Environmental Protection
Agency March, 1988
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CHLORINATED CYCLOPENTADIENES
Prepared for
OFFICE OF SOLID HASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: 00 NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy and policy Implications.
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Offlice of Solid Waste and Emergency Response (OSWER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included 1n "Appendix: Literature Searched.*
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include: Reference doses
(RfDs) for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 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 llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
' In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980a) 1s provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and carcino-
gen IcHy are derived. The RQ 1s used to determine the quantity of a
hazardous substance for which notification Is required In the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxlclty
and carc1nogen1c1ty) represent two of six scores developed (the remaining
four reflect 1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian
toxlclty). Chemical-specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxlclty and cancer based RQs are
defined 1n U.S. EPA, 1983a and 1986a, respectively.
111
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EXECUTIVE SUMMARY
No Information on the physical and chemical properties of any chlori-
nated cyclopentadlenes other than the hexa-lsomer was located In the litera-
ture cited 1n Appendix A. Hexachlorocyclopentadlene Is a light lemon yellow
liquid with a pungent odor (Stevens, 1979). It 1s not soluble In water but
Is soluble In acetone, carbon tetrachlorlde, ethanol and hexane (U.S. EPA,
1978). Chemically, It 1s highly reactive towards addition and substitution
reactions (Stevens, 1979).
Velslcol Chemical Corporation 1s currently the only company that
produces hexachlorocyclopentadlene 1n the United States (SRI, 1987; USITC,
1986). The current United States production volume for this chemical 1s not
available. According to U.S. EPA (1984a), an estimated 18 million pounds of
hexachlorocyclopentadlene was produced In the United States In 1983.
Hexachlorocyclopentadlene Is used primarily as an Intermediate 1n the
production of pesticides and flame retardants (Stevens, 1979). With the
exception of endosulfan and pentac, the use of hexachlorocyclopentadlene-
based pesticides Is banned, suspended or severely restricted (U.S. EPA,
1980a).
The atmospheric half-life of hexachlorocyclopentadlene, which Is due
primarily to Its reaction with HO* and 0~, was estimated to be 3.5 hours
(Cupltt, 1980). Based on Its atmospheric half-life and Henry's Law
constant, the compound may not significantly transport from air to the
hydrosphere or geosphere; however, the compound may undergo 1ntramed1a
transport from Its source to other points In the atmosphere. In water,
hexachlorocyclopentadlene will be degraded primarily by photolysis and
1v
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hydrolysis. In clear and shallow water, the half-life of hexachlorocyclo-
pentadlene may be as low as <1 hour because of photolysis (Wolfe et al.,
1982), but the effect of photolysis may be less Important In deeper and
turbid water, and hydrolysis may assume a more Important role. The
half-life of hexachlorocyclopentadlene In these waters may be several days
(Wolfe et al., 1982). The rate of volatilization of
hexachlorocyclopentadlene from distilled water can be as high as 4.7-8.8X of
the applied dose 1n the first hour (Kllzer et al., 1979). The rate of
volatilization from natural water bodies will depend on the turbulence of
the water and the wind speed. Adsorption to sediments will greatly reduce
the rate of evaporation from natural waters (U.S. EPA, 1984a).
Significant loss of hexachlorocyclopentadlene from soil surface may
occur due to photolysis. But the Importance of photolysis will not be
significant below the surface layers, due to light attenuation. In moist
soils, hydrolysis may account for significant loss of hexachlorocyclopenta-
dlene; however, the .hydrolysis, rate In soils with high organic carbon
content may be greatly reduced due to strong sorptlon of hexachlorocyclo-
pentadlene 1n such soils. Due to strong sorptlon, hexachlorocyclopentadlene
will remain Immobile In most soils, although the mobility may be higher 1n
sandy soils containing low organic carbon (Chou et al., 1981).
The volatilization of hexachlorocyclopentadlene from soils will be much
less than from water, and this rate will be even slower as the organic
carbon content of soils Increases (Kllzer et al., 1979). Hexachlorocyclo-
pentadlene will not bloaccumulate significantly 1n edible aquatic organisms
as Is Indicated by a BCF of 11-29 1n the fathead minnow, Plroeohales promelas
(Velth et al., 1979; Spehar et al., 1979) and 100-323 1n goldfish, Carasslus
auratus (Podowskl and Khan, 1984).
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Limited data on the level of hexachlorocyclopentadlene 1n the atmosphere
are available. Hexachlorocyclopentadlene was detected at a maximum concen-
tration of 0.10 vg/m3 1n homes near a hazardous waste site In Hardeman
County, Tennessee, and at a maximum concentration of 39 jig/m3 In area
air samples from a wastewater treatment plant 1n Memphis. TN, which handled
wastewater from a nearby pesticide manufacturing plant (S. Clark et al.,
1982; EUa et al., 1983). Hexachlorocyclopentadlene has been detected In
ambient surface water (Fielding et al., 1981). 1n Industrial effluents
(McMahon, 1983) and In drinking water (Benolt and Williams, 1981; Thruston,
1978; Suffet et al., 1980; K1m and Stone, n.d.). The maximum concentrations
of hexachlorocyclopentadlene detected 1n water were 100 ng/l In ambient
surface water from Wheeling, WV (Ohio River Valley Water Sanitation Commis-
sion, 1980) and 650 ng/l in drinking water from Niagara Falls, NY (K1m and
Stone, n.d.). Hexachlorocyclopentadlene has been qualitatively Identified
In fish samples taken from water near a pesticide manufacturing plant 1n
Michigan (Spehar et al., 1977) and from major watersheds near the Great
Lakes (Kuetil et al., 1983), No information regarding the contamination of
foods with hexachlorocyclopentadlene or cases of dermal exposure to
hexachlorocyclopentadlene was located 1n the available literature cited 1n
Appendix A.
Aquatic toxIcUy data for the chlorinated cyclopentadlenes are limited
to studies of hexachlorocyclopentadlene. Hexachlorocyclopentadlene Is
highly toxic to freshwater organisms, with the LC5Q for Daphnla roaqna
reported to range from 39-180 yg/l (Buccafusco and LeBlanc, 1977;
Vllkas, 1977). A 30-day study with fathead minnows found that mortality was
only slightly higher than at 96 hours at the same concentration. Indicating
that hexachlorocyclopentadlene Is not a cumulative toxin (Spehar et al..
v1
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1977, 1979). The only data for a freshwater algae was a 96-hour EC5Q for
Selenastrum caprlcornutus of 0.19 mg/i (Shell 011 Company, 1982).
The data for saltwater species are more limited. LC5Q values for
three Invertebrates and three fish species were reported to range from 32-48
wg/l for all species except the polycheate for which the LC5Q value
was 371 vg/l (U.S. EPA, 1980c). In four species of saltwater algae.
7-day EC-- values were reported 1n the range of 3.5-100 pg/1 (Walsh,
1981).
Comparative pharmacoklnetlc studies of l4C-hexach1orocyc1opentad1ene
have shown higher levels of fecal excretion following oral exposure than for
Intravenous or Inhalation exposure, (El Dareer et al., 1983; Lawrence and
Oorough, 1982). Increased elimination of radioactivity following oral
exposure 1s consistent with toxlclty data which Indicate that hexachloro-
cyclopentadlene 1s more toxic following Inhalation exposure than oral
exposure.
Following . Inhalation exposure to **C-hexach1orocyclopentad1ene,
considerable radlolabel remained In the lung and trachea. Indicating that
hexachlorocyclopentadlene reacts with biological material (Oorough, 1980;
Lawrence and Oorough, 1981, 1982; El Dareer et al.. 1983). The low level of
extractable radioactivity from tissues exposed to hexachlorocyclopentadlene
both ht vivo and jlrt vitro provide further evidence of the high reactivity of
hexachlorocyclopentadlene and/or Us metabolites (El Career et al., 1983).
Following oral exposure, the highest levels of hexachlorocyclopentadlene are
associated with the kidney and liver.
The metabolites of hexachlorocyclopentadlene have not been characterized.
It has been proposed, however, that tetra- and pentachlorocyclopentadlene
are metabolized to the reactive tetrachlorocyclopentadlenone (Gdggelmann et
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al., 1978). The additional chlorine atom may hinder the formation of the
pentadlenone from hexachlorocyclopentadlene.
Following oral exposure to l4C-hexachlorocyc1opentad1ene, the radio-
activity Is excreted predominantly In the feces. Biliary excretion accounted
for **18% of an oral dose (Lawrence and Dorough, 1982). When compared with
oral exposure, higher levels of radioactivity are excreted In the urine
following Inhalation exposure.
Except for mutagenlclty assays of penta- and tetrachlorocyclopentadlene,
toxlclty data are limited to studies concerning hexachlorocyclopentadlene.
Subchronlc Inhalation studies of hexachlorocyclopentadlene have shown a
steep dose-response curve. In a 6- to 30-week study by Treon et al. (1955),
rabbits, mice and rats exposed to 0.34 ppm hexachlorocyclopentadlene by
Inhalation 7 hours/day, 5 days/week at 0.34 ppm died, while guinea pigs
survived. At 0.15 ppm, only the mice died. Renal and hepatic degeneration
was observed In all species, and lung lesions were noted 1n mice, rats and
guinea pigs.
0. Clark et al. (1982) reported that rats exposed by Inhalation to 0.5
ppm hexachlorocyclopentadlene died; no significant treatment-related effects
were observed at 0.1 ppm. The rats were exposed 6 hours/day, 5 days/week
for 30 weeks followed by a 14-week recovery period. In a 13-week study by
Rand et al. (1982a,b), no effects were observed In monkeys exposed by Inha-
lation to hexachlorocyclopentadlene at 0.01, 0.05 or 0.2 ppm, 6 hours/day, 5
days/week. In rats exposed at the same hexachlorocyclopentadlene concentra-
tion, the only consistent treatment-related effect was ultrastructural
changes In the Clara cells of the lungs.
A 13-week study sponsored by the NTP (Battelle Northwest Laboratories,
1984; Abdo et al., 1986) found no effects In mice at
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0.04 ppm and 1n rats at 0.15 ppm. Mice exposed to hexachlorocyclopentadlene
at >0.15 ppm developed lung lesions, with deaths occurring at >0.4 ppm.
Lung lesions were observed In rats at >0.4 ppm, with deaths at >1 ppm. The
animals were exposed 6 hours/day, 5 days/week. A chronic Inhalation study
using rats and mice Is In progress (NTP, 1987).
A 13-week gavage study (SRI, 1981a; Abdo et al., 1984) found ulceratlon
of the stomach In mice treated 5 days/week at >38 mg/kg, and at >19 mg/kg In
rats. No effects were observed 1n mice at 19 mg/kg or In rats at 10 mg/kg.
No effects were reported 1n rats fed hexachlorocyclopentadlene In the diet
at up to 300 ppm for 90 days (IBT, 1975).
The lowest oral LD5Q 1s 315 mg/kg 1n female weanling rats (SRI,
1981a). The lowest Inhalation LC_Q reported 1s 1.6 ppm In young adult
male rats (Rand et al., 1982a). A short-term Inhalation study In rats at
0.5 ppm (Rand et al., 1982a) found that lung lesions observed when rats were
exposed for five 6-hour periods were not present after 14-21 days of
recovery.
The odor recognition concentration for hexachlorocyclopentadlene was
reported to be 0.0017 mg/m3 (Levin, 1980). Questionnaires completed by
workers at the Morris Forman Uastewater Treatment Plant In Louisville, KY,
where an acute exposure Incident occurred. Indicated that 95% of the
respondents detected the odor of hexachlorocyclopentadlene before symptoms
of Irritation occurred (Norse et al., 1978, 1979).
Mortality studies of hexachlorocyclopentadlene production workers have
not. shown Increased cancer death rates. No animal studies of the carcino-
genic 1ty of hexachlorocyclopentadlene were available.
1x
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Results of mutagenldty assays of penta- and tetrachlorocyclopentadlene
1n bacteria have been positive (Gdggelroann et al.( 1978; Grelm et al..
1977); however, hexachlorocyclopentadlene has consistently tested negative
In mutagenldty assays.
Oral teratogenlclty studies of hexachlorocyclopentadlene using rats
(IRDC, 1978), mice and rabbits (Murray et a!., 1980) have reported negative
results, although an Increase In skeletal anomalies was observed at 75
mg/kg/day, a dose that also resulted 1n maternal toxldty. Hexachlorocyclo-
pentadlene has also tested negative for dominant lethal effects In mice
(Litton B1onet1cs, Inc., 1978a).
Using the 13-week NTP-sponsored rat study (Battene Northwest
laboratories, 1984), human subchronlc and chronic RfDs for hexachlorocyclo-
pentadlene of 0.01 mg/day (0.0007 mg/m») and 0.001 mg/day (0.00007
rag/raa), respectively, were calculated. Confidence In the Inhalation RfDs
Is medium. Subchronlc and chronic oral RfDs for hexachlorocyclopentadlene
of 5 mg/day (0.07 mg/kg/day) and 0.5 mg/day (0.007. mg/kg/day), respectively.
were calculated from the 13-week gavage study using rats sponsored by the
NTP (SRI, 1981a; Abdo et al., 1984). Because of the lack of additional oral
studies, confidence In the oral RfDs Is low. A chronic toxldty RQ for
hexachlorocyclopentadlene of 10 pounds was calculated from the NTP-sponsored
13-week Inhalation study using mice (Abdo et al., 1986). Because of the
lack of data an RQ based on care1nogen1city could not be calculated.
The lack of toxlclty data for chlorocyclopentadlene, trlchlorocyclo-
pentadlene, tetrachlorocyclopentadlene and pentachlorocyclopentadlene
precludes the calculation of risk assessment estimates.
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 4
1.4. USE DATA 4
1.5. SUMMARY 5
2. ENVIRONMENTAL FATE AND TRANSPORT 6
2.1. AIR 6
2.2. HATER 7
2.3. SOIL 11
2.4. SUMMARY 13
3. EXPOSURE 15
3.1. INHALATION 15
3.2. HATER 16
3.3. FOOD 17
3.4. DERMAL 17
3.5. SUMMARY 17
4. AQUATIC TOXICITY 19
4.1. ACUTE TOXICITY 19
4.2. CHRONIC EFFECTS 21
4.3. PLANT. EFFECTS. . . . 21
4.4. SUMMARY 25
5. PHARMACOKINETCS 26
5.1. ABSORPTION 26
5.2. DISTRIBUTION 27
5.3. METABOLISM 30
5.4. EXCRETION 32
5.5. SUMMARY 33
6. EFFECTS 36
6.1. SYSTEMIC TOXICITY 36
6.1.1. Inhalation Exposures 36
6.1.2. Oral Exposures 39
6.1.3. Other Relevant Information 41
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TABLE OF CONTENTS (cont.)
Page
6.2. CARCINOGENICITY 46
6.2.1. Inhalation 46
6.2.2. Oral 46
6.2.3. Other Relevant Information 46
6.3. MUTAGENICITY 46
6.4. TERATOGENICITY 49
6.5. OTHER REPRODUCTIVE EFFECTS 51
6.6. SUMMARY 51
7. EXISTING GUIDELINES AND STANDARDS 54
7.1. HUMAN 54
7.2. AQUATIC 54
8. RISK ASSESSMENT 56
8.1. CARCINOGENICITY 56
8.1.1. Inhalation 56
8.1.2. Oral 56
8.1.3. Other Routes 56
8.1.4. Weight of Evidence 56
8.1.5. Quantitative Risk Estimates 56
8,2. . SYSJEMC TOXICITY. 56
8.2.1. Inhalation Exposures 56
8.2.2. Oral Exposures 62
9. REPORTABLE QUANTITIES 64
9.1. BASED ON SYSTEMIC TOXICITY 64
9.2. BASED ON CARCINOGENICITY 64
10. REFERENCES 70
APPENDIX A: LITERATURE SEARCHED 91
APPENDIX B: SUMMARY TABLE FOR HEXACHLOROCYCLOPENTADIENE 94
xll
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LIST OF TABLES
No. Title Page
1-1 Identities of Selected Chlorinated Cyclopentadlenes 2
1-2 Selected Physical Properties of Hexachlorocyclopentadlene . . 3
4-1 Acute Toxlclty Data for Freshwater Species Exposed to
Hexachlorocyclopentadlene 20
4-2 Acute Toxic1ty Data on Marine Organisms Exposed to
Hexachlorocyclopentadlene 22
4-3 Effects of 28 Days Exposure of Mysld Shrimp, Mvsldopsls
bahla. to Hexachlorocyclopentadlene 24
5-1 Distribution of Hexachlorocyclopentadlene Equivalents In
Tissues and Excreta of Rats 72 Hours After Oral, Inhalation
and Intravenous Exposure to 14C-Hexachlorocyclopentad1ene . . 29
5-2 Distribution of Radioactivity Expressed as Percentage
of Administered Dose from l4C-Hexachlorocyclopentad1ene
In Rats Dosed by Various Routes 34
6-1 Acute Toxlclty of Hexachlorocyclopentadlene 42
6-2 MutagenlcUy Testing of Chlorinated Cyclopentadlenes 47
9-'l Toxlclty Summary for Hexachlorocyclopentadlene 65
9-2 Composite Scores for Hexachlorocyclopentadlene 67
9-3 Hexachlorocyclopentadlene: Minimum Effective Dose (MED)
and Report able Quantity (RQ) 68
9-4 Chlorocyclopentadlene, TMchlorocyclopentadlene,
Tetrachlorocyclopentadlene and Pentachlorocyclopentadlene:
Minimum Effective Dose (MED) and Reportable Quantity (RQ) . . 69
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LIST OF ABBREVIATIONS
ATP Adenoslne tMphosphate
BCF Bloconcentratlon factor
CS Composite score
DMA DeoxyMbonuclelc acid
DUEL Drinking water exposure level
EC5Q Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
HA Health advisory
K Soil sorptlon coefficient
K Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
LD50 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
NED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppb Parts per billion
ppm Parts per million
RBC Red blood cell
RQ Reportable quantity
RV Effect-rating value
Q
RfD Reference dose
RVd Dose-rating value
SO Standard deviation
SGOT Serum glutamlc oxaloacetlc transamlnase
TLC Thin layer chromatography
TLV Threshold limit value
TWA Time-weighted average
v/v Volume per volume
w/v Height per volume
xlv
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The five chlorinated eye1opentadlenes selected for examination 1n this
document are chlorocyclopentadlene, trlchlorocyclopentadlene, tetrachloro-
cyclopentadlene, pentachlorocyclopentadlene and hexachlorocyclopentadlene.
