice and New Zealand White rabbits. Mice were dosed at 0, 5, 25 or 75 mg/kg/day HEX by gavage from days 6-15 of gestation, while rabbits received the same dose from days 6-18 of gestation. The fertility of both the treat- ed mice and the rabbits was not significantly different from the control groups. In the mice, no evidence of maternal toxldty, embryotoxldty or teratogenlc effects was observed. A total of 249-374 fetuses (22-33 Utters) were examined 1n each dose group. In rabbits, maternal toxldty was noted at 75 mg/kg/day (diarrhea, weight loss and mortality), but there was no evidence of maternal toxldty at the lower levels. There were no embryotoxlc effects at any dose level. Although there was an Increase 1n the proportion of fetuses with 13 ribs at 75 mg/kg/day over controls, this was considered a minor skeletal variation, and the authors concluded that HEX was not teratogenlc at the levels tested. 3.3.2. Inhalation. Studies on the teratogenlc potential of Inhaled HEX were not located 1n the review of the scientific literature. There were no studies located 1n the literature that addressed other reproductive effects from exposure to HEX. 3.4. TOXICANT INTERACTIONS In the review of available literature, HEX has not been shown to Inter- act with other compounds. However, 1n many experiments on absorption of HEX, some common observations have been ascertained regarding HEX and living tissue. Repeated exposure of several animal species to levels of HEX vapor -13- ------- 1n the 0.1-0.2 ppm range has been found to cause pulmonary degenerative changes (Treon et a!., 1955; Clark et al., 1982a). The Interaction of HEX within human tissue has caused mild degenerative changes In the kidneys, "liver, brain, heart and adrenal glands. There are Insufficient data to Identify clearly the site most sensitive to prolonged, repeated exposure of HEX. However, researchers found 1n comparing routes of administration over a wide variety of doses and lengths of exposures that, regardless of which route was used, damage to the lungs occurred (Lawrence and Dorough, 1982). When HEX 1s administered orally to animals, the kidneys may be the most sensitive site, since subchronlc dosing of rats and mice was found to cause nephrosls. Although the oral route may not be significant In human exposure, the fact that the kidneys are a possible target organ 1n subchronlc exposure Indicates that low-level, prolonged systemic exposure from any ambient route may affect the kidneys. -14- ------- 4. CARCINOGENICITY 4.1. HUMAN DATA Mortality studies have been conducted on workers Involved In the produc- tion of HEX or formulation of HEX products. The Shlndell and Associates (1980) report was a cohort study of workers employed at the Velslcol Chemi- cal Corporation plant at Marshall, IL between 1946 and 1979. The analysis showed no significant differences 1n mortality rates between these employees and the United States population. Wang and MacMahon (1979) conducted a study on a group of 1403 males employed In plants producing or using HEX. The SMR was used to compare the workers with the general population. The two highest SMRs were 134 for lung cancer and 183 for cerebrovascular disease, but only the latter was statis- tically significant. The authors noted that these effects were unrelated to exposure because the deaths showed no consistent pattern with duration of employment or with duration of follow-up. Other studies (Shlndell and Associates, 1981; Buncher et al., 1980) showed similar results. In all of these studies, no carcinogenic effects of HEX exposure were noted. 4.2. BIOASSAYS There are no animal bloassay data Indicating that HEX 1s carcinogenic to animals by any route of exposure. An Inhalation cardnogenesls bloassay 1n rats and mice 1s being conducted by NTP (Abdo, 1983). 