Environmental Protection
Agency December, 1987
4>EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS PROFILE
FOR HEXACHLOROCYCLOHEXANES
Prepared for
OFFICE OF SOLID WASTE 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DRAFT: DO NOT CITE OR QUOTE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 repres nt Agency policy. It Is being circulated for comments
on Us technical accuracy and pollry 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.
U.S. Environmental Protection
Region 5, Library \PL-12J)
77 West Jackson Boulevard, 12th fkwr
go, it 60604-3b90
11
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PREFACE
Health and Environmental Effects Profiles (HEEPs) are prepared for the
Office of Solid Waste and Emergency Response by the Office of Health and
Environmental Assessment. The HEEPs are Intended to support listings of
hazardous constituents of a wide range of waste streams under Section 3001
of the Resource Conservation and Recovery Act (RCRA), as well as to provide
health-related limits for emergency actions under Section 101 of the Compre-
hensive Environmental Response, Compensation and Liability Act {CERCLA).
Both published literature and Information obtained from 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 and the dates of the searches are Included 1n the
section titled "Appendix: Literature Searched." The literature search
material 1s current through November, 1985.
Quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these Include Reference doses (RfDs) for
chronic exposures. An RfD 1s defined as the amount of a chemical to which
humans can be exposed on a dally basis over an extended period of time
(usually a lifetime) without suffering a deleterious effect. In the case of
suspected carcinogens, RfDs are not estimated 1n this document series.
Instead, a carcinogenic potency factor of q-|* Is 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 toxldty and carclno-
genldty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of a release
as specified under CERCLA. These two RQs (chronic toxldty and cardnogen-
1c1ty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty and acute mammalian toxldty).
The first draft of this document was prepared by Syracuse Research
Corporation under EPA Contract No. 68-03-3228. The document was subse-
quently revised after reviews by staff within the Office of Health and
Environmental Assessment: Carcinogen Assessment Group, Reproductive Effects
Assessment Group, Exposure Assessment Group, and the Environmental Criteria
and Assessment Office In Cincinnati.
The HEEPs will become part of the EPA RCRA and CERCLA dockets.
111
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EXECUTIVE SUMMARY
The Isomers of hexachlorocyclohexane (HCH) are white or yellowish
powders or flakes, with differing odors depending on the Isomer. The
Isomers are soluble to varying degrees 1n a variety of organic solvents
Including ethyl alcohol, chloroform, acetone, dloxane, ether and others
(Colson, 1979). HCHs can be decomposed by alkaline substances and are
expected to undergo reactions typical of alkyl halldes Including hydrolysis
and dehydrohalogenatlon (Morrison and Boyd, 1973).
Technical grade HCH (T-HCH), a 65:7:17:4:10 mixture of a, B, Y. c
and other Isomers of HCH, respectively, 1s produced by the photochemically-
Induced reaction between benzene and chlorine In the presence of a free
radical Initiator. A variety of physical separation methods are used to
purify Y-HCH to 99.9% from T-HCH for use as an Insecticide (llndane)
(Colson, 1979).
y-HCH 1s used as an Insecticide on hardwood logs and lumber, a variety
of seeds, vegetables and fruits, woody ornamentals Including Christmas
trees, hardwood forests, livestock and pets (external parasite control) and
existing structures (control of woodborlng beetles and termites) (Federal
Register, 1983). Pertinent data regarding uses of the other Isomers 1n the
pure state could not be located 1n the available literature as dted In the
Appendix. The technical product has been used as an Insecticide In the past
but Is no longer used as such (Colson, 1979).
Half-lives of Y-HCH 1n water at 25°C were reported to be 92, 771 and
648 hours 1n natural water samples from a eutrophlc pond In Texas (pH 9.3),
a dystrophlc reservoir 1n Louisiana (pH 7.3) and an ollgotrophlc rock quarry
In Indiana (pH 7.8), respectively (Saleh et a!., 1982). Hydrolysis experi-
ments In M1111-Q water at pH values of 5, 7 and 9 yielded half-lives of 936,
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4331 and 95 hours, respectively (Saleh et al., 1982). Therefore, hydrolysis
at alkaline pH values Is expected to be Important In the fate of y-HCH,
while hydrolysis at acidic and neutral pH values 1s not. Pertinent data
regarding the hydrolysis of the other Isomers of HCH could not be located In
the available literature; however, all these Isomers contain more equatorial
bonds than y-HCH, and since these bonds are generally more stable than
axial bonds, 1t 1s expected that the remaining Isomers will be more stable
to hydrolysis than y-HCH.