Of the five chlorinated cyclopentadlenes listed above, the first four can
exist 1n more than one Isomerlc form, depending on the position of the
chlorine substitution on the cyclopentadlene ring. No Information on the
physical and chemical properties of any other chlorinated cyclopentadlenes
(other than the hexa-lsomer) could be found In the available literature
cited 1n the Appendix; however, the formation of lower chlorinated cyclo-
pentadlenes during the chlorlnatlon of cyclopentadlene (Stevens, 1979) and
the photolysis of hexachlorocyclopentadlene (Section 2.2.) are mentioned
frequently 1n the literature. Table 1-1 gives the molecular formula,
molecular weight and CAS numbers for the selected chlorinated cyclopenta-
dlenes and the synonyms and structure for hexachlorocyclopentadlene.
1.2.. PHYSICAL AND CHEMICAL PROPERTIES
In the absence of data on other chlorinated cyclopentadlenes, only
hexachlorocyclopentadlene will be discussed. Hexachlorocyclopentadlene Is a
nonflammable liquid at room temperature (Stevens, 1979). Selected physical
properties of hexachlorocyclopentadlene are given In Table 1-2. Hexachloro-
cyclopentadlene Is stable towards storage In moisture-free and Iron-free
environments. Chemically, hexachlorocyclopentadlene 1s a highly reactive
dlene that readily undergoes addition and substitution reactions. The
products of the addition reactions are generally 1:1 endo adducts containing
a hexach1orob1cyclo-[2,2,1]heptene structure (Stevens, 1979). Hexachloro-
cyclopentadlene Is also susceptible to hydrolysis and photolysis, and these
reactions are discussed In Chapter 2.
0077d -1- 04/05/88
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TABLE 1-1
Identities of Selected Chlorinated Cyclopentadlenes
Conpounds
Synonyms3
Molecular
Formula
Holecular
Weight
Structure CAS No.
Chlorocyclopentadlene0
IS)
I
Hexachlorocyclopentadlene
NA
C5H5C1
Tr1chlorocyc1opentad1eneb NA
Tetrach1orocyclopentad1eneb NA
Pentachlorocyclopentadlene0 NA
C56; HRS 1655
graphlox; perchloro-
cyclopentadlene;
hexachloro-1,3-cyclo-
pentadlene; 1.2,3,4,5.5-
hexachloro-1,3-cyclo-
pentadlene; hexachloro-
cyclopentadlene
C5H2C14
C5HC15
C5C16
100.55
169.44
203.88
238.33
272.77
ci
ci
Cl
Cl
41851-50-7
77323-84-3
ci 77323-85-4
25329-35-5
77-47-4
S *U.S. EPA. 1987a
3 These compounds can exist In several Isoroerlc forms
NA a Not available
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TABLE 1-2
Selected Physical Properties of Hexachlorocyclopentadlene
Property
Value/Description
Reference
Physical form at ambient
temperatures:
Color:
Odor:
A1r odor threshold:
Water odor threshold:
Melting point, °C:
Boiling point, °C:
Density, g/cm»:
Vapor pressure, mm Hg
at 25°C:
Water solubility:
Organic solvents:
Log octanol/water parti-
tion coefficient (Kou):
Henry's Law constant
(atmos-m'/mol):
Soil partition co-
efficient (Koc):
Wavelength at maximum
absorption (50% aceto-
nltrlle In water):
liquid
light lemon yellow (pure)
greenish tinge (Impure)
pungent
0.03 ppm (v/v)
0.0077 ppm (w/v)
9.5-11.35
239
1.7019
0.06-0.08
2.10 rag/1 at 25°C
1.8 rog/j. at 28°C
3.4 mg/i at 20°C
soluble In acetone,
CC14, ethanol and hexane
5.04 at 28*C
3.99
5.51
2.7xlO~a
1.64x10'*
12,000 (estimated)
322 nm
Stevens, 1979
Stevens, 1979
Stevens. 1979
Amoore'and Hautala,
1983
Amoore and Hautala,
1983
U.S. EPA, 1978;
Stevens, 1979
U.S. EPA, 1978;
Stevens, 1979
Horvath, 1982
U.S. EPA, 1978
U.S. EPA, 1978
Wolfe et al., 1982
Horvath, 1982
U.S. EPA, 1978
Wolfe et al., 1982
Yoshlda et al.. 1983
Mackay. 1982
Wolfe et al., 1982
Shen. 1982
Wolfe et al.. 1982
Wolfe et al.. 1982
0077d
-3-
12/23/87
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1.3. PRODUCTION DATA
Hexachlorocyclopentadlene Is produced for commercial use only by
Velslcol Chemical Corporation at Us Memphis, TN site (SRI, 1987; USITC,
1986). Hexachlorocyclopentadlene produced by Velslcol Chemical Corporation
at Us Marshall, IL site Is used captlvely for the production of chlordane
(U.S. EPA, 1984a). Because there Is only one producer of hexachlorocyclo-
pentadlene, current production data are not available. According to U.S.
EPA (1984a), an estimated 18 million pounds of hexachlorocyclopentadlene was
produced 1n 1983.
The three primary processes commonly used for the production of hexa-
chlorocyclopentadlene are chloMnatlon of cyclopentadlene, dechlorlnatlon of
octachlorocyclopentene and the dehydrochlor1nation of hexachlorocyclopen-
tane. In the first process, freshly prepared cyclopentadlene Is mixed with
alkaline hypochlorlte solution at -40°C. The hexachlorocyclopentadlene Is
recovered from lower chlorinated products by fractional distillation. In
the dechlorlnatlon process, octachlorocyclopentene Is thermally dechlorl-
nated at 470-480'C to produce hexachlorocyclopentadlene. Hexachlorocyclo-
pentadlene can be dehydrochloMnated at elevated temperatures 1n the
presence of a catalyst to produce hexachlorocyclopentadlene (Stevens, 1979).
1.4. USE DATA
Although hexachlorocyclopentadlene has essentially no end use of Us
own. It has been used as a chemical Intermediate In the production of
several Insecticides Including aldrln, dleldrln, endrln, chlordane,
heptachlor, endosulfan, pentac, mlrex and others (Stevens, 1979) and as an
Intermediate In the manufacture of flame retardants Including wet acid and
anhydride, chlorendlc acid and anhydride and dechlorane plus (Stevens,
0077d .4- 04/05/88
-------
1979). As a flame retardant, U 1s used In a number of plastics and epoxy-
reslns (U.S. EPA, 1980b). With the exception of endosulfan and pentac, both
of which are currently used, the use of hexachlorocyclopentadlene-based
pesticides 1s banned, suspended or severely restricted.
1.5. SUMMARY
No Information on the physical and chemical properties of any chlori-
nated cyclopentadlenes other than the hexa-1somer was located 1n the
literature cited In Appendix A. Hexachlorocyclopentadlene Is a light lemon
yellow liquid with a pungent odor (Stevens, 1979). It 1s not soluble 1n
water but Is soluble 1n acetone, carbon tetrachloMde, ethanol and hexane
(U.S. EPA, 1978). Chemically, It Is highly reactive towards addition and
substitution reactions (Stevens, 1979).
Velslcol Chemical Corporation 1s currently the only company that
produces hexachlorocyclopentadlene 1n the United States (SRI, 1987; USITC.
1986). The current U.S. production volume for this chemical Is not
available. According to U.S. EPA (1984a), an estimated 18 million pounds of
hexachlorocyclopentadlene was produced 1n the United States 1n 1983.
Hexachlorocyclopentadlene 1s used primarily as an Intermediate In the
production of pesticides and flame retardants (Stevens, 1979). With the
exception of endosulfan and pentac, the use of hexachlorocyclopentadlene-
based pesticides 1s banned, suspended or severely restricted (U.S. EPA,
1980b).
0077d -5- 04/05/88
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Available data on the fate and transport of hexachlorocyclopentadlene 1n
the atmosphere are limited. Cupltt (1980) estimated the rate constants for
HO* and ozone reactions with vapor phase hexachlorocyclopentadlene to be
5.9x10"" and 8xlO~ia cma/molecule~sec, respectively. Based on atmo-
spheric HO* and 0. concentrations of 10* and 10" molecules/cm3,
respectively, the half-life of hexachlorocyclopentadlene 1n the atmosphere
can be estimated as 3.5 hours. Cupltt (1980) reported phosgene, dlacyl-
chlorldes, ketones and Cl radicals as anticipated reaction products, all of
which are likely to react with other species In the atmosphere. The
photolysis of hexachlorocyclopentadlene sorbed to silica gel with light of
wavelengths >290 nra (wavelengths available 1n sunlight) was reported by
FreHag et al. (1982, 1985). Korte (1978) reported 46X mineralization of
hexachlorocyclopentadlene 1n 17 hours of Irradiation with the formation of
Cl" (44.9X). C02 (48.3X), C^ (5.4%) and CO (1.2X). According to
E1senre1ch et al. (1981), organlcs with vapor pressure >10~* mm Hg should
exist almost entirely 1n the vapor phase 1n the atmosphere. Therefore,
hexachlorocyclopentadlene, with a vapor pressure of 0.06-0.08 mm Hg, Is
expected to exist primarily In the vapor phase and not 1n the partlcle-
sorbed state as reported by Freltag et al. (1982, 1985). Nonetheless, the
experiments of Freltag et al. (1982, 1985) Indicate the susceptibility of
hexachlorocyclopentadlene to degradation under natural sunlight conditions.
Hexachlorocyclopentadlene may also undergo hydrolysis 1n moist air (U.S.
EPA, 1984a).
Pertinent data regarding the 1ntra- and Intermedia tranport of hexa-
chlorocyclopentadlene present 1n the atmosphere were not located In the
0077d -6- 04/06/88
-------
literature cited 1n Appendix A. Given that the transport characteristics of
a chemical In the atmosphere are likely to be controlled by Us air
residence time and air/water partition coefficient, this property may be
predicted as follows: since the atmospheric residence time of hexachloro-
cyclopentadlene Is likely to be short, and the Henry's Law constant predicts
higher concentrations 1n the vapor phase, significant transfer of hexa-
chlorocyclopentadlene from the atmosphere to water and soil 1s not expected,
and the chemical may not travel long distances 1n the atmosphere from Us
source.
2.2,. HATER
A detailed discussion of the fate and transport of hexachlorocyclopenta-
dlene 1n aquatic media Is available In U.S. EPA (1984a). The photolysis of
hexachlorocyclopentadlene 1n water was reported by Zepp et al. (1984) and
Wolfe et al. (1982). Neither huralc materials nor algae In natural water was
found to photosensitize the process. The rate constant for near-surface
.photolysis of hexachlorocyclopentadlene at 40°M latitude on a clear day was
estimated as 3.9 hour'1. This corresponds to a half-life of -11 minutes.
Although no product was Identified, Zepp et al. (1984) and Wolfe et al.
(1982) speculated that the primary phototransformatlon product was hydrated
tetrachlorocyclopentadlenone, which dlmerlzed or reacted to form higher
molecular weight products. The dlmerlzatlon of hexachlorocyclopentadlene to
form higher molecular weight products represented a minor pathway according
to Butz et al. (1982) and Yu and Atallah (1977a). According to Chou et al.
(1987), the photolysis half-life of hexachlorocyclopentadlene 1n water was
<4 minutes when exposed to sunlight. These authors positively or tenta-
tively Identified at least eight photoproducts: 2,3,4.4,5-pentachloro-2-
cyclopentenone; hexachloro-2-cyclopentenone; hexachloro-3-cyclopentenone
0077d -7- 04/05/88
-------
(primary product); pentach1oro-c1s-2,4-pentad1eno1c add; Z- and E-penta-
chloro-butadlene, tetrachlorobutyne (secondary products) and hexachloro-
Indenone (minor product).
Studies of the hydrolysis of hexachlorocyclopentadlene Indicate that Us
hydrolytlc half-life 1s 3-11 days at 25-30°C and a pH range of 5-9 (Wolfe et
al., 1982; Yu and Atallah, 19775). In both studies, the authors concluded
that the hydrolysis rate was higher as temperatures Increased, and that
sorptlon to sediments would not significantly affect the rate of hydrolysis.
Although the hydrolysis products were not Identified, high molecular weight
polyhydroxy compounds appeared to be the major products.
The rate constants for the oxidation of hexachlorocyclopentadlene with
singlet oxygen (^O.) and peroxy radicals In water were estimated as
<10» and 12 NT* hour'1, respectively (Mabey et al., 1982). If the
concentrations of ML and R0_ radicals In water are assumed to be
10'" and 10~* N, respectively (Mill and Nabey, 1985), It 1s probable
that under ordinary environmental conditions, oxidation of hexachlorocyclo-
pentadlene will not be significant.
Tabak et al. (1981) conducted a static-culture flask-screening procedure
with settled domestic wastewater as mlcroblal Inoculum to test the
b1odegradab111ty of several compounds. Including hexachlorocyclopentadlene.
Hexachlorocyclopentadlene at original concentrations of 5 and 10 rag/l
degraded completely with rapid adaptation 1n 7 days Incubation time. The
authors reported that volatilization of hexachlorocyclopentadlene from
aquatic solution was not significant but failed to account for the loss of
hexachlorocyclopentadlene that was due to hydrolysis. Based on the
hydrolytlc half-life data for hexachlorocyclopentadlene, hydrolysis alone
0077d -8- 04/05/88
-------
cannot account for the 100X observed loss of hexachlorocyclopentadlene.
Therefore, U can be assumed that some of the observed loss was due to
blodegradatlon.
The blodegradabHUy of radlolabelled hexachlorocyclopentadlene with
acclimated mixed microorganisms and several pure cultures of Pseudomonas
putIda was studied by Atallah et al. (1980). Only a small percent (<2.5X)
of added hexachlorocyclopentadlene completely mineralized to CO. In 2-3
weeks. Wolfe et al. (1982) observed no detectable difference In the
degradation rate when sterile and nonsterlle natural sediments were added to
hexachlorocyclopentadlene solutions. Hence, these Investigators concluded
that aerobic blodegradatlon may not be significant 1n water. The anaerobic
blodegradatlon of hexachlorocyclopentadlene 1n water was reportedly very
slow or not significant, and at higher concentrations (100 mg/l), hexa-
chlorocyclopentadlene was Inhibitory to anaerobic microorganisms (Johnson
and Young, 1983)..
The Intermedia' transport of .hexachlorocyclopentadlene from water may
occur through volatilization Into air, adsorption onto suspended partlculate
matters and subsequent sedimentation and uptake by plants and animals In
water. The Intramedla transport of hexachlorocyclopentadlene may be
responsible for transporting the pollutant from Us source to other points
1n the water. The significance of hexachlorocyclopentadlene sorptlon In
water was predicted by Wolfe et al. (1982) on the basis of a computer
simulated Exposure Analysis Modeling System (EXAMS). The distribution of
hexachlorocyclopentadlene 1n the sediments of a river, pond, eutrophlc and
ollgotrophlc lake was estimated to be 98.8, 86, 87 and 97.1%, respectively,
of total hexachlorocyclopentadlene 1n the system, and the residual portions
were suspected to be 1n the water column.
0077d -9- 04/05/88
-------
From an experimental anaerobic blodegradatlon study, Johnson and Young
(1983) observed that adsorption plays an Important role In reducing the con-
centration of hexachlorocyclopentadlene In aqueous solutions. The predicted
strong sorptlon of hexachlorocyclopentadlene In sediments Is supported by
the experimental sorptlon data In soils (discussed 1n Section 2.3).
The volatility of hexachlorocyclopentadlene from water was reported by
Weber (1979). When an unstoppered, half full, glass bottle containing a
0.41 mg/l aqueous solution of hexachlorocyclopentadlene was left at
ambient temperature, -45-47X of hexachlorocyclopentadlene was lost 1n a day,
presumably from volatilization. Kllzer et al. (1979) reported that
volatility of hexachlorocyclopentadlene ranged from 4.7-8.8%/hour from a
static aquatic solution of concentration 50 yg/l. In their aqueous
blodegradabHUy test, Atallah et al. (1980) observed a high rate of
volatilization of (>80% 1n 1 day) hexachlorocyclopentadlene from unlnocu-
lated media containing .45 rag/l hexachlorocyclopentadlene. Tabak et al.