4.3. OTHER RELEVANT DATA 4.3.1. Mutagen1c1ty. Goggelman et al. (1978) found that HEX was not mutagenlc before or after liver mlcrosomal activation at 2.7xlO~3 M 1n an Escherlchla coll K,2 back mutation system. In this test there was 70% survival of bacteria at 72 hours. HEX was not tested at higher concentra- tions because H was cytotoxlc to E.. coll. An earlier report by Grelm et -15- ------- al. (1977) from the same laboratory Indicated that HEX was also not muta- genlc 1n Salmonella typhlmurlum strains TA1535 (base-pair mutant) or TA1538 (frame shift mutant) after liver mlcrosomal activation; however, no details of the concentrations tested were given. Although tetrachlorocyclopenta- dlene Is mutagenlc 1n these systems, probably through metabolic conversion to the dlenone, 1t appears that the chlorine atoms at the C-l position of HEX hindered metabolic oxidation to the corresponding acylatlng dlenone (Grelm et al., 1977). A study conducted by Industrial B1o-Test Laboratories (IBT, 1977) also suggests that HEX 1s not mutagenlc In S. typhlmurlum. Both HEX and Us vapors were tested with and without metabolic activation. The vapor test was done In desiccators with only the TA100 strain of J>. typhlmurlum. It 1s not clear from the presented data of the vapors test that sufficient amounts of HEX or adequate times of exposure were used. Exposure times of 30, 60 or 120 minutes were 'studied. Longer exposures 1n the presence of the HEX vapors may be necessary for observation of a potential mutagenlc effect. The statement 1n the text that testing was conducted 1n the toxic range 1s not supported convincingly by the Investigators' results. At concentrations of up to 1.25xlO~3 yg/ms. In the presence of an S-9 Hver activating system, HEX was not mutagenlc 1n the mouse lymphoma muta- tion assay. Mutagenldty could not be evaluated at higher concentrations because of the cytotoxldty of HEX (Litton B1onet1cs, Inc., 1978b). This assay uses L5178Y cells that are heterozygous for thymldlne klnase (TK+/-) and are bromodeoxyuMdine (BUdR) sensitive. The mutation 1s scored by cloning with BUdR 1n the absence of thymldlne. HEX 1s highly toxic to these cells, particularly 1n the absence of an activating system (at 4xlO~5 yfc/ms.); a positive control, dimethylnitrosamine, was mutagenlc at 0.5 yl/ms.. -16- ------- Williams (1978) found that HEX (10 6 M) was Inactive 1n the Hver epithelial culture hypoxanthlne-guanlne-phosphorlbosyl transferase locus/ mutation assay. At 10~s M HEX also failed to stimulate DNA repair synthe- sis in hepatocyte primary cultures. Negative results were also obtained in an additional unscheduled DNA synthesis assay (Brat, 1983). Two recent studies provided by NTP (Juodeika, 1983) also failed to demonstrate the mutagenidty of HEX. In S. typhimurium strains TA98, TA100, TA1535 and TA1537, levels of up to 3.3 yg/plate were not mutagenic without activation and levels of up to 100.0 vg/plate were not mutagenic after mlcrosomal activation. Higher levels could not be tested because of exces- sive bacterial mortality. In the Drosophila sex-linked recessive lethal test, HEX was not mutagenic. The doses used 1n this study were 40 ppm by feeding for 3 days or by a single injection of 2000 ppm. HEX has also been assayed 1n the mouse dominant lethal test (Litton Bio- netlcs, Inc., 1978a). In this assay, 0.1, 0.3 or 1.0 mg/kg HEX was adminis- tered by gavage to 10 male CD-I mice for 5 days and these mice were then mated throughout spermatogenesls (7 weeks). This test determines whether the compound induces lethal genetic damage to the germ cells of males. There was no evidence of dominant lethal activity at any dose level by any parameter; e.g., fertility Index, implantations/pregnancy, average resorp- tions/pregnancy. In this study, the highest dose used was the LD,., deter- mined by a 5-day mortality study in male CD-I mice. 4.4. WEIGHT OF EVIDENCE No reports of carclnogenicity of HEX have been found 1n the available literature. The data base is neither extensive nor adequate for assessing the carcinogenicity of HEX. The National Toxicology Program has recently completed a subchronlc animal study and Is conducting a chronic animal -17- ------- Inhalation bloassay using both rats and mice (Abdo, 1984). Applying the criteria proposed by the Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984) for evaluating the overall weight of evidence, HEX 1s most appropriately considered a Group D - Not Classified chemical. -18- ------- 5. REGULATORY STANDARDS AND CRITERIA 5.1. OCCUPATIONAL STANDARDS There 1s no current Occupational Safety and Health Administration (OSHA) standard for HEX levels 1n the