First-order photolysis half-lives for y-HCH of 169, 1791 and 1540
hours were observed In natural water samples from a eutrophlc pond 1n Texas,
a dystrophlc reservoir In Louisiana and an ollgotrophlc rock quarry 1n
Indiana, respectively (Saleh et al., 1982). The relatively short photolysis
half-life observed In the Texas sample was attributed to the alkaline pH
that, H was concluded, generated hydrolysis products more susceptible to
photolysis than y-HCH (Saleh et al., 1982). After 50 days exposure to
sunlight, the concentrations of y- and a-HCH 1n purified water dropped
from -9300 to -7600 vg/mfc and from 1480 to -1130 yg/ma, respectively
(Malalyandl et al., 1982). Pertinent data regarding the photolysis of the
other HCH Isomers could not be located In the available literature as cited
1n the Appendix. Direct photolysis, however, 1s not expected to be a major
fate process for any of the HCH Isomers since they do not have conjugated
unsaturated systems.
Of the y-HCH added to unsterlllzed natural waters In capped bottles,
<30X remained after 16 weeks (Sharom et al., 1980). About 25X of the
Y-HCH 1n raw wastewater from Cincinnati was removed during aerobic
blodegradatlon In a wastewater treatment plant (Petrasek et al., 1983).
Pertinent data regarding the aqueous blodegradatlon of the other HCH Isomers
could not be located In the available literature as cited In the Appendix.
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The volatilization half-life of y-HCH has been estimated to be 115
days (Lyman et al., 1982} and 191 days (Mackay and Lelnonen, 1975), assuming
a depth of 1 m. Volatilization half-lives of 3.2 and 1.5 days were observed
for Y-HCH from still and stirred water 4.5 cm deep (Chlou et al., 1980).
The measured volatilization half-life of 3.2 days was used to estimate a
half-life of 692 days from water 1 m deep. Since the half-lives of 115 and
191 days are of the same order of magnitude as the half-life estimated from
experimental data, the former values are considered to be accurate estimates
of the tendency of q-HCH to volatilize. Henry's Law Constant values for the
other Isomers have been estimated and suggest that volatilization of all HCH
Isomers occurs at a rate dependent upon the rate of diffusion through the
air {Lyman et al., 1982). Volatilization of HCH Isomers In water Is not
expected to be significant 1n the environment.
A mean K for Y-HCH of 1080.9 was obtained from K determlna-
oc T oc
tlons on three soils (Rao and Davidson, 1982). Based on this K and a
low water solubility of 7.5 ppm (U.S. EPA, 1981), Y-HCH Is expected to
leach slowly to groundwater. K values for the remaining HCH Isomers
were estimated (Lyman et al., 1982) and, combined with the fairly low water
solubilities of the Isomers, suggest that they are expected to bind fairly
tightly to soil and to leach slowly to groundwater. Fifteen years following
the application of technical HCH to a sandy loam soil In Canada, >90X of the
applied a-, B-, y- and i-HCH remained 1n the upper 20 cm of soil,
Indicating minimal leaching had taken place (Stewart and Chlsholm, 1971).
BCFs for Y-. «-t 8- and 4-HCH 1n a variety of species ranged from
63-1613 (Matsumura and Benezet, 1973; Ramamoorthy, 1985; Kanazawa, 1983;
Schlmmel et al., 1977; Metcalf et al., 1973; Yamato et al., 1983; Suglura et
al., 1979). No BCF values were available for e-HCH, but 1t Is expected to
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bloaccumulate similarly to 6-HCH, to which H bears a close structural
similarity. None of the HCH Isomers are expected to bloconcentrate signifi-
cantly 1n aquatic organisms.
Based on degradation data, the persistence half-lives for y-HCH 1n
river, lake and groundwater were estimated to be 3-30, 30-300 and >300 days,
respectively (Zoeteman et al., 1980). Pertinent data regarding the persis-
tence of the other Isomers could not be located 1n the available literature
as cited In the Appendix.