(1981),. on. the other hand, observed Insignificant volatilization of
hexachlorocyclopentadlene from aqueous solutions (5 and 10 mg/l) In a
blodegradablllty test. The studies of Atallah et al. (1980) and Tabak et
al. (1981) were not designed to test the volatility of hexachlorocyclopenta-
dlene from aqueous solutions and both studies used substrate concentrations
that exceeded the solubility of the compound. Wolfe et al. (1982) predicted
the volatility of hexachlorocyclopentadlene from aqueous solution using the
mathematical EXAMS model. The model predicted that volatilization of hexa-
chlorocyclopentadlene from a river, pond, eutrophlc lake and oHogotrophlc
lake would account for only 0.69, 1.33, 1.56 and 1.08% loss of water. These
values are much lower than values obtained from laboratory studies. The
EXAMS model assumes that a large percent of hexachlorocyclopentadlene
(86-99X) will remain adsorbed to sediment; whereas, the laboratory studies
0077d -10- 04/05/88
-------
were performed using distilled water without any sediments In them. The
EXAMS model also predicted 72% loss of hexachlorocyclopentadlene by Intra-
medla transport from a typical river and Insignificant loss of hexachloro-
cyclopentadlene from pond water, eutrophlc lake water and ollogotrophlc lake
water.
The uptake and bloconcentratlon of hexachlorocyclopentadlene 1n aquatic
plants and animals was studied In a laboratory model aquatic ecosystem (Lu
et al., 1975). The BCFs for hexachlorocyclopentadlene In alga, Edoqonlum.
snail, Phvsa. mosquito, Culex. and fish, Gambusla. were 340, 929, 1634 and
448, respectively. In green alga, Chlorella fusca. the BCF for hexachloro-
cyclopentadlene was 1090 (Geyer et al., 1981). The BCFs for hexachloro-
cyclopentadlene In several species of fish were as follows: <11 1n the
fathead minnow, Plmeohales promelas (Spehar et al., 1979); 29 1n the fathead
minnow, Plmephales promelas (Velth et al.. 1979) and 100-323 1n goldfish,
Carasslus auratus (Podowskl and Khan, 1984).
2.3. SOIL , .., . . . .
Although experimental data on photolysis and hydrolysis, Important
abiotic processes that may be responsible for some loss of hexachlorocyclo-
pentadlene from soils, were not available In the literature cited In
Appendix A, U Is likely that significant loss will occur as a result of
photolysis of hexachlorocyclopentadlene from soil surfaces (see Sections
2.1,. and 2.2.). Below the surface layer, the photodegradatlon losses may
not be significant because of light attenuation and strong sorptlon of hexa-
chlorocyclopentadlene 1n soil. Hydrolytlc losses of hexachlorocyclopenta-
dlene 1n moist soils may also be significant, but the significance of this
process will be reduced greatly by strong sorptlon of hexachlorocyclo-
pentadlene 1n soils.
0077d -11- 04/05/88
-------
Pertinent data regarding the loss of hexachlorocyclopentadlene by blotlc
processes were located 1n the available literature. R1eck (1977a) provided
Indirect evidence of the blodegradatlon of hexachlorocyclopentadlene In
soils under both aerobic and anaerobic conditions. Thuma et al. (1978)
Isolated seven pure cultures of microorganisms that could blodegrade >33% of
hexachlorocyclopentadlene In soils 1n 14 days.
The estimated K value for hexachlorocyclopentadlene 1s 12,000 (Wolfe
et al., 1982). According to Kenaga (1980). compounds with K values
>1000 remain tightly bound and Immobile In soils. Therefore, hexachloro-
cyclopentadlene 1s expected to remain strongly sorbed to soils. The experi-
mental results of Weber (1979), with flooded soil confirm this hypothesis.
Weber (1979) reported that an average of 68% of applied hexachlorocyclo-
pentadlene In aqueous solution was adsorbed to a loam soil In 24 hours. The
adsorption of hexachlorocyclopentadlene In different kinds of soils was
studied by Chou et al, (1981). These authors reported that the adsorption
of hexachlorocyclopentadlene can be represented by Freundllch's adsorption
equation. From both soil TIC and soil column experiments, they concluded
that the mobility of hexachlorocyclopentadlene was proportional to the soil
organic carbon content, and that hexachlorocyclopentadlene was significantly
more mobile In low organic sandy soil than 1n high organic muck soil. When
leached with tap water or landfill leachate, however, hexachlorocyclopenta-
dlene remained Immobile In all soils. Hexachlorocyclopentadlene was highly
mobile when leached with acetone/water, acetone and methanol. Chou et al.
(1981) also concluded that polar degradation products of hexachlorocyclo-
pentadlene may have a tendency to migrate through soils rather than
hexachlorocyclopentadlene Itself.
0077d -12- 12/23/87
-------
The volatilization of hexachlorocyclopentadlene from silt loam soils was
examined by Rleck (1977b), who reported evaporation of 9.3% of hexachloro-
cyclopentadlene and Us nonpolar metabolites from the soil In 1 day.
Following the first day. the evaporation rate was slow, as Indicated by an
additional 2% evaporation In 14 days. These results suggest that the
evaporation that occurred during the first day was probably associated with
the surface soil only. KHzer et al. (1979) also studied the evaporation of
hexachlorocyclopentadlene from soil and concluded that the evaporation rate
was related to the soil organic carbon content, with the evaporation slowest
for humus soils and highest for sandy soil. Only 0.7-1.2% of applied
hexachlorocyclopentadlene evaporated from a sandy soil 1n the first hour,
and the evaporation rate was
-------
al., 1982), but the effect of photolysis may be less Important In deeper and
turbid water, and hydrolysis may assume a more Important role. The
half-life of hexachlorocyclopentadlene In these waters may be several days
(Wolfe et al., 1982). The rate of volatilization of
hexachlorocyclopentadlene from distilled water can be as high as 4.7-8.8% of
the applied dose In the first hour (Kllzer et al., 1979). The rate of
volatilization from natural water bodies will depend on the turbulence of
the water and the wind speed. Adsorption to sediments will greatly reduce
the rate of evaporation from natural waters (U.S. EPA, 1984a).
Significant loss of hexachlorocyclopentadlene from soil surface may
occur due to photolysis. But the Importance of photolysis will not be
significant below the surface layers, because of light attenuation. In
moist soils, hydrolysis may account for significant loss of
hexachlorocyclopentadlene; however, the hydrolysis rate In soils with high
organic carbon content may be greatly reduced due to strong sorptlon of
hexachlorocyclopentadlene In such soils. Due to strong sorptlon.
hexachlorocyclopentadlene will remain Immobile 1n most soils, although the
mobility may be higher 1n sandy soils containing low organic carbon (Chou et
al., 1981).
The volatilization of hexachlorocyclopentadlene from soils will be much
less than from water, and this rate will be even slower as the organic
carbon content of soils Increases (Kllzer et al., 1979). Hexachlorocyclo-
pentadlene will not bloaccumulate significantly 1n edible aquatic organisms
as Is Indicated by a BCF of 11-29 1n the fathead minnow, Plmephales promelas
(Velth et al., 1979; Spehar et al., 1979) and 100-323 1n goldfish, Carasslus
auratus (Podowskl and Khan, 1984).
0077d -14- 04/05/88
-------
3. EXPOSURE
3.1. INHALATION
Release of hexachlorocyclopentadlene to the atmosphere can occur during
the production, use and disposal of the chemical. Limited data regarding
the level of hexachlorocyclopentadlene In the atmosphere were available In
the literature cited 1n Appendix A. Hexachlorocyclopentadlene was detected
1n three out of five homes near a hazardous waste disposal site In Hardeman
County 1n Tennessee, 1n 1978 (S. Clark et al., 1982; Harris et al., 1984).
In the monitored homes, concentrations ranged .from 0.006-0.10 pg/ma.
Hauser and Bromberg (1982) reported the qualitative detection of hexachloro-
cyclopentadlene In Love Canal (Niagara Falls) air samples collected 1n
1980. Area air samples collected at a Memphis wastewater treatment plant 1n
Tennessee that handled wastewater from a pesticide manufacturer showed
hexachlorocyclopentadlene concentrations In the range of 0.03-39 jig/m9
(Ellia et al., 1983). The average hexachlorocyclopentadlene emission rate
from an abandoned. waste- site In Michigan was reported to be 0.26 g/hour
(U.S. EPA, 1984a). An Inventory of atmospheric hexachlorocyclopentadlene
emissions In the United States was reported by Anderson (1983a,b). The
total emission was estimated to be 59.500 pounds/year, and an estimated 1.38
million people In the United States were exposed to hexachlorocyclopenta-
dlene; however, this estimate, made with the 1978 production Inventory, Is
no longer valid since two of the three production companies used to estimate
the total emission of hexachlorocyclopentadlene do not produce the compound
currently. Inhalation exposure to hexachlorocyclopentadlene for the general
population 1n the United States cannot be estimated because of limited
monitoring data.
0077d -15- 04/06/88
-------
3.2. WATER
BenoU and Williams (1981) monitored both raw and drinking waters from
an Ottawa water treatment plant for the presence of hexachlorocyclopenta-
dlene. Although hexachlorocyclopentadlene was not detected In the raw
waters, 1t was found In the concentration range of 57-110 pg/l In the
drinking water. The source of hexachlorocyclopentadlene In the drinking
water was possibly the chloMnatlon step of the treatment process. Hexa-
chlorocyclopentadlene at a concentration range of 20-80 ng/i was detected
1n drinking water from Athens, 6A, collected In 1976 (Thruston, 1978). The
Great Lakes Water Quality Board (1983) qualitatively detected hexachloro-
cyclopentadlene In water from Lake Ontario but not from waters of Lake Erie,
Lake Michigan and Lake Superior. The concentrations of hexachlorocyclo-
pentadlene In the drinking water from Niagara Falls monitored In 1979 by the
NY State Department of Health were In the range of <0.01-0.65 jig/l (Kim
and Stone, n.d.). The results of monitoring hexachlorocyclopentadlene In
the Ohio River were as follows: 0.1 yg/l In T of 12 samples from
Wheeling. UV; <0.1 »g/l 1n 2 of 21 samples from Hunting ton, WV; <0.1
wg/l 1n 2 of 11 samples from Louisville, KY; and <0.1 yg/l In 1 of
11 samples from Evansvllle, IN (Ohio River Valley Hater Sanitation Commis-
sion, 1980). No hexachlorocyclopentadlene was detected (detection limit of
0.04 pg/l) In 51 other samples collected from different sites of the
river. Hexachlorocyclopentadlene was qualitatively Identified In water as
follows: In Philadelphia drinking water (Suffet et al., 1980); In wastewater
from a gas diffusion plant at Oak Ridge, TN (HcMahon, 1983); In Rhine River
water (Haberer and Normann, 1979) and 1n surface water In England (Fielding
et al., 1981). Using data from U.S. EPA's STORET data base, which reflected
good quality assurance practices. Staples et al. (1985) reported that
0077d -16- 04/05/88
-------
hexachlorocyclopentadlene was detectable 1n 0.9X of 1228 effluent samples at
a median concentration of <10 vg/i and 1n 0.1% of 854 ambient water
samples at a median concentration of <10 vg/l.
3.3,. FOOD
Hexachlorocyclopentadlene was qualitatively Identified In fish samples
taken from water near a pesticide manufacturing plant In Michigan (Spehar et
a!., 1977) and from water of the Great Miami River In Hamilton, OH and Mill
Creek In Cincinnati, OH (Kuehl et al., 1983). No other Information
regarding hexachlorocyclopentadlene contamination 1n food was located In the
literature cited 1n the Appendix A.
3.4. DENIAL
No Information regarding dermal exposure to hexachlorocyclopentadlene
was available 1n the literature dted 1n Appendix A.
3.5. SUMMARY
Limited data on the level of hexachlorocyclopentadlene 1n the atmosphere
are available. Hexachlorocyclopentadlene was detected at a maximum concen-
tration of 0.10 jig/m* In homes near a- hazardous waste site In Hardeman
County 1n Tennessee and at a maximum concentration of 39 yg/m8 1n area
air samples from a wastewater treatment plant In Memphis, TN that handled
wastewater from a nearby pesticide manufacturing plant (S. Clark et al..
1982; EUa et al., 1983). Hexachlorocyclopentadlene has been detected 1n
ambient surface water (Fielding et al., 1981), In Industrial effluents
(McNahon, 1983) and In drinking water (Benolt and Williams, 1981; Thruston,
1978; Suffet et al., 1980; Kim and Stone, n.d.). The maximum concentrations
of hexachlorocyclopentadlene detected In water were 100 ng/i 1n ambient
surface water from Wheeling, WV (Ohio River Valley Water Sanitation Commis-
sion, 1980) and 650 ng/ft In drinking water from Niagara Falls, NY (Kim and
0077d -17- 04/05/88
-------
Stone, n.d.). Hexachlorocyclopentadlene has been qualitatively Identified
In fish samples taken from water near a pesticide manufacturing plant In
Michigan (Spehar et al.t 1977) and from major watersheds near the Great
Lakes (Kuehl et a!., 1983). No Information regarding the contamination of
foods with hexachlorocyclopentadlene or cases of dermal exposure to
hexachlorocyclopentadlene was located In the available literature cited In
Appendix A.
0077d -18- 12/23/87
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Data concerning the acute toxldty of hexachlorocyclopentadlene to
freshwater species are presented 1n Table 4-1. In studies completed under
static conditions (Buccafusco and LeBlanc, 1977; Vllkas, 1977), 48-hour
LC50 values for Daohnla maqna ranged from 39-52 yg/l, while the
48-hour no effect level ranged from 18-32 yg/l.
Spehar et al. (1977, 1979) reported a 96-hour LC5Q value of 7 yg/l
for fathead minnow larvae In a flowthrough test with measured toxicant
concentrations. Acute toxldty tests In several species of fish have found
96-hour LC_Q values ranging from 59-180 yg/l (Henderson, 1956;
Buccafusco and LeBlanc, 1977; Podowskl and Khan, 1979; Khan et al., 1981).
The results reported by Davis and Hardcastle (1957) for blueglll (25,000
yg/ft) and largemouth bass (20,000 yg/l) are abnormally high, with
values well above the solubility limit of 800-2100 yg/l. These values
may be high as a result of failure to properly disperse the toxicant or to
volatilization of the compound (or both), since the water was aerated during
the study.
Slnhasenl et al. (1982) exposed rainbow trout, Salmo qalrdnerl. to
hexachlorocyclopentadlene at 130 yg/l In a nonredrculatlng flowthrough
chamber. Oxygen consumption, measured polarographlcally. Increased by 195X
within 80 minutes, followed by a gradual decrease until death at -5 hours.
ID. vitro studies In which hexachlorocyclopentadlene was added to normal
trout mitochondria resulted 1n Increased basal oxygen consumption. In a
similar study (Slnhasenl et al., 1983), acclimated rainbow trout were
exposed to hexachlorocyclopentadlene at 130 yg/l 1n a flowthrough well
water circuit designed to permit measurements of oxygen consumption In fish.
0077d -19- 04/05/88
-------
TABLE 4-1
Acute Toilclty Data for Freshwater Species Eiposed to Hexachlorocyclopentadlene*
g
~J
•J
o.
1
o
1
_«
»v
£
00
Species
Cladoceran
Oaphnta imani
Fathead Minnow
(larvae. <0.1 g)
PlMephales proielas
Fathead Minnow (1-1.5 g)
PlMephales proMelas
Fathead Minnow (0.72 g)
PlMephales, proMelas
Goldfish
Carasslus auratus
Channel catfish (2.1 g)
Ictalurus punctatuf
Blueglll (0.45 g)
LeppMls Macrochlrus
Bluegtll (8-13 CM)
LepoMls Macrochlrus
LargeMouth bass (0-13 CM)
Hlcfopterut sa IMP Ides
•Source: U.S. EPA. 1984a
DNiMbers In parentheses are
NR . Not reported; NO • not
Method
s.u
s.u
FT.N
S.U
s.u
NR
S.U
S.U
s.u
s.u
the 95X
24-Hour
93.0
(78.9-109.6)
130
(68-260)
NR
115
93
75
240
(170-320)
NR
190
(140-250)
170
(140-210)
>500.000
>500.000
LC$o (vg/l)D
48-Hour
52. 2
(44.3-60.9)
39
(30-52)
NR
110
78
59
210
(180-250)
NR
ISO
(130-180)
150
(120-180)
30.000
35.000
Acute No-Effect
Concentration CoM»ents
96-Hour (wg/t)
NO
NO
7.0
104
78
59
180
(160-220)
70
97
(81-120)
130
(110-127)
25.000
20.000
•
32
18
3.7
NR
NR
NR
07
NR
56
65
NR
NR
17*C. soft water
22*C. soft water
25*C. soft water
hard water, acetone soln.
soft water, acetone soln.
i hard water, ewlston
(no acetone)
22*C. soft water
no details given
22*C. soft water
22*C. soft water
water aerated during test
water aerated during test
Reference
Vllkas. 1977
Buccafusco and LeBlanc
. 1977
Spehar et al.. 1977. 1979
Henderson. 1956
Buccafusco and LeBlanc
. 1977
Podowskt and Khan. 1979
Buccafusco and LeBlanc
Buccafusco and LeBlanc
Davis and Hardcastle.