workplace. However, the AC6IH (1982) has adopted a TLV, expressed as an 8-hour TWA of 0.1 mg/m3 (0.01 ppm). A STEL, the maximum allowable concentration 1n a !5-m1nute period, of 0.3 mg/m3 (0.03 ppm) for HEX has also been adopted (ACGIH, 1982). The levels are based on Treon et al. (1955). NIOSH (1978) classlfed HEX as a Group II pesticide and recommended criteria for standards for occupations 1n pesticide manufacturing and formu- lating. These standards rely on engineering controls, work practices and medical surveillance programs, rather than workplace air limits, to protect workers from the adverse effects of pesticide exposure 1n manufacturing and formulating (NIOSH, 1978). 5.2. TRANSPORTATION REGULATIONS The Hazardous Materials Transportation Act specifies the requirements to be observed 1n the preparation for shipment and transport of hazardous materials. The transport of HEX by air, land and water 1s regulated by these statutes, and the Department of Transportation has designated HEX as a "hazardous material," a "corrosive material" and a "hazardous substance." The maximum net quantity for transport by passenger-carrying aircraft or rallcar has been set at 10 gallons per package. Transport on deck or below deck by cargo vessel 1s also permitted. 5.3. SOLID WASTE REGULATIONS Under the Resource Conservation and Recovery Act (RCRA), the U.S. EPA has designated HEX as a hazardous toxic waste, Hazardous Waste No. U 130, subject to disposal and permit regulations (40 CFR 262-265 and 122-124). -19- ------- 5.4. FOOD TOLERANCES Under the Federal Insecticide Fumlgant and Rodentldde Act (FIFRA), a tolerance of 0.3 ppm has been established for chlordane residues, which are not to contain >1% of HEX (40 CFR 180.122). 5.5. WATER REGULATIONS Under Section 311 of the Federal Water Pollution Control Act, the U.S. EPA designated HEX as a hazardous substance and established an RQ of 1 pound (0.454 kg) for HEX. Discharges equal to or greater than the RQ Into or upon United States waters are prohibited unless the discharge 1s In compliance with applicable permit programs. Under the Clean Water Act, the U.S. EPA has designated HEX as a toxic pollutant (I.e., priority pollutant). Effluent limitations guidelines, new source performance standards, and pretreatment standards have been developed or will be developed for the priority pollutants for 21 major Industries. Under the Clean Water Act, Ambient Water Quality Criteria (AWQC) for HEX were also developed (U.S. EPA, 1980a). Based on available toxldty data for the protection of public health, the level derived was 206 yg/l. Using organoleptlc data for controlling undesirable taste and odor of ambient water, the estimated level was 1 yg/8, (U.S. EPA, 1980a). 5.6. AIR REGULATIONS HEX 1s not regulated under the Clean A1r Act. 5.7. OTHER REGULATIONS Pursuant to rules under sections 8{a) and 8(d) of the Toxic Substances Control Act, all manufacturers of HEX are required to report health and safety Information on HEX to EPA's Office of Toxic Substances. The deadline for submission of Preliminary Assessment Information Manufacturer's Report on HEX was November 19, 1982. -20- ------- In 1979, the Interagency Testing Committee recommended that HEX be considered for health and environmental effects testing under Section 4{a) of the TSCA (44 FR 31866). This recommendation was based on evidence of potential human exposure and a potential for environmental persistence and bloaccumulatlon. The U.S. EPA (1982) responded 1n the Federal Register. The following 1s the statement from that notice: EPA has decided not to Initiate rulemaklng to require testing of HEX under section 4 of TSCA because EPA does not believe that there Is a sufficient basis to find that current manufacture, distribu- tion 1n commerce, processing, use or disposal of HEX may present an unreasonable risk of Injury to the environment or of mutagenlc and teratogenlc health effects. Neither has the EPA found evidence that there 1s substantial or significant environmental release of HEX. In addition, certain new studies have become available since the ITC's report or are underway, making additional testing for chronic and oncogenlc effects unnecessary. -21- ------- 6. RISK ASSESSMENT Pertinent risk assessment data are summarized In the Appendix of this report. 