Anaerobic soil preparations were found to readily degrade y-HCH
(Kohnen et al., 1975; Mathur and Sana, 1975; Llchtensteln et al., 1971;
Sethunathan and Yoshlda, 1973; Haider, 1979). Degradation of a-HCH by
anaerobic soils has also been observed (Castro and Yoshlda, 1974; HacRae et
al., 1984; Haider, 1979). Doelman et al. (1985) observed greater aerobic
than anaerobic degradation of a-HCH 1n polluted soil. Anaerobic degrada-
tion of a-, B- and 6-HCH by several organisms has been observed (Haider,
1979). Pertinent data regarding the blodegradatlon of c-HCH could not be
located In the available literature as cited In the Appendix.
After 50 hours, 26 and 100% of the surface applied y-HCH remained on
Hatboro silt loam and Norfolk sandy loam, respectively (Glotfelty et al.,
1984). The low volatility of the y-HCH was attributed to the dryness of
the sandy loam. From a moist soil surface, the y-HCH content decreased to
50 and 10% of the amount applied after 6 hours and 6 days, respectively,
while 50 hours after the application of y-HCH to dry soil, 88% of the
applied compound remained (Glotfelty et al., 1984). Pertinent data regard-
Ing the volatilization of the other HCH Isomers could not be located 1n the
available literature as cited In the Appendix. The estimated Henry's Law
constants, K and measured water solubility values suggest that the
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Isomers will bind fairly tightly to soil and will have Uttle tendency to
volatilize from dry soils. Volatilization from moist soils, however, may be
significant.
T-HCH concentrations of 0.01-0.319 ppb have been detected 1n drinking
water from various rural and urban areas (Keith et a!., 1976; Sandhu et al.,
1978; Bevenue et al., 1972). Based on these figures and assuming an average
dally consumption of 2 J. of water, an average dally y-HCH Intake of
0.02-0.638 pg was estimated. A y-HCH concentration of 1.3 ppb was
detected 1n Ottawa, Ontario (Krayblll, 1977). The average dally Intake
based on this figure 1s 2.6 yg, but this figure 1s considered to be
nonrepresentatlve since the monitoring data on which It Is based 1s so high
relative to the other values. Surface water and precipitation (rain and
snow) samples contained measurable concentrations of y-HCH (U.S. EPA,
1985a; Oliver and Charlton, 1984; Cole et al., 1984; Saleh et al., 1982;
Sandhu et al., 1978; Bevenue et al., 1972; Page, 1981; Strachan and
Huneault, 1979; Pankow et al., 1984; Brooksbank, 1983; Strachan, 1985).
a-HCH has been detected at 2.7-20.3 and 0.45-9.7 ppt municipal drinking
water samples collected during the winter and summer, respectively (Williams
et al., 1982) and at 17 yg/i 1n tap water from Ottawa, Ontario
(Krayb.111, 1977). An average dally Intake of a-HCH of 0.90-40.6 ng was
estimated, assuming an average dally consumption of 2 & of water (exclud-
ing the Ottawa result). Based on the high a-HCH content of the tap water
from Ottawa, an average dally Intake of 34 yg was estimated. Because of
the relatively high value of a-HCH 1n the Ottawa sample, this value 1s
thought to be nonrepresentatlve. Samples of surface water and precipitation
(rain and snow) from a variety of locations contained a-HCH (U.S. EPA,
1985a; Kuntz and Warry, 1983; Page, 1981; Cole et al., 1984; Strachan and
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Huneault, 1979; Elsenrelch et al., 1981; Pankow et al., 1984; Brooksbank,
1983; Strachan, 1985). In the Netherlands, B-HCH was found 1n ng quantities
1n a variety of locations (Dulnker and Hlllebrand, 1979). Samples of
surface water 1n the United States contained a mean B-HCH concentration of
0.1725 yg/i (U.S. EPA, 1985a). Pertinent monitoring data for i- or
c-HCH could not be located In the available literature as dted 1n the
Appendix.
A wide variety of foodstuffs, Including dairy products, meat, vege-
tables, fruits and seafood, contain one or more HCH Isomers (Duggan et al.,
1983; Steffey et al., 1984; Podrebarac, 1984; SchmHt et al., 1985; U.S.