Davis and Hardcastle.
. 1977
. 1977
1957
1957
confidence Intervals.
deteralned; S • static;
FT • flowthrough; U • umeasured
concentrations; N • Measured concentrations
-------
Oxygen consumption rates Increased 186% In -84 minutes with decreases until
death at -6.5 hours. Slnhasenl et a "I. (1983) postulated that hexachloro-
cyclopentadlene Intoxication 1n the Intact fish may be due to Increased
oxygen consumption and Impaired oxldatlve ATP synthesis, a result of the
mitochondria! uncoupling action of hexachlorocyclopentadlene.
In a study by Applegate et al. (1957), sea lamprey, rainbow trout and
blueglll were exposed to hexachlorocyclopentadlene at concentrations of 1000
or 5000 ug/l. Death or distress was observed In 0.5-1.0 hours.
Acute toxlclty data for hexachlorocyclopentadlene to saltwater species
are presented In Table 4-2. The least sensitive species was the sediment
dwelling polycheate, Neanthes arenaceodentata. with a 96-hour LC5Q of 371
pg/l. The most sensitive species was the mysld shrimp, Hysldopls bahla.
with a 96-hour LC5Q of & yg/t In a flowthrough test.
Acute toxlclty data In aquatic species for other chlorinated cyclopenta-
dlenes are limited to one study of tetrachlorocylcopentadlene. Loeb and
Kelly (1963) reported that carp force fed tetrachlorocyclopentadlene at 174
and 279 rag/kg showed no effects In 95 minutes. Carp fed a dose of 257 rag/kg
died 1n 4.5 hours.
4.2. CHRONIC EFFECTS
Spehar et al. (1977, 1979) conducted 30-day early life stage flowthrough
toxlclty tests with fathead minnows beginning with 1-day-old larvae. The
96-hour mortality data Indicated a sharp toxlclty threshold, with 94%
survival at 3.7 »g/l, 70% at 7.3 ug/l and 2% at 9.1 wg/l. At
the end of the 30-day exposure period, mortality was only slightly higher
with 90% survival at 3.7 wg/l. 55% at 7.3 vg/t and 0% at 9.1
tig/i. From these results and the determination of a BCF value <11
(Spehar et al., 1979), the authors concluded that hexachlorocyclopentadlene
0077d -21- 12/23/87
-------
TABLE 4-2
Acute Toxlclty Data on Marine Organisms
Exposed to Hexachlorocyc1opentad1enea
Species
Polychaete
Neanthes arenaceodentata
Grass shrimp
Palaemonetes puqlo
Nysld shrimp
Nysldopls bah la
Nysld shrimp
Nvsldopls bah la
Nysld shrimp
Nvsldopls bahla
Plnflsh
Laqodon rhomboldes
Spot
Lelostorous xanthurus
Sheepshead minnow
Cyprlnodon varleqatus
Nethod
S.U
S.U
S.U
FT.U
FT.N
S.U
S.U
S.U
96~?8Jj?l7C5°b
371
(297-484)
42
(36-50)
32
(27-37)
12
(10-13)
7
(6-8)
48
(41-58)
37
(30-42)
45
(34-61)
aSource: U.S. EPA. 1980c. 1984a
b95X confidence Interval
N « Neasured concentrations; S
concentrations
static; FT • flowthrough; U » unmeasured
0077d
-22-
04/05/88
-------
does not bloaccumulate In fish as a result of continuous low-level exposure
to hexachlorocyclopentadlene. The body length and weight of surviving
larvae did not differ from controls at any concentration tested. Based on
these data, Spehar et al. (1977, 1979) concluded that 3.7 yg/l was the
highest concentration of hexachlorocyclopentadlene that produced no adverse
effects on fathead minnow l.arvae.
In a study by U.S. EPA (1981), groups of 40 mysld shrimp (saltwater)
were exposed to hexachlorocyclopentadlene at measured, flowthrough concen-
trations for 28 days. The results are presented In Table 4-3. Mortality
occurred at all concentrations except the control, but there was no
consistent dose-response relationship. A dose-related decrease 1n the
number of offspring per female was observed.
Pertinent data regarding the chronic toxldty of other chlorinated
cyclopentadlenes In aquatic species were not located In the available
literature cited In Appendix A.
4.3. PLANT EFFECTS
The Shell 011 Company (1982) reported a 96-hour EC5Q for the green
algae, Selenastrum caprlcornutus. of 0.19 mg/i. Walsh (1981) reported
unpublished data on the effects of hexachlorocyclopentadlene on four species
of marine algae. The 7-day ECSQ was calculated as the concentration
causing a SOX decrease In blomass compared with the control. Isochrvsls
galbana and Skeletoneroa costatum were the most sensitive species, with 7-day
EC5Q values of 3.5 and 6.6 yg/t, respectively. The 7-day EC5Q
values for Dunallella tertlolecta and Porphyrldlum cruentum were 100 and 30
wg/l, respectively. Walsh (1983) found that after 48 hours of exposure
to hexachlorocyclopentadlene at 25 yg/l, mortality of S. costatum was
only 4%, Indicating that the alglcldal effect of hexachlorocyclopentadlene
was less pronounced then Us effect on growth.
0077d -23- 12/23/87
-------
TABLE 4-3
Effects rf 28 Days Exposure of Mysld Shrimp.
Hvsldops L bahla. to Hexachlorocyclopentad1enea
Concentration
Nominal
Control
0.75
1.5
3.0
6.0
12.0
(ug/t)
Heasured
NO
0.30
0.70
3.0
2.9
6.2
Mortality
(X)
0
18.9
43. 6b
18. 4C
23.1
97. 5b
Total
Offspring
195
167
67
79
72
0
Offspring
per Female
15.7
11.6
5.0b
5.4"
5.5b
Ob
aSource: U.S. EPA. 1981 1984a
Significantly dlffereni Prom the control (p<0.05)
cNo explanation was g1 n 1n original text as to this value In comparison
with the next measured ilue of 2.9
NO - Not detected
0077d .24- 04/05/88
-------
No studies concerning the effects of other chlorinated cyclopentadlenes
on aquatic plants were located.
4.4. SUMMARY
Aquatic toxldty data for the chlorinated cyclopentadlenes are limited
to studies of hexachlorocyclopentadlene. Hexachlorocyclopentadlene 1s
highly toxic to freshwater organisms, with the LC5Q for Daphnla maqna
reported to range from 39-180 yg/l (Buccafusco and LeBlanc, 1977;
Vllkas, 1977). A 30-day study with fathead minnows found that mortality was
only slightly higher than at 96 hours at the same concentration. Indicating
that hexachlorocyclopentadlene 1s not a cumulative toxin (Spehar et al.,
1977, 1979). The only data for a freshwater algae was a 96-hour EC.Q for
Selenastrum capMcornutus of 0.19 mg/i (Shell 011 Company, 1982).
The data for saltwater species are more limited. LCSQ values for
three Invertebrates and three fish species were reported to range from 32-48
yg/9, for all species except the polycheate for which the LC5Q value
was 371 ug/l (U.S. EPA, 1980c). In four species of saltwater algae,
7-day ECfQ values were reported In the range of 3.5-100 i*g/l (Walsh,
1981).
0077d -25- 04/05/88
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
In a comparative study of the pharmacoklnetlcs of 14C-hexachlorocyc1o-
pentadlene In rats after intravenous and oral dosing, Yu and Atallah (1981)
found results Indicating that only a fraction of an oral dose may be
absorbed. After rats were given an Intravenous Injection of 14C-hexa-
chlorocyclopentadlene at 0.25 mg, 20% of the dose was excreted In the feces;
however, after a 3-6 mg oral dose of l4C-hexach1orocydopentad1ene, 72%
was excreted In the feces.
Lawrence and Oorough (1982) examined the uptake, disposition and elimi-
nation of hexachlorocyclopentadlene after Intravenous, Inhalation and oral
routes of exposure. The Investigators noted that 1n order to obtain measur-
able levels of radioactivity 1n the tissues, oral doses (6 mg/kg In corn
oil) 250 times larger than Inhalation doses (24 yg/kg) and 600 times
larger than Intravenous doses (10 yg/kg 1n DMSO or 10:4:1 sallne-.propylene
glycolrethanol) were required. The authors attributed this to the poor
bloavallablllty of hexachlorocyclopentadlene when administered by the oral
route. In the Inhalation studies, rats were exposed to 14C-hexachloro-
cyclopentadlene for 30-120 minutes using respirators, so that they received
doses that ranged from 1.4-37.4 yg/kg. Immediately following exposure, 1t
was found that the rats retained 76.8-95.2% of the dose, with higher
retention at the longer exposure periods.
In a similar comparative study by El Dareer et al. (1983). radioactivity
In the tissues of rats 72 hours after dosing with l4C-hexachlorocyclo-
pentadlene was 39, 11.5 and 2.4X by Intravenous, Inhalation or oral routes
of exposure, respectively. From these results 1t 1s clear that relatively
0077d -26- 04/05/88
-------
low levels of hexachlorocyclopentadlene or metabolites are available for
tissue distribution following oral exposure. This result may be due to low
gastrointestinal absorption of hexachlorocyclopentadlene and metabolites, or
to rapid hepatic metabolism and biliary excretion.
5.2. DISTRIBUTION
Seven days after rats were given single oral doses of 14C-labeled
hexachlorocyclopentadlene by gavage (5 ymol), -0.5X of the radioactivity
was retained In the kidney with <0.5X In the liver (Mehendale, 1977). Fat.
lung, muscle and blood had smaller traces, of radioactivity.
Yu and Atallah (1981) administered single oral doses of 3 or 6 mg
(8.S-25.6 mg/kg) l4C-hexachlorocyclopentad1ene to Sprague-Daw!ey rats.
The l*C-act1v1ty was found 1n the blood shortly after dosing and reached a
maximum 1n -4 hours. Tissues were analyzed for *4C-act1v1ty 8. 24. 48,
72, 96 and 120 hours after dosing. At 24 hours after-dosing, the highest
levels of activity were found In the kidneys and liver with 0.96 and 0.75%
of the dose, respectively.
Rats and mice were treated by gavage with a single dose of 14C-hexa-
chlorocyclopentadlene at 2.5 or 24 mg/kg (Dorough, 1979; Dorough and
Ran1er1, 1984). The animals were killed at 1, 3 and 7 days after dosing,
and samples of muscle, brain, liver, kidney, fat and ovaries or testes were
analyzed for l*C-act1v1ty. The results Indicated that the liver, kidney
and fat were the most significant sites of deposition for 14C-res1dues In
both rats and mice, with levels In the kidneys of rats and livers of mice
being the highest.
Dorough (1979) also examined the distribution of radioactivity In rats
and mice fed l4C-hexachlorocyclopentad1ene 1n the diet at 1, 5 or 25 ppm
0077d -27- 04/06/88
-------
for 30 days. Feed was replaced every 12 hours to minimize the loss of
14C-hexach1orocyclopentad1ene. During the treatment period, rats and mice
were killed at 1, 3, 7, 12, IS and 30 days. The remaining animals were fed
a normal diet and were sacrificed at 1, 3, 7, 15 or 30 days after the last
day of treatment. In all cases, the liver, kidney and fat contained the
highest levels of 14C-label, and steady-state for these levels appeared to
be reached after 15 days of feeding. A good correlation was observed
between the level of hexachlorocyclopentadlene 1n the diet and the
14C-leve1s found In all of the tissues examined.
In a comparative study (Dorough, 1980; Lawrence and Dorough, 1981,
1982), rats were exposed to single doses of l4C-hexachlorocyclopentad1ene
by oral, Inhalation and Intravenous routes. Data regarding distribution of
l4C-act1v1ty following the three routes of exposure are presented 1n Table
5-1. The results showed that 72 hours following oral and Intravenous
exposure, the highest level of l4C-act1v1ty was 1n the kidneys. Following
Inhalation exposure, l4C-act1v1ty was highest In the trachea and lungs.
The kidneys were also a site of accumulation following Inhalation exposure.
In the comparative study by El Dareer et al. (1983), the highest levels
of radioactivity were found 1n the kidneys and liver of rats following oral
and Intravenous dosing with 14C-hexachlorocyclopentad1ene, while radio-
activity levels were highest In the kidneys and lung following Inhalation
exposure. The majority of the radioactivity (>99X) associated with the
tissues could not be extracted with organic solvents.
In. vitro studies Indicate that hexachlorocyclopentadlene readily binds
to biological material. El Dareer et al. (1983) found that within 60
minutes 61.8, 30.2 and 58.6X of the radioactivity from 14C-hexachloro-
cyclopentad1ene could not be extracted from rat liver tissue, plasma and
whole blood, respectively.
0077d -28- 04/05/88
-------
TABLE 5-1
Distribution of Hexachlorocyclopentadlene Equivalents 1n Tissues
and Excreta of Rats 72 Hours After Oral, Inhalation and Intravenous
Exposure to ^C-Hexachlorocyclopentadlene3^*0
Sample
Oral Dose
(6 rag/kg )d
Inhaled Dose
(-24 ,,g/kg}
Intravenous Dose
(10 ,,9/kg)
Trachea
Lungs
Liver
Kidneys
Fat
Remaining carcass
nq/q of Tissue
292 + 170
420 + 250
539 * 72
3272 7 84
311 * 12
63 7 40
107.0 + 65.0
71.5 7 55.2
3.6 7 1.9
29.5 7 20.2
2.8 7 0.4
1.3 7 0.6
3.3 + 1.7
14.9 7 1.1
9.6 7 1.1
22.3 7 0.6
2.3 7 0.2
0.5 + 0.1
Percent of Dose
Whole body
Urine
Feces
Total Recovery
2.8 + 1.1
15.3 + 3.3
63.6 * 8.5
81.7 * 6.7
12.9 * 4.7
33.1 * 4.5
23.1 + 5.7
69.1 + 9.6
31.0 * 7.8
22.1 + 5.7
31.4 * 1.9
84.6 + 4.6
aSources: Dorough, 1980; Lawrence and Dorough, 1982; U.S. EPA, 19865
bOne hexachlorocyclopentadlene equivalent Is defined as the amount of
radlolabel equivalent to one nanograro of hexachlorocyclopentadlene based on
the specific activity of the dosing solution.
CA11 values are the mean+SD of three replicates.
dNote that the oral dose was 250 and 600 times that of the Inhaled and
Intravenous doses, respectively. That was necessary since residues were
not detected In Individual tissues of animals treated orally at doses of
5-25
0077d
-29-
04/05/88
-------
5.3. METABOLISM
Autoradlographs of urine extracts from rats given single doses of
14C-labe1ed hexachlorocyclopentadlene revealed at least four metabolites
(Mehendale, 1977). These metabolites were not Identified or characterized.
Yu and Atallah (1981) found no unchanged hexachlorocyclopenta dlene In
the urine or feces of rats given single oral doses of "C-hexachloro-
cyclopentadlene. Both the urinary and fecal metabolites were charac-
terized as polar, with 11X of the 14C-content soluble In organic solvents
and 32% rendered organo-soluble after acid-catalyzed hydrolysis, suggesting
the formation of metabolic ester-conjugates.
In an in vitro study of the ability of rat liver and fecal homogenates
and gut contents to metabolize hexachlorocyclopentadlene, Yu and Atallah
(1981) found that hexachlorocyclopentadlene was metabolized with half-lives
of 14.2, 1.6 and 10.6 hours, respectively. The addition of mercuric
chloride to the gut contents and fecal homogenate as a bacteMdde resulted
In an Increase 1n half-lives to 17.2 and 6.2 hours, respectively. Denatura-
tlon of the liver homogenate had virtually no effect on the .in vitro
metabolic rate. These results Indicate that gut and fecal flora may have a
major role In the metabolism of hexachlorocyclopentadlene, while the role of
enzyme dependent processes may be limited.
Given the positive results for tetra- and pentachlorocyclopentadlene and
negative results for hexachlorocyclopentadlene 1n mutagenldty assays with
metabolic activation, Gdggelmann et al. (1978) proposed the metabolic
pathway shown In Figure 5-1. In this pathway, tetra- and pentachloroyclo-
pentadlene can be transformed to the reactive tetrachlorocyclopentadlenone.
The additional chlorine atom may hinder the formation of tetrachlorocyclo-
pentadlenone from hexachlorocyclopentadlene.
0077d -30- 04/07/88
-------
Cl Cl
HtiachUr*-
c jc lop*ntaifl«n«
NuclMphilc
Tetr«hlor»-
cyclepcntadicntne
FIGURE 5-1
Proposed Metabolic Formation of Reactive
Tetrachlorocyclopentadlenone from Chlorinated Cyclopentadlenes
Source: Gdggelmann et al., 1978
007 7d
-31-
12/23/87
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5.4. EXCRETION
Rats given single oral doses of 14C-labeled hexachlorocyclopentadlene
(5 ymol) excreted 33% of the dose In the urine and 10% of the dose 1n the
feces 1n 7 days (Nehendale, 1977). About 87% of the dose eliminated In the
urine and 60% of the dose eliminated 1n the feces were excreted In the first
24 hours. Nehendale (1977) suggested that the remaining hexachlorocyclo-
pentadlene was excreted through the lungs. This was later disproved by
Dorough (1979) who found that <1% of an oral dose of 14C-hexachlorocyclo-
pentadlene given to rats was excreted In the lungs. The level of fecal
excretion reported In the Nehendale (1977) study was probably low because
the feces were dried and powdered before analysis. Whltacre (1978) and El
Oareer et al. (1983) reported that hexachlorocyclopentadlene and Us
volatile metabolites can be lost during this kind of preparation.