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 6.1.1. Oral. Short-term studies by IROC (1978) and Abdo et al. (1984) provide Information on oral toxldty to rats and mice; however, the study sizes were small (5 and 10 animals/dose group, respectively). The studies by Abdo et al. (1984) are the only short-term studies yielding no-adverse- effect levels. Based upon the rat and mouse data, these short-term oral studies Indicate a lowest-effect level for dally exposure to be 19 and 38 mg/kg, respectively. Multiplying by 5/7 to estimate a continuous exposure expanded from treatment on 5 days/week results In estimates of 13.6 and 27.14 mg/kg/day, respectively. The NOAELs estimated for continuous exposure for the rat and mouse were 7 and 14 mg/kg/day, respectively. Using the rat NOAEL of 7 mg/kg/day an AIS can be calculated. For a 70 kg man, an AIS for HEX by oral exposure would be 7 mg/kg/day x 70 kg * 100 = 4.9 mg/day. Division by 100 represents an uncertainty factor of 10, Introduced for Interspedes extrapolation, combined with another uncertainty factor of 10 1n an attempt to protect unusually sensitive populations. 6.1.2. Inhalation. In 14-week Inhalation studies a NOAEL for cynomolgus monkeys of 0.2 ppm HEX was established when exposures were 6 hours/day, 5 days/week. This same concentration was determined to be a NOAEL for rats using the same exposure regimen. Using a monkey respiratory volume of 1.4 mVday, a dally exposure estimate can be calculated as follows: 2.27 mg/m3 (0.2 ppm) x 1.4 mVday x 6/24 x 5/7 = 0.568 mg/day. Dividing this exposure estimate by 2.0 kg, the average body weight of the monkeys used 1n this experiment, -22- ------- applying an uncertainty factor of TOO and multiplying by 70 kg, the assumed body weight of an average human, results in an AIS for Inhalation exposure of 0.2 mg/day for a human. This AIS assumes that exposure will be uniformly distributed over the day. An RQ has been calculated for the effect of mortality In mice exposed by Inhalation to 0.15 ppm (1.7 mg/m3) HEX, 7 hours/day, 5 days/week for up to 150 exposures (Treon et al., 1955). A human MED was calculated by expanding to continuous exposure, assuming a human Inhalation rate of 20 mVday and an Inhalation absorption coefficient of 0.5, and applying an uncertainty factor of 10 to extrapolate from subchronlc to chronic data. A human MED of 0.35 mg/day was calculated, which corresponds to an RV. of 6.2. Mortality 1s assigned an RV of 10. The CS of 62 was obtained as the product of RV . and RV . d e 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 6.2.1. Oral. No chronic oral toxlcity evaluations of HEX were located which could be used for risk assessment purposes. Based on subchronlc oral data (Abdo et al., 1984) an AIC of 0.49 mg/man/day for oral exposure is estimated by application of an additional uncertainty factor of 10. 6.2.2. Inhalation. Treon et al. (1955) exposed rats, guinea pigs, rabbits and mice to 0.15 ppm HEX 7 hours/day, 5 days/week for up to 7 months. No effects were seen in any species except mice: 4/5 mice died before the end of the exposure period. The dose-response relationship appears to be very steep in an earlier segment of the Treon et al. (1955) report. Exposure to 0.33 ppm HEX resulted 1n the death of 4/6 rabbits before 25 exposure sessions were completed; no rats or mice survived 20 exposure periods and guinea pigs survived the planned series of 30 exposures. -23- ------- Clark et al. (1982a) exposed groups of Wlstar rats (8/sex/dose) to HEX concentrations of 0, 0.05, 0.1 or 0.5 ppm 6 hours/day, 5 days/week for 30 weeks followed by a 14-week recovery period. At the 0.5 ppm exposure level, 4 males and 2 females did not survive and body weights were depressed 1n both sexes; pulmonary degenerative changes were noted, with males more severely affected. M1ld degenerative changes were seen 1n the Hvers and kidneys, and kidney weights were elevated 1n females. At 0.1 ppm female body weights were depressed. No effects were noted at 0.05 ppm. The reason for the discrepancy between these studies Is unclear. Treon et al. (1955) reported 100% mortality In rats exposed to 0.33 ppm for 20 6-hour exposure