EPA, 1985a). The average dally Intake of y-HCH was estimated to be 0.27
vg, based on the y-HCH content 1n foods from 1971-1976, and that of
a-HCH was estimated to be 10.5 and 9.1 ng/kg bw/day, based on 1977 and
1978 data, respectively. Since monitoring data In foods are available only
for mixtures of the Isomers, 0-, 4- and e-HCH, It Is not possible to
estimate the average dally Intakes of Individual Isomers.
The mean concentration of y-HCH In positive samples of ambient air In
the United States In 1970-1972 was 0.9 ng/m3 (Kutz et al., 1976). Based
on this value and assuming an average Intake of 20 m3 air/day, the average
dally Intake of Y-HCH Is 18 ng. Monitoring data during the years
1970-1972 revealed a mean a-HCH concentration In ambient air of 1.2
ng/m3 1n the positive samples collected across the United States (Kutz et
al., 1976). Assuming an average dally Intake of 20 m3 of air, this figure
1s equivalent to an average dally Intake of 24 ng. Pertinent monitoring
data regarding the other Isomers of HCH could not be located 1n the avail-
able literature as cited In the Appendix.
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A large volume of Information Is available concerning effects of HCH on
aquatic organisms. Llndane (y-HCH) Is generally more toxic to freshwater
and saltwater fish and Invertebrates than other HCH Isomers or mixtures
(U.S. EPA, 1980b). The lowest reported acutely toxic concentrations for
freshwater species were 1.7 vg/t Undane, which was a 96-hour LC5Q for
brown trout (Johnson and Flnley, 1980) and 1 v9/& Undane, which was a
96-hour LC5Q for stonefHes (Cope, 1965, Snow, 1958). The lowest reported
acutely toxic Undane concentrations for marine fish and Invertebrates,
respectively, were 7.3 yg/J., a 96-hour LC5Q for striped bass (Korn and
Earnest, 1974), and 0.17 yg/l, a 96-hour LC5Q for pink shrimp
(Schlmmel et al., 1977). Among the freshwater fishes, salmonlds appeared to
be more sensitive than other species. Crustaceans other than cladocerans
were generally the most sensitive Invertebrate species both In freshwater
and saltwater (U.S. EPA, 1980b). Fish and Invertebrates appeared to be
about equally sensitive to HCH.
In chronic toxiclty studies, no adverse effects were reported at concen-
trations lower than the acutely toxic levels for the most sensitive species;
however, chronic toxiclty data for the most acutely sensitive species were
generally unavailable.
The available Information Indicated that aquatic plants were much less
sensitive to HCH than fish or Invertebrates.
HCH accumulates In aquatic biota primarily In fatty tissue; however, HCH
Is less I1poph1!1c and less persistent than other organochloMnes and there-
fore 1s not bloaccumulated or blomagnlf led to a great extent.
Two studies provide direct evidence that y-HCH 1s absorbed from the
gastrointestinal tract (Turner and Shanks, 1980; Ahdaya et al., 1981). The
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appearance of a-HCH and B-HCH In the blood and tissues after oral adminis-
tration 1s also Indicative of gastrointestinal absorption {Elchler et al.,
1983; Altmann et al., 1983; Macholz et al., 1982a,b).
In general, Isomers of HCH and their metabolites tend to accumulate 1n
fatty tissue (Elchler et al., 1983; Chand and Ramachandran, 1980; Lakshmanan
et al., 1979; Chadwlck et al., 1978a; Altmann et al., 1983; Baumann et al.,
1980; S1dd1qu1 et al., 1981a; Szymczynskl and Wallszewskl, 1981a,b). In a
comparative study where a-HCH or y-HCH was fed to rats In the diet for
56 days, Elchler et al. (1983) found that a-HCH accumulated 1n the fat and
brain to a greater extent than did y-HCH. Furthermore, the retention of
a-HCH In the tissues (fat, brain, liver, kidney) was 12-30 times greater
than that of y-HCH. Tissue concentrations of y-HCH declined to a much
greater extent than did tissue levels of a-HCH during the 15 days follow-
ing termination of exposure.