Yu and Atallah (1981) found that during 120 hours following a 3 or 6 mg
oral dose of l4C-hexachlorocyclopentad1ene, rats excreted -72% of the
radioactivity 1n the feces and -17% 1n the urine.
In a single-dose study, Dorough (1979) found that 73-96% of the radio-
label of l4C-hexachlorocyclopentad1ene was excreted In the urine and feces
of rats and mice given a gavage dose of 2.5 or 25 mg/kg. In rats and mice
fed diets containing 1, 5 or 25 ppm l4C-hexachlorocyclopentad1ene for 30
days 63-79% of the radioactivity was excreted In the urine and feces. In a
separate experiment with male rats. In which the bile duct was cannulated
and a single dose of 25 mg/kg 14C-hexachlorocyclopentad1ene was adminis-
tered orally, only 16% of the dose was excreted 1n the bile.
In a comparative study, Lawrence and Dorough (1982) found that rats
orally dosed with l4C-hexachlorocyclopentad1ene at 6 mg/kg excreted 2-3
0077d -32- 04/05/88
-------
tiroes more of the dose 1n the feces than rats dosed by the Intravenous or
Inhalation routes. Biliary excretion was greater following oral exposure
and accounted for 18% of the dose.
Data regarding excretion of radioactivity following oral. Intravenous
and Inhalation exposure of rats to *4C-hexach1orocyc1opentad1ene are
presented 1n Table 5-2 (El Dareer et al., 1983). This study supports the
observation that little hexachlorocyclopentadlene or Its metabolites Is
excreted 1n the respiratory tract. Following oral and Intravenous exposure,
fecal excretion predominates, while a larger percentage of the radioactivity
Is excreted 1n the urine following Inhalation exposure.
5.5. SUMMARY
Comparative pharmacoklnetlc studies of l4C-hexachlorocyclopentad1ene
have shown higher levels of fecal excretion following oral exposure than for
Intravenous or Inhalation exposure (El Dareer et al., 1983; Lawrence and
Dorough, 1982). Increased elimination of radioactivity following oral expo-
sure 1s consistent with toxldty data which Indicate that hexachlorocyclo-
pentadlene Is more toxic following Inhalation exposure than oral exposure.
Following Inhalation exposure to l4C-hexachlorocyc!opentad1ene,
considerable radlolabel remained In the lung and trachea. Indicating that
hexachlorocyclopentadlene reacts with biological material (Dorough, 1980;
Lawrence and Dorough, 1981, 1982; El Dareer et al., 1983). The low level of
extractable radioactivity from tissues exposed to hexachlorocyclopentadlene
both in vivo and Ui vitro provide further evidence of the high reactivity of
hexachlorocyclopentadlene and Us metabolites or both (El Dareer et al.,
1983). Following oral exposure, the highest levels of hexachlorocyclo-
pentadlene are associated with the kidney and liver.
00774 -33- 04/05/88
-------
§
—j
•4
O.
TABLE 5-2
Distribution of Radioactivity Expressed as Percentage of Administered
Dose from *4C-Hexachlorocyclopentad1ene In Rats Dosed by Various Routes*»D
Feces
Urine
Tissues
C02
Other volatile
TOTAL RECOVERY
Oral Dose
Low Dosec
(4.1 mg/kg)
79.4 * 2.9
35.5 * 2.5
2.4 ± 0.6
0.8 ±0.0
0.2 i 0.0
118.3 * 3. 0^
M
High Dosec
(61 mg/kg)
65.3 i 6.9
28.7 * 4.2
2.4 ± 0.1
0.6 i 0.0
0.3 ± 0.0
97.3 * 7.0
. Intravenous Dose (X)c
(0.59 mg/kg)
34.0 f 1.0e
15.8 ± 1.4
39.0 * 1.0
0.1 ± 0.0
0.1 ± 0.0
89.0 i 2.0
Inhalation
Group Ad
(1.0 mg/kg)
28.7 i 4.3
41.0 ± 4.8
28.9 ± 1.6
1.4 ± 0.3
NR
(100)
Dose (X)
Group Bc
(1.4 mg/kg)
47.5 » 6.4
40.0 ± 6.6
11.5 i 0.8
1.0 ± 0.5
NR
(100)
aSource: El Dareer et al.. 1983; U.S. EPA. 1986b
^The values represent the mean % of dose ± SO for three rats.
cAt 72 hours after dosing or exposure
dAt 6 hours after exposure
ePlus Intestinal contents
an unexplained reason, the total recovery for this dose was higher than theoretical. If the
percent recoveries for this dose are •normalized* to 100X. differences In disposition for the two doses
are minimal, an Indication that no saturable process Is operative In this dose range.
NR * Not reported
-------
The metabolites of hexachlorocyclopentadlene have not been character-
ized. It has been proposed, however, that tetra- and pentachlorocyclo-
pentadlene are metabolized to the reactive tetrachlorocyclopentadlenone
(Goggelmann et al.. 1978). The additional chlorine atom may hinder the
formation of the tetrachlorocyclopentadlenone from hexachlorocyclopentadlene.
Following oral exposure to l4C-hexachlorocyclopentad1ene, the radio-
activity 1s excreted predominantly 1n the feces. Biliary excretion
accounted for -18X of an oral dose (Lawrence and Dorough, 1982). When
compared with oral exposure, higher levels of radioactivity are excreted In
the urine following Inhalation exposure.
0077d -35- 04/06/88
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. • Inhalation Exposures.
6.1.1.1. SUBCHRONIC — Treon et al. (1955) exposed two guinea pigs,
six rabbits, five mice and four rats to hexachlorocyclopentadlene (89.5%
pure) at 0.34 ppm (3.7 mg/raa), 7 hours/day, 5 days/week for up to 25-30
exposures. Both guinea pigs survived 30 exposures, while only two rabbits
survived 30 exposures and no rats or mice survived 5 exposures. Degenera-
tive changes were observed In the brain, heart, liver, adrenal glands and
kidneys with severe pulmonary edema and hyperemla and acute necrotlzlng
bronchitis. The study did not discuss the severity or Incidence of these
effects 1n the various species. Using a lower concentration (0.15 ppm, or
1.7 mg/ma, hexachlorocyclopentadlene), 2/2 guinea pigs, 4/4 rats, 3/3
rabbits and only 1/5 mice survived up to 150 seven-hour exposure periods 5
days/week. Slight renal and hepatic degeneration was noted In all species.
Nice, rats an.d guinea pigs also developed lung lesions. This study differs
from more recent studies (Battelle Northwest Laboratories. 1984; Abdo et
al., 1986), which found no deaths 1n mice exposed to 0.15 ppm, and no
effects 1n rats exposed to 0.15 ppm.
In a NTP sponsored study (Battelle Northwest Laboratories, 1984; Abdo et
al., 1986), groups of 10 F344 rats/sex and 10 B6C3F1 mice/sex were exposed
to hexachlorocyclopentadlene (99.42%) at 0, 0.04, 0.15, 0.4, 1 or 2 ppm (0,
0.45, 1.67, 4.46. 11.1 or 22.3 mg/m*) 6 hours/day, 5 days/week for 13
weeks. Information concerning the mouse study was available only In an
abstract (Abdo et al., 1986). All rats and mice exposed to >1 ppm died,
with 5/10 male and 2/10 female mice dying at 0.4 ppm [the abstract Incor-
rectly stated that mice died at 0.04 ppm rather than 0.4 ppm (Abdo, 1987)].
0077d -36- 04/06/88
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Exposure-related changes In hematology and clinical chemistry changes were
not observed In either rats or mice. Body weight gain was significantly
(p<0.05) reduced 1n male rats at 0.4 ppm; a similar but less severe effect
was observed 1n female rats (Battelle Northwest Laboratories, 1984). At 0.4
ppm, relative lung weights were higher 1n females and significantly (p<0.5)
higher In males. Relative weights of heart, kidney and testes In 0.04 ppm
males were also Increased. Dose-related hlstopathologlcal changes In the
respiratory tract epithelium were observed 1n rats at >0.4 ppm. The changes
observed Included necrosis and acute Inflammation. No effects were observed
In rats at 0.15 ppm.
In mice (Abdo et al., 1986), body weight gains were 10% lower In both
sexes at 0.4 ppm. The only change 1n organ weight was an Increase In
relative lung weights of males exposed to 0.4 ppm. Dose-related hlstopatho-
loglcal alterations In the respiratory epithelium. Including hyperplasla and
metaplasia, were observed In mice at >0.15 ppm. No effects were observed 1n
mice at 0.04 ppm*
In a study by D. Clark et al. (1982), groups of eight male and eight
female Wlstar rats were exposed to hexachlorocyclopentadlene (96X pure) at
nominal concentrations of 0, 0.05, 0.1 or 0.5 ppm (0, 0.56, 1.1 or 5.6
rog/ra8), 6 hours/day, 5 days/week for 30 weeks, followed by a 14-week
recovery period without hexachlorocyclopentadlene exposure. At 0.5 ppm,
four male and two female rats died. In males exposed to 0.5 ppm, depressed
body weight gain relative to controls was observed at 7 weeks of exposure
and persisted through the remainder of the study. In females, body weights
1n the 0.5 and 0.1 ppm groups were significantly Increased compared with
controls during the first half of the exposure period; however, body weights
were significantly (p<0.01) decreased 1n these groups compared with controls
0077d -37- 04/05/88
-------
at the end of the recovery period. At 0.5 ppm, pulmonary degenerative
changes were noted In both sexes, with males affected more severely. N11d
degenerative changes In the liver and kidney were also observed In a few
rats at 0.5 ppm, with kidney weights significantly Increased 1n females.
Changes In organ weights or hlstopathologlcal changes were not observed In
rats exposed to 0.05 or 0.1 ppm hexachlorocyclopentadlene.
Rand et al. (1982a) exposed groups of 40 male and 40 female Sprague-
Dawley rats (160-226 g), and groups of 6 male and 6 female cynomolgus
monkeys (1.5-2.5 kg, average 2.0 kg) to hexachlorocyclopentadlene at 0,
0.01, 0.05 or 0.2 ppm (0, 0.1, 0.6 or 2.2 mg/m3), 6 hours/day, 5 days/week
for up to 14 weeks. No effects were observed In monkeys at any concentra-
tion. Evaluation Included mortality, clinical signs, body weight, pulmonary
function, eye examinations, hematology, clinical chemistry and hlstopatho-
loglc examinations. Male rats In this study had a transient appearance of
dark-red eyes at 0.05 and 0.2 ppm hexachlorocyclopentadlene. There were no
treatment-related changes 1n body wetght gain or food or water consumption.
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 0.2 ppm rats of both sexes. No treatment-
related abnormalities In gross pathology or hlstopathology were observed.
Rand et al. (1982b) examined the Clara cells of the lungs from exposed
monkeys and rats from the study described above, using electron microscopy.
No ultrastructural changes were observed In monkeys. In rats, the examina-
tions showed a dose-related Increase In the Incidence of electron-lucent
Inclusions In the bronchlolar Clara cells. These Increases were statisti-
cally significant (p<0.01) compared with controls at all exposure concentra-
tions. According to Evans et al. (1978), Clara cells respond to Injury by
0077d -38- 04/05/88
-------
regression to a more primitive cell type. Rand et al. (1982b) noted that
some of the ultrastructural changes 1n the exposed rats were similar to
changes described In the Evans et al. (1978) study. The toxlcologlcal
significance of these changes Is not known. The Clara cell contributes
Important materials to the extracellular lining of the peripheral airways,
and If this effect from hexachlorocyclopentadlene vapors causes the content
of the contributed material to be changed, then the extracellular lining may
be altered and breathing may be Impaired (Rand et al., 1982b).
Pertinent data regarding the toxlclty of other chlorinated cyclopenta-
dlenes following subchronlc Inhalation exposure were not located 1n the
available literature cited In Appendix A.
6.1.1.2. CHROMIC — Wang and MacMahon (1979) found a statistically
significant (p<0.05) Increase 1n deaths from cerebrovascular disease among a
group of 1403 males employed at plants producing hexachlorocyclopenta-
dlene. Because the deaths showed no consistent pattern with duration of
employment or- with duration- of follow-up, the- authors suggested that
cerebrovascular disease was not related to exposure.
The NTP Is sponsoring a chronic Inhalation study of hexachlorocyclo-
pentadlene In rats and mice (NTP, 1987).
Pertinent data regarding the toxlclty of other chlorinated cyclopenta-
dlenes were not located In the available literature cited In Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — IBT (1975) fed groups of IS male and 15 female
albino rats hexachlorocyclopentadlene 1n the diet at concentrations of 0.
10V 100 or 300 ppm for 90 days. Treatment began when the rats were 28 days
old. No treatment-related effects on survival, behavior, hematology.
0077d -39- 04/05/88
-------
clinical chemistry or urlnalysls were noted. Gross and hlstopathologlc
examinations of tissues revealed no lesions that could be considered
treatment-related.
In a study by SRI (1981a), which was also reported by Abdo et al.
(1984), groups of 10 male and 10 female B6C3F1 mice were treated by gavage
with hexachlorocyclopentadlene (94.3-97.4% pure) In corn oil at 0. 19, 38.
75, 150 or 300 mg/kg, 5 days/week for 13 weeks. At 300 mg/kg, all male mice
died by day 8 and three female mice died by day 14. A dose-related
depression 1n mean body weight gain was observed, with mice In the 150 and
300 mg/kg groups gaining significantly (p<0.05) less weight than controls.
A significant (p<0.05) Increase In k1dney-to-bra1n and llver-to-braln weight
ratios was observed In females at all doses, with Increases In Iung-to-bra1n
weight also observed In females at 300 mg/kg. Toxic nephrosls was observed
In female mice at doses >75 mg/kg. This effect was not observed In males.
Treatment at >38 mg/kg resulted 1n forestomach lesions. Including alteration
and Inflammatory changes In the epHhella 1n both male'and female mice. No
effects were noted at 19 mg/kg In either male or female mice.
In a similar study (SRI, 1981b; Abdo et al.. 1984). groups of 10 F344
rats/sex were dosed by gavage with hexachlorocyclopentadlene In corn oil at
0, 10, 19. 38. 75 or 150 mg/kg. 5 days/week for 13 weeks. Mortality was
Increased at 150 and 300 mg/kg, with toxic nephrosls observed 1n both sexes
at doses >38 mg/kg. A dose-related depression of body weight gain relative
to controls was noted, with significant (p<0.05) depressions compared with
controls 1n males at 38, 75 and 150 mg/kg and females at 75 and 150 mg/kg.
The 11ver-to-bra1n weight ratios were significantly (p<0.05) Increased 1n
females at >38 mg/kg, and k1dney-to-bra1n ratios were significantly (p<0.05)
Increased 1n females at >75 mg/kg. A dose-related Incidence of forestomach
0077d -40- 04/05/88
-------
les'ions (ulceratlon and Inflammation) was observed beginning at 19 mg/kg 1n
femiile rats and at 38 mg/kg 1n male rats. No effects were observed In
either sex at 10 mg/kg.
Pertinent data regarding the toxldty of other chlorinated cyclopenta-
dlenes following subchronlc oral exposure were not located 1n the available
literature cited In Appendix A.
6.1.2.2. CHRONIC — Pertinent data regarding the toxlclty of the
chlorinated cyclopentadlenes following chronic oral exposure were not
located In the available literature cited 1n Appendix A.
6.1.3. Other Relevant Information. Acute toxldty data for hexachloro-
cyclopentadlene are presented 1n Table 6-1. Reported oral LD5Qs 1n rats
range from 315 and 425 mg/kg In weanling female and male rats (SRI, 1980) to
926 mg/kg In young adult male and female rats (IRDC, 1968). Rand et al.
(19B2a) reported 4-hour Inhalation LC5Qs of 1.6 and 3.5 ppm In male and
female rats, respectively. The acute data Indicate that hexachlorocyclo-
pentadlerie Is Irritating to the eyes and skin (IRDC, 1972; Treon et al.,
1955). No acute data were available for other chlorinated cyclopentadlenes.
In a range-finding study, Litton B1onet1cs (1978a) determined the oral
LD50 of hexachlorocyclopentadlene In CD-I mice to be 76 mg/kg. When the
dose was administered to 24 mice for 5 consecutive days, all the mice died.
SRI (1980) conducted a range-finding study 1n groups of five Fischer
rats/sex. The rats were treated by gavage with hexachlorocyclopentadlene at
25, 50, 100, 200 or 400 mg/kg for 12 doses In 16 days. No deaths occurred
at doses <100 mg/kg. At both 200 and 400 mg/kg, all male and 4/5 female
rats died. In a similar gavage study, using groups of five B6C3F1 mice/sex.
mice treated at 400 and 800 mg/kg died. Nice treated at 50, 100 or 200
mg/kg survived. Pathologic changes of the stomach wall were observed In
both rats and mice at all doses except 25 mg/kg.