sessions. In contrast, Clark et al. (1982a) exposed rats for 0.5 ppm for 30 weeks and noted 50% mortality 1n males and 25% mortality 1n females. Some differences may be attributable to the purity of the compound. Clark et al. (1982a) reported that the compound was 96% pure, with hexachloro-1,3-d1ene and octachlorocyclopentene as Impurities, while Treon et al. (1955) reported 89.5% purity with contaminants not Identified. It would be helpful to have another study 1n mice with a compound of similar purity to that used by Clark et al. (1982a) 1n order to evaluate whether mice are, 1n fact, more sensitive to HEX. Using the Clark et al. (1982a) data which defined a NOEL for the rat of 0.05 ppm (0.5 mg/m3), an exposure dose of 0.066 mg/kg/day can be esti- mated by assuming a rat ventllatory volume of 0.26 mVday, a body weight of 0.35 mg and 100% absorption, and multiplying by 6 hours/24 hours and 5 days/7 days to estimate continuous exposure. Applying an uncertainty factor of 1000 (10 for Interspedes conversion, 10 to reflect concern about discrepancies 1n the available data and 10 to protect especially sensitive members of the population) and multiplying by 70 kg, an assumed average -24- ------- human body weight, results In an Inhalation AIC of 0.00462 mg/day. This corresponds closely to that estimated from the TLV of 0.1 mg/m3. Using a human 8-hour ventHatory volume of 10 m3/8 hour workday and multiplying by 5 days/7 days and dividing by an uncertainty factor of 100 (10 to protect potentially more sensitive segments of the general population, 10 to reflect deficiencies 1n the available data base) would result 1n an estimated dally Intake of 0.0071 mg/day based on the TLV. The AIC, 1n units of mg/day, makes an Implicit assumption that exposure will be uniformly distributed over the day. 6.3. CARCINOGENIC POTENCY (q.,*) There are no available data on the long-term effects of exposure to HEX. Because the NTP 1s testing HEX In a chronic bloassay, the U.S. EPA Carcino- gen Assessment Group will defer any decision on the carclnogenlcity of HEX until the completion of the bloassay. -25- ------- 7. REFERENCES Abdo, K. 1983. Chemical Manager. Personal Communication. National Toxi- cology Program, Research Triangle Park, NC. January 13, 1983. Abdo, K. 1984. Public comment response. National Toxicology Program, Research Triangle Park, NC, May 1984. ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1982. Documentation of Threshold Limit Values for Substances In Workroom Air, 4th ed. Cincinnati, OH. p. 213. Alexander, D.J., G.C. Clark, G.C. Jackson, et al. 1980. Subchronlc Inhal- ation Toxlclty of Hexachlorocyclopentadlene 1n monkeys and rats. Prepared for Velslcol Chemical Corporation, Chicago, IL. 373 p. Atallah, Y.H., D.M. WhHacre, R.G. Butz. 1980. Fate of hexachlorocyclo- pentadlene 1n the environment. 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Prepared by Velslcol Chemical Corp., Chicago, IL. Williams, C.M. 1978. Liver cell culture systems for the study of hepato- cardnogens. Proc. 12th Int. Cancer Cong. Plenum Press, Vahalla, NY. Wolfe, N.L., R.6. Zepp, P. Schlotzhaver and M. Sink. 1982. Transformation pathways of hexachlorocyclopentadlene 1n the aquatic environment. Chemos- phere. 11(2): 91-101. Yu, C.C. and Y.H. Atallah. 1981. Pharmacok1net1cs and metabolism of hexa- chlorocyclopentadlene 1n rats. Library report No. 10, Project 482428. Velslcol Chemical Corporation, Chicago, IL. Zepp, R.G., G.L. Baughman and P.F. Schlotzhauer. 1979. Dynamics of pro- cesses Influencing the behavior of hexachlorocyclopentadlene 1n the aquatic environment. Presented at Ann. Meet. Am. Chem. Soc., Washington, DC. -34- ------- APPENDIX Summary Table for Hexachlorocyclopentadlene GO tn i Species Inhalation AIS monkey AIC rat Maximum mice composite score Oral AIS mouse AIC Experimental Dose/Exposure 2 mg/m3 for 14 weeks 0.5 mg/m3 for 30 weeks 0.15 ppm (1.7 mg/m3) 7 hours/day, 5 days/week for up to 150 exposures RVd=6.2) 27.1 mg/kg/day for 13 weeks Effect Acceptable Intake Reference (AIS or AIC) NOEL 0.2 mg/day Rand et al., 1982 NOEL 0.0046 mg/day Clark et al., 1982a mortality 62 Treon et al., (RVe=10) 1955 forestomach 4.9 mg/man/day SRI, 1981a hyperplasla ND ND = Not determined ------- |