The metabolism of HCH Isomers primarily Involves ' dehydrogenatlon,
dehydrochloMnatlon and dechloMnatlon. Conjugation reactions with sulfurlc
and glucuronlc add are also Important (Macholz et al., 1982a; Engst et al.,
1976, 1979; Chadwlck et al., 1975; Grover and S1ms, 1965; Freal and Chad-
wick, 1973; Chadwlck and Freal. 1972; Allsup and Walsh, 1982). In mammals,
Including humans, common metabolites of HCH Include chlorinated phenols,
chlorinated benzenes and pentachlorocyclohexenes. These metabolites are
usually excreted In conjugated form (or a degradation product of a previ-
ously conjugated form) 1n the urine, and have also been detected In blood,
liver, kidney, spleen, heart and brain (Engst et al., 1976; Chadwlck et al.,
1975, 1978a; Freal and Chadwlck, 1973; Chadwlck and Freal, 1972; Angerer et
al., 1983; Kujwa et al., 1977; Grover and S1ms, 1965). A number of In vitro
studies have shown that the metabolism of HCHs In mammals Is mediated to a
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great extent by oxldatlve processes 1n hepatic mlcrosomes (Gopalaswamy and
Alyar, 1984; Yamamoto et al., 1983; FHzloff et al., 1982; FHzloff and Pan,
1984; Baker et al., 1985; Tanaka et al., 1979; Portlg et al., 1973).
HCH Isomers and metabolites have been recovered In the urine and feces
(Ahdaya et al., 1981; KuMhara et al., 1979; Chadwlck et al., 1975, 1978a,b;
Allsup and Walsh, 1982; Zesch et al., 1982; Angerer et al., 1981; Stein et
al., 1980; Macholz et al., 1982a,b), and trace amounts (as 14CO ) have
been detected In expired air (Ahdaya et al., 1981; Chadwlck et al., 1978a).
In comparative studies, KHamura et al. (1970) and Elchler et al. (1983)
demonstrated that the disappearance of y-HCH from the bodies of mice given
a single oral dose or rats given repeated oral doses was more rapid than
that of B-HCH or
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Dietary B-HCH has been shown to cause Increased Incidences of liver
tumors 1n CF1 and ICR-JCL mice (Thorpe and Walker, 1973; Goto et al., 1972)
but not 1n dd mice (Ito et al., 1973a,b; Hanada et al., 1973; Nagasaki et
al., 1972a) or Wlstar rats (Ito et al., 1975; FHzhugh et al., I960). The
reproductive and teratogenlc effects of B-HCH have not been Investigated.
Nonneoplastlc and neoplastlc hlstologlcal changes 1n the liver were not
observed In studies that were designed to Investigate hepatic carcinogenic
response (Ito et al., 1973a,b, 1975); Increases In absolute and relative
liver weight were observed at dietary concentrations >250 ppm. FHzhugh et
al. (1950) observed Increases In liver weight accompanied by hlstologlcal
changes In rats fed >100 ppm B-HCH; Increased relative liver weight was the
only effect observed at 10 ppm. Early mortality was also observed among
rats fed 800 ppm. No tumors were observed 1n this study, though It should
be noted that not all of the rats started on the test were examined hlsto-
loglcally-(no criterion for selection was given). No other chronic effects
were reported.
Dietary y-HCH was shown to cause an Increased Incidence of liver
tumors 1n male CF1 mice fed 400 ppm for 110 weeks (Thorpe and Walker, 1973),
and marginally In male dd mice fed 600 ppm for 32 weeks, then examined 5-6
weeks posttreatment (Hanada et al., 1973), and 1n male ICR-JCL mice fed 600
ppm for 26 weeks (Goto et al., 1972). No liver tumors were observed 1n dd
mice fed up to 500 ppm for 24 weeks (Ito et al., 1973a,b; Nagasaki et al.,
1972a) or In Wlstar rats fed 500 ppm for up to 48 weeks (Ito et al., 1975).