0077d -41- 12/23/87
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TABLE 6-1
Acute Toxlclty of Hexachlorocyclopentadlene*
Species, Age
Results
Reference
Rat, young adult
Rabbit, adult
Rat. young adult
Rat. young adult
Mouse, young adult
Rat. weanling
Mouse, weanling
Rabbit, adult
Rabbit, adult
Rat, young adult
Rat, young adult
Rabbit, adult
oral
: males - 510 mg/kg
females - 690 mg/kg
oral 1050: females - 640 mg/kg
oral LD.5Q: males and females -
926 mg/kg
oral 1050: males and females -
651 mg/kg
oral LDsg: males and females -
600 mg/kg
oral 1050: males - 425 mg/kg
females - 315 mg/kg
oral LDSQ: males and females -
680 mg/kg
dermal 1059: females - 780 mg/kg
dermal LD-so,: males - 200 mg/kg
females - 340 mg/kg
3.5-hour Inhalation 1059: males
and females - 3.1 ppra
4-hour Inhalation LCsg: males -
1.6 ppra, females - 3.5 ppm
3.5-hour Inhalation 1053:
females - 5.2 ppm
Treon et al..
1955
Treon et al.,
1955
IROC, 1968
Dorough, 1979
Dorough, 1979
SRI, 1980
SRI, 1980
Treon et al.,
1955
IROC, 1972
Treon et al.,
1955
Rand et al.,
1982a
Treon et al.,
1955
Guinea pig,
young adult
Mouse, adult
3.5-hour Inhalation LCs(
and females - 7.1 ppm
3.5-hour Inhalation LC$(
and females - 2.1 ppm
j: males
j: males
Treon et al.,
1955
Treon et al.,
1955
0077d
-42-
12/23/87
-------
TABLE 6-1 (cont.)
Species, Age Results Reference
Rabbit, adult severe eye Irritant (0.1 ml for IRDC, 1972
5 minutes or 24 hours) all dead by
day 9 of study (primary eye
Irritation study)
Rabbit, adult moderate skin Irritant (250 mg/kg), Treon et al..
one application (primary dermal 1955
Irritation study)
Rabbit, adult severe skin Irritant (200 mg/kg); IROC. 1972
all males died 1n study (primary
dermal Irritation study)
Monkey, adult mild skin discoloration (0.05 ml Treon et al.,
of 10X hexachlorocyclopentadlene 1955
solution) (primary dermal Irritation
study)
*Source: U.S. EPA, 1986b
0077d -43- 04/05/88
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In an Inhalation range finding study (Rand et al., 1982a), groups of 10
male and 10 female Sprague-Dawley rats were exposed to hexachlorocyclopenta-
dlene (97.7X pure) at 0, 0.022, 0.11 or 0.5 ppm (0, 0.25, 1.2 or 5.6
rag/m»), 6 hours/day, 5 days/week for 10 exposures. Four additional groups
of 5 rats/sex were exposed for 5 dally periods and were allowed to recover
for 14 or 21 days following the exposure. Nine male rats and one female rat
exposed to 0.5 ppm were moribund after 5-7 exposures. All females and two
males 1n the recovery group survived 5 exposures and the 21-day recovery
period. At 0.5 ppm, dark red eyes, labored breathing and paleness of the
extremities were observed. A significant (p<0.05) decrease 1n body weight
was observed In males at 0.022 and 0.11 ppm. Body weights were significantly
reduced at day 1 after the exposure at 0.5 ppm In both sexes (p<0.001,
males; p<0.01, females). The packed cell volume, hemoglobin and RBC counts
of rats at 0.5 ppm were significantly higher than controls. The hematology
changes showed some recovery after exposure was ended. No significant
macroscopic or hlstopathologlc changes were observed 1n tissues at 0.022 or
0.11 ppm. At 0.5 ppm, pale areas of consolidation were observed In the
lungs and hlstopathologlc lesions were observed 1n the bronchioles and nasal
passages. These changes were not observed after 14-21 days of recovery.
In humans exposed to hexachlorocyclopentadlene by Inhalation, the most
noticeable effect 1s the pungent. Irritating odor. Levin (1980) reported
that the odor recognition for 100% of the Individuals on the panel was
0.0017 mg/ma (0.00015 ppm). Other than stating that the study was
completed 1n a dynamic chamber, details of the study design were not stated.
In 1977, an acute exposure Incident occurred at the Morris Forman Waste-
water Treatment Plant 1n Louisville. KY (Wilson et al.. 1978; Norse et al.,
0077d -44- 04/05/88
-------
1979; Komlnsky at al., 1980; U.S. EPA, 1984a, 1986b). The Louisville treat-
ment facility was contaminated with large amounts of hexachlorocyclopenta-
dlene and lower levels of octachlorocyclopentene, a waste by-product of
hexachlorocyclopentadlene manufacture (Morse et al., 1979). Concentrations
of hexachlorocyclopentadlene detected In the sewage water at the plant were
as high as 1000 ppm. Airborne levels of hexachlorocyclopentadlene 1n the
primary treatment areas (screen and grit chamber) measured 4 days after the
plant closed ranged between 270 and 970 ppb. During the clean-up, when the
workers used steam to remove the contamination, hexachlorocyclopentadlene
concentrations were reported to be 19.2 ppm (Komlnsky et al.. 1980).
Employees of the plant were given questionnaires regarding the type and
duration of symptoms (Norse et al.. 1979; Komlnsky et al., 1980). A total
of 193 employees were Identified as potentially exposed for >2 days during
the 2 weeks before the plant was closed (Norse et al., 1979). The results
of the questionnaire, completed by 145 (75X) of the workers. Indicated that
the most common symptoms were eye Irritation (59X). headaches (45X) and
throat Irritation (27X). In 9SX of the workers responding to the question-
naire, the odor of hexachlorocyclopentadlene was detected before the onset
of symptoms. Of the 41 workers physically examined, 6 had signs of eye
Irritation and 5 had signs of skin Irritation. Laboratory analyses of blood
and urine specimens from workers given physical exams revealed elevation of
lactic dehydrogenase 1n 27% and protelnurla 1n 15X. No clinical abnormali-
ties were reported 3 weeks later (Norse et al.. 1978, 1979).
During the cleanup, the clinical chemistry parameters of the workers
were monitored. The only abnormalities noted were several minimal-to-mild
abnormalities In liver function tests (SGOT, serum alkaline phosphatase,
serum total blllrubln, serum lactate dehydrogenase). All persons showing
these changes also had physical signs of mucous membrane Irritation.
0077d -45- 04/05/88
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Because these workers used protective equipment during the cleanup and
because of possible prior exposure, exposure levels could not be accurately
estimated (Norse et al., 1979).
6.2. CARCINOGENICITY
6.2.1. Inhalation. A number of mortality studies (Shlndell and
Associates, 1980, 1981; Wang and MacHahon, 1979; Buncher et al., 1980) have
not shown Increased cancer death rates 1n workers Involved In the produc-
tion of hexachlorocyclopentadlene. These studies are reviewed In U.S. EPA
(1984a. 19865).
An NTP Inhalation care1nogen1city bloassay of hexachlorocyclopentadlene
1n rats and mice Is 1n progress (NTP, 1987).
Pertinent data regarding the cardnogenlclty of the other chlorinated
cyclopentadlenes following Inhalation exposure were not located 1n the
available literature cited In Appendix A.
6.2.2. Oral. Pertinent data regarding the cardnogenlclty of the chlori-
nated cylcopentadlenes following oral exposure were not located In the.
available literaturedted 1n Appendix A. A chronic oral toxlclty study of
hexachlorocyclopentadlene being conducted by SRI for the NTP was terminated
1n April, 1982 because Inhalation was determined to be the more relevant
route of exposure (U.S. EPA, 1986b).
6.2.3. Other Relevant Information. Pertinent data regarding the carcino-
gen 1c1ty of the chlorinated cyclopentadlenes following other routes of
exposure were not located In the available literature cited In Appendix A.
6.3. MUTAGENICITY
In vitro and jn, vivo mutagen1c1ty data for the chlorinated cyclopenta-
dlenes are presented In Table 6-2. Negative results for hexachlorocyclo-
pentadlene have been reported 1n mutagenlclty assays 1n bacteria (Goggelmann
0077d -46- 04/05/88
-------
TABLE 6-2
Hutagentclty Testing of Chlorinated Cyclopentadlenes
I
fj
fO
ro
Assay
Reverse
autatlon
Reverse
autatlon
Reverse
autatlon
Reverse
autatlon
Reverse
autatlon
Reverse
autatlon
Reverse
autatlon
Indicator/
Organlsa
Escherlchla
coll k12
i. coll k12
I. colt k!2
Salaonella
typhlaurlua
TA1535.
TA1538
J. typhlaurlua
TA1535. TA1538
§. typhlaurlua
TA100
f. typhtaurlua,
A98. TA100.
1A1S35, TA1S37
Coapound
and/or
Purity
hexacnloro-
cyclopenta-
dtene/gas-
chroaato-
graphlcally
pure
pentachloro-
cyclopenta-
dlene/gas-
chroaato-
graphlcally
pure
tetrachloro-
cyclopenta-
dlene/gas-
chroaato-
graphlcally
pure
hexachloro-
cyclopenta-
dlene
tetracbloro-
cyclopenta-
dlene
hexachloro-
cyclopenta-
dlene
hexachloro-
cyclopenta-
dtene/9BX
Application
prelncuba-
batlon
prelncuba-
batlon
pretncuba-
batlon
MR
MR
vapor
prelncuba-
tlon
Concentration Activating
or Dose Systea
2. 7x10" * - i aouse liver
2.7xlO~* H alcrosoaal
protein
2.4xlO"» - » aouse liver
2.4xlO~* N atcrosoaal
protein
1.0x10"" - i aouse liver
1.0x10~» N atcrosoaal
protein
MR » aouse liver
alcrosoaal
protein
MR • » aouse liver
alcrosoaal
protein
MR »S-9
3.3 pg/plate -S-9
100 |ig/plate »S-9
Response Coanent
• 70X survival at 72 hours.
cytotoxtc at higher
concentrations
i Positive results with.
but not without aeta-
bollc activation
i Positive results with.
but not without aeta-
bollc activation
NC
» NC
• Exposure tlaes of 30. 60
and 120 atnutes were used
which Bay not have been
long enough to observe
a autagenlc effect.
Higher levels could not
be tested due to cyto-
toxtctty.
Reference
Gfiggelaann
et al.. 1978
Gflggelaann
et al.. 1978
GOggelaann
et al.. 1978
Greta
et al.. 1977
Greta
et al.. 1977
IBT. 1977
Haworth
et al.. 1983
-------
TABLE 6-2 (cont.)
1
a.
h
Assay
forward
mutation
OKA repair
Cell trans-
formation
Sex-linked
recessive
lethal
Dominant
lethal
Indicator/
Organism
mouse lymphoma
U178Y cells
rat primary
hepatocytes
IALI/3T3
cells
Drosophlla
melanooaster
CD-I mice
Compound
and/or
Purity
hexachloro-
cyclopenta-
dlene
hexachloro-
cyclopenta-
dlene
hexachloro-
cyclopenta-
dlene
hexachloro-
cyclopenta-
dlene
hexachloro-
cyclopenta-
dlene
Application
added to
cultures
added to
cultures
added to
cultures
feeding
Injection
gavage.
S days
Concentration Activating
or Dose System
1.25xlO~* »S-9
t>9/tt
10~« - NA
10'« N
0-0. 156 nt/iil
40 ppm NA
200 ppm
i
0.1. 0.3 or NA
l.Omg/kg/day
Response Comment
Cytotoxlclty was ob-
served at higher con-
centrations.
NC
Doses selected allowed
80-100X survival.
NC
Nice were mated for
7 weeks.
Reference
Litton
Blonetlcs.
Inc.. 1978b
Brat. 1983
Litton
Blonetlcs.
Inc.. 1977
Juodelka,
1983
Litton
Blonetlcs.
lnc.,1978a
NA . Not applicable; NC . no conwnt; NR - not reported
-------
et al.. 1978; Greta et al.. 1977; IBT. 1977; Haworth et al.. 1983) and 1n a
mutation assay 1n mouse lymphoma cells (Litton B1onet1cs, Inc., 1978b).
Hexachlorocyclopentadlene also tested negative for cell transformation 1n
BALB/3T3 cells (LHton B1onet1cs, Inc., 1977). DNA repair In rat primary
hepatocytes (Brat, 1983), sex-1Inked recessive lethal mutations 1n Droso-
phlla melanoqaster (Juodelka, 1983) and a dominant lethal mutation study 1n
mice (LHton Blonetlcs, Inc.. 1978b).
Studies of penta- and tetrachlorocyclopentadlene In bacteria (Gdggelmann
et al.. 1978; Grelra et al.. 1977) have reported positive results for reverse
mutation In the presence of metabolic activation. Gdggelmann et al. (1978)
suggested that penta- and tetrachlorocyclopentadlene can be metabolized to
tetrachlorocyclopentadlenone, which can react with nucleophlles. The addi-
tional chlorine atom on hexachlorocyclopentadlene may hinder the formation
of the dlenone, preventing mutagenlc activity.
6.4. TERATOGENICITY
•* * * • •» ,
In a teratogenlclty study, pregnant Charles River CO rats were treated
by gavage with hexachlorocyclopentadlene (98.25% pure) In corn oil at 3, 10
or 30 rag/kg on gestation days 6-15 (IROC. 1978; Root et al., 1983). A
control group was treated with corn oil at a volume of 10 mi/kg/day. All
rats survived, with no differences 1n maternal body weight gain observed.
Persistent anogenltal staining was observed 1n dams at the highest dose. No
differences 1n the number of Implantations, corpora lutea, live fetuses,
mean fetal body weight or male/female sex ratios were observed. Examina-
tions of fetuses revealed no statistically significant differences In the
number of external, soft tissue or skeletal abnormalities.
In an Yn vivo teratology screening study of hexachlorocyclopentadlene In
pregnant CD-I mice, no effects were noted on maternal weight gain, pup
0077d -49- 04/05/88
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survival or average pup weight (Chernoff and Kavlock. 1982). The pregnant
mice were treated by gavage with hexachlorocyclopentadlene at 45 rag/kg on
gestation days 8-12. Gray and Kavlock (1984) studied these offspring
further and found no effects on growth, morphology, locomotor function or
reproductive function. Gray et al. (1986) observed no effect on figure-
eight maze activity In these offspring.
Hurray et al. (1980) treated pregnant CF-1 mice and New Zealand WhHe
rabbits by gavage with hexachlorocyclopentadlene In cottonseed oil at 0, 5,
25 or 75 rag/kg/day. Nice were treated on gestation days 6-15 and sacrificed
on day 18, while rabbits were treated on gestation days 6-18 and sacrificed
on day 29. The fetuses (23-33 litters/group, rats; 12-24 Utters/group,
rabbits) were weighed, measured and examined for external alterations.
One-third of the fetuses were examined for soft tissue abnormalities, with
all the fetuses cleaned and stained for skeletal examinations. No signs of
maternal toxldty were observed In mice. Rabbits treated at 75 mg/kg/day
had diarrhea and significant weight loss and several (number unspecified)
died. No significant effects on the average number of Implantations, live
fetuses, resorptlons, or mean fetal body weight and length were noted In
either species. No Increases In gross or soft tissue abnormalities were
observed. The proportion of rabbit fetuses with 13 ribs was Increased at 75
mg/kg/day. No other significant Increases In skeletal variations were
observed In either species.
Pertinent data regarding teratogenlc effects for other chlorinated
cyclopentadlenes were not located In the available literature cited 1n
Appendix A.
0077d -50- 12/23/87
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6.5. OTHER REPRODUCTIVE EFFECTS
No evidence of a dominant lethal effect was observed In male CD-I mice
given hexachlorocyclopentadlene by gavage at 0.1, 0.3 or 1.0 mg/kg for 5
days (LUton B1onet1cs( Inc., 1978a). The mice were mated throughout
spermatogenesls (7 weeks).
Pertinent data regarding other reproductive effects for other chlori-
nated cyclopentadlenes were not located In the available literature cited 1n
Appendix A.
6.6. SUMMARY
Except for mutagenldty assays of penta- and tetrachlorocyclopentadlene,
toxldty data are limited to studies concerning hexachlorocyclopentadlene.
Subchronlc Inhalation studies of hexachlorocyclopentadlene have shown a
steep dose-response curve. In a 6- to 30-week study by Treon et al. (1955),
rabbits, mice and rats exposed to 0.34 ppm hexachlorocyclopentadlene by
Inhalation 7 hours/day, 5 days/week at 0.34 ppm died, while guinea pigs
survived. At 0.15 ppm, only the mice died. Renal and hepatic degeneration
was observed In all species, and lung lesions were noted In mice, rats and
guinea pigs.
0. Clark et al. (1982) reported that rats exposed by Inhalation to 0.5
ppm hexachlorocyclopentadlene died; no significant treatment-related effects
were observed at 0.1 ppm. The rats were exposed 6 hours/day, 5 days/week
for 30 weeks followed by a 14-week recovery period. In a 13-week study by
Rand et al. (1982a,b), no effects were observed 1n monkeys exposed by
Inhalation to hexachlorocyclopentadlene at 0.01, 0.05, or 0.2 ppm, 6
hours/day, 5 days/week. In rats exposed at the same hexachlorocyclopenta-
dlene concentration, the only consistent treatment-related effect was ultra-
structural changes In the Clara cells of the lungs.
0077d -51- 04/05/88
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A 13-week study using rats and mice sponsored by the NTP (Battelle
North- west Laboratories, 1984; Abdo et al., 1986) found no effects In mice
at 0.04 ppro and 1n rats at 0.15 ppm. Nice exposed to
hexachlorocyclopentadlene at >0.15 ppm developed lung lesions, with deaths
occurring at >0.4 ppm. Lung lesions were observed 1n rats at >0.4 ppro, with
deaths at >1 ppm. The animals were exposed 6 hours/day, 5 days/week. A
chronic Inhalation study using rats and mice Is In progress (NTP, 1987).
A 13-week gavage study using rats and mice (SRI, 1981a; Abdo et al..
1984) found ulceratlon of the stomach 1n mice treated 5 days/week at >38
rag/kg, and at >19 mg/kg In rats. No effects were observed In mice at 19
mg/kg or In rats at 10 mg/kg. No effects were reported 1n rats fed
hexachlorocyclo- pentadlene 1n the diet at up to 300 ppm for 90 days (IBT,
1975).
The lowest oral LD5Q Is 315 mg/kg 1n female weanling rats (SRI,
1981a). The lowest Inhalation LC.Q reported Is 1.6 ppm In young adult
male rats (Rand et al., I982a). A short-term Inhalation study using rats at
0.5 ppm (Rand et al., 1982a) found that lung lesions observed when rats were
exposed for five 6-hour periods were not present after 14-21 days of
recovery.
The odor recognition concentration for hexachlorocyclopentadlene was
reported to be 0.0017 rag/m* (Levin, 1980). Questionnaires completed by
workers at the Morris Forman Wastewater Treatment Plant In Louisville, KY,
where an acute exposure Incident occurred. Indicated that 95X of the
respondents detected the odor of hexachlorocyclopentadlene before symptoms
of Irritation occurred (Norse et al., 1978, 1979).
NortalHy studies of hexachlorocyclopentadlene production workers have
not shown Increased cancer death rates. No animal studies of the carcino-
gen 1c1ty of hexachlorocyclopentadlene were available.
0077d -52- 04/05/88
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Results of mutagenldty assays of penta- and tetrachlorocyclopentadlene
1n bacteria have been positive (Goggelmann et a1.( 1978; Grelm et al.,
1977); however, hexachlorocyclopentadlene has consistently tested negative
1n mutagenlcUy assays.
Oral teratogenldty studies of hexachlorocyclopentadlene using rats
(IROC, 1978), mice and rabbits (Murray et al., 1980) have reported negative
results, although an Increase In skeletal anomalies was observed at 75
mg/kg/day, a dose that also resulted 1n maternal toxldty. Hexachlorocyclo-
pentadlene has also tested negative for dominant lethal effects In mice
(Litton Blonetlcs, Inc., 1978a).
0077d -53- 04/05/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
Hexachlorocyclopentadlene 1s the only chlorinated cyclopentadlene for
which guidelines and standards have been developed. ACGIH (1986) has
recommended a TLV-TWA of 0.01 ppra (0.1 mg/ma) for persons occupatlonally
exposed to hexachlorocyclopentadlene. NIOSH (1978) has classified hexa-
chlorocylopentadlene as a Group II pesticide. Standards based on engineer-
Ing controls, work practices and medical surveillance programs have been
recommended to protect workers (NIOSH, 1978).
An RQ of 10 pounds has been proposed for hexachlorocyclopentadlene (U.S.
EPA, 1987b). The ambient water quality criteria for hexachlorocyclo-
pentadlene to protect human health Is 206 vg/l. Using organoleptlc data
for controlling undesirable taste and odor, the estimated level 1s 1
tig/ft (U.S. EPA. 198Gb). U.S. EPA (1988a) has recommended the following
HAs for hexachlorocyclopentadlene: 1-day HA for a child. 1.5 mg/l; 10-day
HA for a child, 0.179 rag/l; longer-term health advisory 0.25 mg/l and
the lifetime DUEL. 0.25 mg/l. An RfO of 0.007 mg/kg/day for
hexachlorocyclopentadlene has been verified and 1s available on IRIS (U.S.
EPA, 1988b).
7.2. AQUATIC
U.S. EPA (1980b) stated that acute and chronic toxlclty to freshwater
aquatic life occur at hexachlorocyclopentadlene concentrations as low as 7.0
and 5.2 yg/l, respectively, and would occur at lower concentrations
among more sensitive species. The limited data for acute hexachlorocyclo-
pentadlene toxlclty to saltwater species Indicate that effects occur at
0077d -54- 04/05/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of the
chlorinated cyclopentadlenes following Inhalation exposure were not located
In the available literature cited 1n Appendix A. An Inhalation carclnogen-
Iclty bloassay of hexachlorocyclopentadlene 1s In progress (NTP, 1987).
8.1.2. Oral. A number of mortality studies (Shlndell and Associates,
1980, 1981; Wang and MacMahon, 1979; Buncher et al., 1980) have not shown
Increased cancer death rates 1n workers Involved In the production of
hexachlorocyclopentadlene. Animal studies regarding the cardnogenlclty of
chlorinated cyclopentadlenes following oral exposure were not located In the
available literature cited In Appendix A.
8.1.3. Other Routes. Pertinent data regarding the cardnogenlclty of the
chlorinated cyclopentadlenes following other routes of exposure were not
located In the available literature cited In Appendix A.
8.T..4. Weight of Evidence. No reports of cardnogenlclty of hexachloro-
cyclopentadlene or the other chlorinated cyclopentadlenes were located 1n
the available literature. Applying the criteria of the Carcinogen Assess-
ment Group (U.S. EPA, 1986b). the chlorinated cyclopentadlenes can be
considered Group D - not classified compounds.
8.1.5. Quantitative Risk Estimates. The lack of cardnogenlclty data for
the chlorinated cyclopentadlenes precludes the derivation of potency factors.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposures.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Inhalation
exposure to hexachlorocyclopentadlene 1s very Irritating and the compound
has a pungent 'odor. ACGIH (1986) stated that "once hexachlorocyclopenta-
dlene has been smelled the odor Is unmistakable and Us lacrlmatory activity
0077d -56- 04/05/88
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Is not conducive to prolonged Inhalation." To prevent Irritation, any
recommended Inhalation RfO should be below the dose resulting from
continuous exposure at the odor threshold. Levins (1980) reported that the
hexachlorocyclopentadlene odor recognition for 100X of the Individuals on a
panel was 0.0017 mg/ma (0.00015 ppm). Multiplying the 0.0017 mg/ma
concentration by 20 mVday, the human breathing rate, and dividing by a
human body weight of 70 kg, a dose of 0.0005 mg/kg/day Is calculated.
During an acute exposure Incident at the Morris Forman Wastewater Treat-
ment Plant In Louisville, KY (Morse et al.. 1978. 1979) It was found that
the majority of workers detected the odor of hexachlorocyclopentadlene
before the onset of symptoms of Irritation, providing support that a dose at
or below the hexachlorocyclopentadlene odor threshold should prevent Irrita-
tion. Human data do not Indicate 1f exposure at or below the odor threshold
will prevent subchronlc or chronic effects.
Treon et al. (1955) exposed guinea pigs, rabbits, mice and rats to hexa-
chlorocyclopentadlene at 0.15 or 0.34 ppm, 7 hours/day, 5 days/week for up
to 150 exposure periods. At 0.34 ppm, deaths occurred In all species except
guinea pigs, with degenerative changes.In major organs. At 0.15 ppm, deaths
occurred only In mice. Slight renal and hepatic degeneration was observed
1n all species, with lung lesions also reported In mice, rats and guinea
pigs. Because only 2-6 animals per species were studied at each exposure
concentration, this study 1s not considered adequate for risk assessment.
In a study by Rand et al. (1982a), groups of 40 rats/sex and 6 cynomol-
gus monkeys/sex were exposed to hexachlorocyclopentadlene at 0, 0.1, 0.6 or
2.2 mg/ra3 (0. 0.01, 0.05 or 0.2 ppm), 6 hours/day, 5 days/week for up to
14 weeks. No effects were observed In monkeys. In rats, transient appear-
ance of dark-red eyes was observed In males at 0.6 and 2.2 mg/m» (Rand et
0077d -57- 12/23/87
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al.,, 1982a). At 12 weeks, marginal changes In hemoglobin were observed In
males at 0.1 mg/m8 and 1n females at 0.6 and 2.2 mg/ma. No treatment-
related changes 1n body weight, food and water consumption, and gross and
hlstopathology were observed. Electron microscopy revealed ultrastructural
changes In the Clara cells In rats at all exposure concentrations, with no
effects 1n monkeys (Rand et al., 1982b). The lexicological significance of
this effect 1s not known.
U.S. EPA (1984b) considered the 2.2 mg/ma exposure concentration In
the Rand et al. (1982a) study to be a NOAEL In both rats and monkeys and
calculated a subchronlc Inhalation RfO based on monkeys. U.S. EPA (1984b)
did not state why the rat data were not, used for RfD derivation. Because
subsequent subchronlc studies have reported effects In rats and mice at
lower concentrations, a new subchronlc Inhalation RfO will be derived.
0. Clark et al. (1982) exposed groups of eight rats/sex to hexachloro-
cyclopentadlene at 0, 0.56, 1.1 or 5.6 mg/m3 (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
without hexachlorocyclopentadlene exposure. At 5.6 mg/m8, four male and
two female rats died, weight gain was depressed 1n males and pulmonary
degenerative changes were noted In both sexes. H1ld degenerative changes 1n
the liver and kidney were also observed In a few rats at 5.6 mg/m8 and
kidney weights Increased significantly In females. In female rats at 5.6
and 1.1 mg/m8, significantly Increased body weights were noted during the
first half of the exposure period, followed by significantly decreased body
weights compared with controls at the end of the recovery period. Because
these body weight gains were transient, they are not clearly related to
hexachlorocyclopentadlene treatment. The LOAEL Identified 1n this study was
0077d -58- 04/05/88
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5.6 rog/ma, a concentration associated with death. Nultlplylng the 5.6
mg/m8 concentration by 6/24 hours and 5/7 days to expand to continuous
exposure, and multiplying by a reference rat breathing rate of 0.223
m'/day and dividing by the reference rat body weight of 0.35 kg (U.S. EPA.
1985), results 1n a LOAEL dose of 0.64 mg/kg/day. Although the D. Clark et
al. (1982) Is study Is the longest duration Inhalation study of hexachloro-
cyclopentadlene available, the NTP-sponsored 13-week study using rats and
mice (Battelle Northwest Laboratories, 1984; Abdo et al., 1986) described
below. Identified lower Inhalation LOAELs; therefore, the NTP study Is a
better basis for a subchronlc Inhalation RfO.
In the NTP-sponsored study (Battelle Northwest Laboratories, 1984; Abdo,
et al., 1986), groups of 10 rats/sex and 10 mice/sex were exposed to hexa-
chlorocyclopentadlene at 0, 0.45, 1.67, 4.46, 11.1 or 22.3 mg/m3 (0. 0.04,
0.15, 0.4, 1 or 2 ppm), 6 hours/day, 5 days/week for 13 weeks. Information
concerning the mouse study was available only In an abstract (Abdo et al.,
1986). All rats and mice exposed to >11.1 mg/m8 died. In rats (Battelle
Northwest Laboratories. 1984), body weight gain was significantly (p<0.05)
reduced 1n males at 4.46 mg/m3; a similar but less severe effect was
observed 1n females. At 0.4 ppm, relative lung weights were higher In
females and significantly (p<0.5) higher 1n males. Relative weights of
heart, kidney and testes In 4.46 rog/ra8 males were also Increased. Dose-
related hlstopathologlcal changes In the respiratory tract epithelium were
observed In rats at >4.46 mg/m8. The changes observed Included necrosis
and acute Inflammation. No effects were observed 1n rats at 1.67 mg/m8.
Multiplying the LOAEL (4.46 mg/m8) and NOAEL (1.67 mg/m8) concentrations
by 6/24 hours and 5/7 days to expand to continuous exposure, and multiplying
by the Inhalation rate of 0.16 mVday calculated by methodology described
0077d -59- 04/05/88
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1n U.S. EPA (1985) from the rat body weight estimated from growth curves,
and dividing by the estimated rat body weight of 0.22 kg, LOAEL and NOAEL
doses of 0.6 and 0.2 mg/kg/day, respectively, are derived.
In mice (Abdo et al., 1986), 5/10 male and 2/10 females died at 4.46
mg/ma, and body weight gains were 10% lower In both sexes at this
concentration. The only change In organ weight was an Increase In relative
lung weights of males exposed to 4.46 mg/ma. Dose-related
h1stopatho1og1ca1 alterations 1n the respiratory epithelium. Including
hyperplasla and metaplasia, were observed 1n mice at >1.67 mg/ma. No
effects were observed In mice at 0.45 mg/m». Multiplying the LOAEL (1.67
mg/m3) and NOAEL (0.45 mg/m3) concentrations by 6/24 hours and 5/7 days
to expand to continuous exposure, multiplying by the reference mouse
Inhalation rate (0.039 mVday) and dividing by the reference mouse body
weight (0.03 kg) (U.S. EPA, 1985) yields LOAEL and NOAEL doses of 0.39 and
0.2 mg/kg/day, respectively.
The lowest LOAEL 1n the NTP-sponsored subchronic studies 1s 0.39
mg/kg/day, a dose at which hyperplasla and metaplasia of the respiratory
epithelium were observed In mice. The highest NOAEL below the mouse LOAEL
1s the rat NOAEL of 0.2 mg/kg/day. Application of an uncertainty factor of
100 (10 for Interspedes extrapolation and 10 to protect sensitive Indi-
viduals) and a modifying factor of 10 results 1n a subchronic Inhalation RfD
of 0.0002 mg/kg/day or 0.014 mg/day for a 70 kg human. The modifying factor
1s used because of the steep dose-response curve Indicated 1n the 0. Clark
et al. (1982) and the NTP-sponsored study (Battelle Northwest Laboratories,
1984; Abdo et al., 1986). The modifying factor also brings the RfD below
the dose that may be associated with Irritation at the odor threshold.
0077d -60- 04/05/88
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Multiplying the 0.0002 rag/kg/day RfD by 70 kg body weight, and dividing by
20 mVday human breathing rate, the subchronlc RfD for hexachlorocyclo-
pentadlene corresponds to a air concentration of 0.0007 mg/m8.
Confidence In the RfD Is medium. Several studies Indicated that the
lungs are the target of Inhalation exposure to hexachlorocyclopentadlene.
These studies also Indicated that the dose-response curve Is very steep.
Acute human data and the odor threshold also Indicate that the subchronlc
Inhalation RfD should protect against Irritation.
A lack of pertinent data regarding the subchronlc Inhalation toxldty of
the other chlorinated cyclopentadlenes precludes the derivation of sub-
chronic Inhalation RfDs.
8.2.1.2. CHRONIC EXPOSURES — There are no chronic Inhalation studies
of hexachlorocyclopentadlene. An NTP chronic bloassay Is In progress (NTP.
1987). U.S. EPA (1984b) considered the 30-week D. Clark et al. (1982) study
(see Section 8.2.1.1.) to be a chronic study. The 0.1 ppm (1.1 mg/m3)
concentration, a level at which the only effect was an Increase In body
weight 1n females during treatment followed by a decrease during the
recovery period, was considered the LOAEL. A chronic Inhalation RfD of
0.00006 rag/kg/day or 0.0046 mg/day was calculated from 0.05 ppm (0.56
mg/m*), the lowest concentration tested (NOAEL). using a rat breathing
rate of 0.26 raVday, a rat body weight of 0.35 kg, an uncertainty factor
of 100 (10 for Interspecles extrapolation, 10 to protect sensitive
Individuals) and a modifying factor of 10 to reflect concern about
discrepancies In the data base. Because the 0.1 ppm concentration should be
considered a NOAEL rather than a LOAEL (weight changes were transient and
not clearly treatment-related), and because the 13-week mouse study (Abdo et
al., 1986) Identifies a lower LOAEL, the mouse study 1s a better basis for a
0077d -61- 04/05/88
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chronic Inhalation RfD. Application of an additional uncertainty factor of
10 to the subchronlc Inhalation RfD results 1n a chronic RfD of 0.00002
rog/kg/day (0.0014 rag/day), or a concentration of 0.00007 mg/m».
As stated for the subchronlc Inhalation RfD for hexachlorocyclopenta-
dlene, confidence 1n the chronic Inhalation RfD Is medium. The chronic RfD
should be reviewed when the chronic NTP study 1s available. Because Irrita-
tion and lung lesions are the major effects of Inhalation exposure to
hexachlorocyclopentadlene, an additional uncertainty factor to extrapolate
from subchronlc to chronic exposure may not be necessary.
A lack of pertinent data regarding the chronic Inhalation toxlclty of
the other chlorinated cyclopentadlenes precludes the derivation of chronic
Inhalation RfDs.
8.2.2. Oral Exposures.
8.2.2.1. LESS THAN LIFETIME EXPOSURES — The only subchronlc oral
study available Is the gavage study using rats and mice completed by SRI
(1981a) and reported 1n Abdo et al. (1984). In this study, groups of 10
B6C3F1 mice/sex were treated by gavage with hexachlorocyclopentadlene In
corn oil at 0, 19. 38. 75. 150 or 300 mg/kg, and similar groups of F344 rats
were treated at 0. 10, 19. 38. 75 or 150 mg/kg. Both species were treated 5
days/week for 13 weeks. Nice treated at 300 mg/kg died, and body weight
gain was significantly depressed at 150 mg/kg. Toxic nephrosls was observed
In female mice at doses >75 mg/kg, but this effect was not observed 1n
males. Treatment at >38 mg/kg resulted In forestomach lesions. Including
ulceratlon In both male and female mice. The NOAEL for both male and female
mice was 19 mg/kg.
0077d -62- 04/05/88
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In rats, mortality and toxic nephrosls were observed In males and
females at doses >38 rag/kg. A dose-related depression of body weight gain
relative to controls was noted, with significant (p<0.05) depressions
compared with controls In male rats at 38, 75 and ISO rag/kg and female rats
at 75 and ISO rag/kg. At 19 rag/kg, the LOAEL, forestomach lesions were
observed 1n female but not male rats. The 10 mg/kg dose level was a NOAEL
In both male and female rats.
Because stomach lesions were observed In female rats at 19 mg/kg, a
NOAEL dose 1n mice, the rat NOAEL of 10 mg/kg Is the most appropriate basis
for a subchronlc oral RfO. Expanding this dose to dally exposure by
multiplying by 5/7 days results In a dose of 7 mg/kg/day. Application of an
uncertainty factor of 100, 10 to protect sensitive Individuals and 10 to
extrapolate from animals to humans, results In a subchronlc oral RfD of 0.07
mg/kg/day or 5 mg/day for a 70 kg human. Confidence In this RfD Is low
because of the lack of additional oral studies.
A lack of pertinent data regarding the subchronlc oral toxlclty of the
other chlorinated cyclopentadlenes precludes the derivation of subchronlc
oral RfOs.
8.2.2.2. CHRONIC EXPOSURES — There are no chronic oral studies of
hexachlorocyclopentadlene. A chronic oral RfO of 0.007 mg/kg/day or 0.5
mg/day for a 70 kg human may be derived by dividing the subchronlc oral
NOAEL by an additional uncertainty factor of 10 to extrapolate from sub-
chronic to chronic exposure. This RfD was verified by the EPA RfD Working
Group on October 9, 1986 and 1s available on IRIS (U.S. EPA, 1988b).
Because supporting oral data are not available, confidence 1n this RfD Is
low.
A lack of pertinent data regarding the chronic oral toxlclty of other
chlorinated cyclopentadlenes precludes the derivation of chronic oral RfDs.
0077d -63- 04/05/88
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9. REPORTABLE QUANTITIES
9.1,. BASED ON SYSTEMIC TOXICITY
The toxldty of hexachlorocyclopentadlene was discussed In Chapter 6 and
the data useful for RQ derivation are summarized 1n Table 9-1. The data
clearly Indicate that hexachlorocyclopentadlene Is more toxic following
Inhalation than oral exposure, with death occurring In rats at a dose as low
as 0.64 mg/kg/day via Inhalation (D. Clark et al., 1982} and at 107.1 mg/kg
(SRI, 1981a; Abdo et al., 1984} by oral exposure. Although the Treon et al.
(1955).study has been used for the derivation of a CS (U.S. EPA, 1984b), It
Is not presented 1n Table 9-1 and Is not being considered for the deriva-
tion of an RQ because only 2-6 animals of each species were exposed, and
better studies are now available.
The derivations of CSs for hexachlorocyclopentadlene are presented 1n
Table 9-2. Because effects following oral exposure occur at much higher
doses than following Inhalation exposure, the 13-week oral gavage study
(SRI, 1981 a; Abdo et al., 1984) 1s not considered for the derivation of an
RQ. The highest CS (59) Is calculated from the NTP-sponsored 13-week
Inhalation study using mice (Abdo et al., 1986) 1n which death occurred at
0.4 ppm, 6 hours/day, 5 days/week (a transformed animal dose of 1.04
mg/kg/day). The chronic human NED of 0.56 nig/day corresponds to an RV. of
5.9. while death corresponds to an RVg of 10.
A CS of 59 corresponds to an RQ of 10 pounds. This RQ Is presented In
Table 9-3. Table 9-4 Indicates that data were not available for the deriva-
tion of RQs for the other chlorinated cyclopentadlenes.
9.2. BASED ON CARCINOGENICITY
The lack of data precludes the derivation of carclnogenlclty based RQs.
0077d -64- 04/05/88
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TABU 9-1
Toxlctty Suiury for Hexachlorocyclopentadtene
Species/
Route Strain Sex
Inhalation rats/Ulstar N.F
Inhalation rats/F344 N.F
Inhalation rats/F344 N.F
Inhalation «lce/B6C3Fl H.F
Inhalation atce/B6C3F1 N.F
Oral Mtce/B6C3F1 N.F
Oral •1ce/B6C3F1 N.F
No. at Average
Start Height
(kg)
8/sex 0.350
10/sex 0.2211
10/sex 0.23d
10/sex 0.03*
10/sex 0.03°
10/sex 0.03°
10/sex 0.03°
'
Vehicle/ Purity • Transformed Equivalent
Physical (X) Exposure AnlMl Dose Hiwan Dose*
State (tig/kg/day) (og/kg/day)
air 96 0.5 pp* 0.64C 0.11
(5.6 •g/a'l.
, 6 hours/day,
S days/week.
for 30 weeks
plus 14 weeks
recovery
air 99.42 1 ppa (11.2 1.45e 0.21
•9/1'K
. 6 hours/day.
5 days/week.
for 13 weeks
i
air 99.42 0.4 ppa (4.5 0.58* 0.08
•g/B*),
6 hours/day.
5 days/week.
for. 13 weeks
air 99.42 0.4 ppa (4.5 1.04C 0.08
•g/B*),
6 hours/day.
5 days/week.
for 13 weeks
air 99.42 0.15 ppm 0.39C 0.03
11.67 •*/••).
6 hours/day.
5 days/week.
for 13 weeks
corn oil 94-97 300 ng/kg by 214. 3f 16.2
gavage, 5
days/week.
for 13 weeks
corn oil 94-97 150 og/kg by 107. 1* 8.1
gavage. 5
days/week.
for 13 weeks
Response
Death of 4/8 Mies and
2/8 feMles; kidney.
liver and pulmnary
degenerative changes
Death of all rats
Decreased body weights of
•ales, necrosis and acute
InflaaMtton of respira-
tory eplthella
Death of 5/10 Mies and
2/10 feMles
Hyperplasla and Meta-
plasia of respiratory
eplthella
Death of all Mies and
3/10 feMles
Toxic nephrosts In fe-
Mles. stoMch lesions.
depressed body weight
gain
Reference
Clark
et al.. 1982b
Battelle
Northwest
Laboratories,
1984
Battelle
Northwest
Laboratories.
1984
Abdo et al..
1986
Abdo et al..
1986
SRI. 19Bla;
Abdo et al..
1984
SRI. 1981a;
Abdo et al..
1984
-------
TABLE 9-1 (cont.)
§
5 Route
o.
Oral
Oral
Species/
Strain
rats/F344
rats/F344
No. at Average
Sex Start Height
(kg)
N.F 10/sex 0.35b
N.F 10/sex 0.35b
Vehicle/
Physical
State
corn oil
corn oil
Purity
(X) Exposure
94-97 150 mg/kg by
gavage. 5
days/week,
for 13 weeks
94-97 19 mg/kg by
gavage. 5
days/week.
for 13 weeks
Transformed
Animal Dose
(mg/kg/day)
107. lf
13.6'
Equivalent
Human Dose4
(mg/kg/day)
18.3
2.3
Response
Death, toxic nephrosls
and stomach lesions
Stomach lesions In
females
Reference
SRI. 1981a;
Abdo et al..
1984
SRI. 1981a;
Abdo et al..
1984
'Calculated by multiplying the animal transformed dose by the cube root ratio of the animal body weight to the human body weight (70 kg)
Reference rat (0.35 kg) and mouse (0.03 kg) body weights (U.S. EPA. 1985)
Calculated by multiplying the concentration by the hours/day, days/week, by the animal Inhalation rate (0.223 mVday rats; 0.039 mVday mice (U.S.
EPA (1985)) and by dividing by the animal body weight
^Estimated from growth curves In the study
'Calculated as described In c except the Inhalation rate of 0.16 mVday calculated from I - 0.105 (w/0.113)2'3 (U.S. EPA. 1985) was used
'Calculated by multiplying the dose by 5 days/7 days
-------
g
TABLE 9-2
Composite Scores for Hexachlorocyclopentadlene
5
i
o
in
Chronic
Species Animal Dose Human NED* RVjj
(rag/kg/day) (mg/day)
Rat 0.64 0.77 5.7
Rat 1.45 1.47 5.2
Rat 0.58 0.56 5.9
Mouse 1.04 0.56 5.9
Nouse 0.39 0.21 6.5
*The dose was divided by an uncertainty factor
Effect RVe CS RQ
Death of 4/8 males, 10 57 10
2/8 females
Death 10 52 10
Decreased body weight. 4 23.6 100
necrosis and acute In-
flammation of respira-
tory epithelium
Death of 5/10 males. 10 59 10
2/10 females
Hyperplasla and met a- 6 39 100
plasla of respiratory
epithelium
of 10 to approximate chronic exposure.
Reference
Clark
et al.. 1982b
Battelle
Northwest
Laboratories,
1984
Battelle
Northwest
Laboratories,
1984
Abdo et al..
1986
Abdo et al..
1986
-------
TABLE 9-3
Hexachlorocyclopentadlene
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species:
Dose*:
Duration:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
Inhalation
Mouse
0.56 rag/day
13 weeks
death
Abdo et al.. 1986; SRI, 1981a
5.9
10
59
10
'Equivalent human dose
0077d
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TABLE 9-4
Chlorocyclopentadlene, Trlchlorocyclopentadlene,
Tetrachlorocyclopentadlene and Pentachlorocyclopentadlene
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Oose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are not sufficient for deriving an RQ for these
compounds.
0077d -69- 12/23/87
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10. REFERENCES
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Assessment Office. Cincinnati, OH. Final Report. EPA-600/8-84-001F. NTIS
PB 85-124915. .
0077d -86- 04/05/88
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U.S. EPA. 1984b. Health Effects Assessment for Hexachlorocyclopentadlene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response. Washington. DC. EPA/540/1-86-001. NTIS PB
86-134129/AS.
U.S. EPA. 1985. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment. Environmental Criteria and
Assessment Office. Cincinnati. OH for the Office of Solid Waste Washington.
DC.
U.S. EPA. 1986a. Methodology for Evaluating Cardnogenlclty 1n Support of
Reportable Quantity Adjustment Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment. Cancer Assessment Group.
Washington, DC for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987a. SANSS (Structure and Nomenclature Search System).
Database. Online.
U.S. EPA. 1987b. Hazardous substances; reportable quantity adjustments;
proposed rules. 40 CFR Parts 117 and 302. Federal Register. 52(50):
8140-8186.
0077d -87- 04/05/88
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U.S. EPA. 1988a. Drinking Mater Criteria Document for Hexachlorocyclo-
pentadlene. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Drinking Water, Washington, DC. External Review Draft.
U.S. EPA. 1988b. Integrated Risk Information System (IRIS): Reference Dose
(RfD) for oral exposure for hexachlorocyclopentadlene. Online. (Verifica-
tion date 10/09/86). Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic
Chemicals. United States Production and Sales, 1985. USITC Publ. 1892,
Washington, DC. p. 41.
Velth, G.O., D.L. DeFoe and B.V. Bergstedt. 1979. Measuring and estimating
the bloconcentratlon factor of chemicals In fish. J. F1sh Res. Board Can.
36: 1040-T048. '
Vllkas, A.G. 1977. The acute toxldty of hexachlorocyclopentadlene to the
water flea, Daphnla maqna straus. Union Carbide Environmental Services.
Prepared for Velslcol Chemical Corp., Chicago, II. (Cited In U.S. EPA,
I984a)
Walsh, G.E. 1981. Effects of chlordane, heptachlor and hexachlorocyclo-
pentadlene on growth of marine unicellular algae. Laboratory report. U.S.
EPA, Gulf Breeze, FL. (Unpublished) (Cited In U.S. EPA, 1984a)
0077d -88- 04/05/88
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Walsh, G.E. 1983. Cell death and Inhibition of population growth of marine
unicellular algae by pesticides. Aquat. Toxlcol. 3: 209-214. (Cited In
U.S. EPA, 19865)
Hang, H.H. and B. NacNahon. 1979. Mortality of workers employed 1n the
manufacture of chlordane and heptachlor. J. Occup. Ned. 21: 745-748.
(Cited In U.S. EPA, 1984a. 1986b)
Weber, J.B. 1979. Adsorption of Hex by Cape Fear Loam Soil. North
Carolina State Univ. Prepared for Velslcol Chemical Corp., Chicago, IL.
(Cited 1n U.S. EPA, 1984a)
Whltacre, O.N. 1978. Letter to R.A. Ewlng, Battelle Columbus Laboratories,
dated August 9, 1978. Comments on document: Review of Environmental Effects
of Pollutants: XII. Hexachlorocylopentadlene. 5 p. (Cited In U.S. EPA,
1984a)
Wilson, J.A., C.P. Bladwln and T.J. McBMde. 1978. Case History: Contami-
nation of Louisville Kentucky Morris Foreman Treatment Plant, Hexachloro-
cyclopentadlene: Control of Hazardous Material Spills, p. 170-177. (Cited
In U.S. EPA, 19843, 19865)
Wolfe, N.L., R.G. Zepp, P. Schlotzhauer and N. Sink. 1982. Transformation
pathways of hexachlorocyclopentadlene 1n the aquatic environment. Chemo-
sphere. 11: 91-101.
0077d -89- 04/05/88
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YoxMda, K., T. Shlgeoka and F. Yaroauchl. 1983. Relationship between molar
refraction and N-octanol/water partition coefficient. Ecotox. Environ.
Safety. 7: 558-565.
Yu, C.C. and Y.H. Atallah. 1977a. Photolysis of Hexachlorocyclopentadlene.
Laboratory report. Project No. 482428. Rep. No. 4. Velslcol Chemical
Corp.. Chicago. IL. (Cited In U.S. EPA, 1984a)
Yu, C.C. and Y.H. Atallah. 1977b. Hex hydrolysis at various pH and
temperature. Laboratory report. Project No. 482428. Rep. No. 8. Velslcol
Chemical Corp.. Chicago. IL. (Cited 1n U.S. EPA, 1984a)
Yu, C.C. and Y.H. Atallah. 1981. Pharmacok1net1cs and metabolism of
hexachlorocyclopentadlene 1n rats. Rep. No. 10, Project 482428. Velslcol
Chemical Corp., Chicago, IL. (Cited In U.S. EPA, 1986b)
Zepp, R.G., P.P. Schlotzhauer, M.S. Simmons, G.C. Miller, 6.L. Baughman and
N.L. Wolfe. 1984. Dynamics of pollutant photoreactlons In the hydrosphere.
Fresenlus Z. Anal. Chem. 319: 119-125.
0077d -90- 04/05/88
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted 1n October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati. OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2A. John Wiley and
Sons. NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons. NY. p. 2879-3816.
Clayton. G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
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Grayson, M. and 0. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International. Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program; .Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M.. Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0077(1 -92- 04/05/88
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In addition, approximately 30 compendia of aquatic tox1c1ty data were
reviewed. Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington. DC.
Johnson, W.W. and N.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
NcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0077d -93- 04/05/88
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APPENDIX B
Summary Table for Hexachlorocyclopentadlene
Species
Exposure
Effect
RfD or
Reference
Inhalation Exposure
Subchrontc rat
0.15 pp« (0.45 ng/n»)
6 hours/day, 5 days/week
for 13 weeks (0.2 rag/kg/day)
NOAEL 0.01 rag/day or
0.0007 ng/m*
Battelle Northwest
Laboratories. 1984;
Abdo et al., 1986
Chronic
rat
0.15 ppra (0.45 rag/a8)
6 hours/day, 5 days/week
for 13 weeks (0.2 mg/kg/day)
NOAEL 0.001 og/day or
0.00007 mg/n*
Battelle Northwest
Laboratories. 1984;
Abdo et al., 1986
Oral Exposure
Subchronlc rat
10 ing/kg, by gavage 5 days/
week for 13 weeks
NOAEL 5 rag/day
SRI. 198la;
Abdo et al.. 1984
Chronic
rat
10 rog/kg, by gavage 5 days/ NOAEL 0.5 rag/day
week for 13 weeks
SRI. 1981a;
Abdo et al.. 1984
REPORTABLE QUANTITIES
Based on Chronic Toxlclty:
Based on Carclnogenlclty:
10 pounds
10
Abdo et al.. 1986
10 = insufficient data
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