Significant compound-related development of tumors of any type was not
observed In NMRI mice (Herbst et al., 1975; Welsse and Herbst, 1977), B6C3F1
mice (NCI, 1977), Osborne-Mendel rats (NCI, 1977) or Wlstar rats (FHzhugh
et al., 1950). The study conducted by NCI (1977) has been criticized for
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poor survival of rats, changes 1n dosing regimen and the possibility that
male rats did not receive MTOs (IARC, 1979). The negative findings of
FHzhugh et al. (1950) are also Inconclusive since only small numbers of
animals were examined hlstologlcally. The negative findings of Ito et al.
(1973a,b), Nagasaki et al. (1972a) and Ito et al. (1975) might be attributed
to small numbers of animals and short duration. Notably, a metabolite of
Y-HCH, 2,4,6-trlchlorophenol, Is carcinogenic 1n mice and rabbits and 1s
considered to be a probable human carcinogen (Group 82).
Orally-administered y-HCH was not found to be teratogenlc or fetotoxlc
In Wlstar rats (Khera et al., 1979), CD rats (Palmer et al., 1978a), CFY
rats (Palmer et al., 1978b), New Zealand White rabbits (Palmer et al.,
1978b) or CD-I mice (Chernoff and Kavlock, 1983; Gray and Kavlock, 1984).
In contrast, a study by Dzlerzawskl (1977) reported Increased numbers of
resorbed fetuses In hamsters (40 mg/kg on day 9 of gestation), rabbits (40
or 60 mg/kg on day 9 of gestation) and rats (40, 50 or 100 mg/kg on various
days of gestation). Maternal toxldty was not reported. These doses are
higher than any of those tested 1n the negative studies of y-HCH, though
Chernoff and Kavlock (1983) reported that 25 mg/kg/day was the maximum dose
that was not toxic to maternal CD-I mice.
Palmer et al. (1978a) failed to observe adverse effects on reproduction
In three generations of CD rats fed up to 100 ppm y-HCH In the diet.
Dlkshlth and Datta (1977) and DlkshHh et al. (1978), however, observed
testlcular atrophy In ITRC rats gavaged with 17.6 mg Y-HCH/kg In peanut
oil for 90 days, suggesting that y-HCH might have adverse effects upon
reproduction.
Long-term oral studies have shown targets for HCH toxldty to be the
liver (a, Y, B) (Olkshlth et al., 1978; FHzhugh et al., 1950); Research
and Consulting Co., Ltd., 1983; Oesch et al., 1982; Ito et al., 1973a,
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Rlvett et al., 1978), kidney (a, y) (Fltzhugh et al., 1950; Research and
Consulting Co., Ltd., 1983). Hematologlcal effects (y) (Earl et al.,
1970; Morgan et al., 1980) and neurotoxldty have also been reported
(FHzhugh et al., 1950; Czegledl-Janko and Avar, 1980). Short-term studies
suggest that y-HCH may cause Imraunosupresslon (Oewan et al., 1980; Desl et
al., 1978).
Dietary i-HCH did not cause neoplastlc or nonneoplastlc changes In the
livers of male dd mice (Ito et al., 1973a; Nagasaki et al., 1972a) or male
Wlstar rats (Ito et al., 1975). These studies used small numbers of animals
and were only conducted for 24 weeks. A mixture of 6- and e-HCH caused
benign and malignant hepatomas 1n male ICR-JCL mice when fed In the diet at
600 ppm for 26 weeks (Goto et al., 1972). Other pertinent data regarding
the teratogenlc, reproductive or chronic effects of 6-HCH could not be
located In the available literature as cited In the Appendix.
Concerning the cardnogenlclty of e-HCH, a mixture of 5- and e-HCH
caused benign and malignant hepatomas In male ICR-JCL. mice when fed In the
diet at 600 ppm for 26 weeks (Goto et al., 1972). Pure c-HCH was not
evaluated. Other pertinent data regarding the health effects associated
with exposure to e-HCH could not be located 1n the available literature as
cited In the Appendix.
T-HCH (technical grade HCH mixture) has been shown to cause Increased
Incidences of liver neoplasms 1n four strains of mice (Hanada et al., 1973;
Goto et al., 1972; Kashyap et al., 1979; N1gam et al., 1984a; Bhatt et al.,
1981; Munlr et al., 1983; Nagasaki et al., 1971, 1972b; Nagasaki, 1973;
Munlr and Bhlde, 1984) but not 1n Wlstar rats (Munlr et al., 1983) or Syrian
golden hamsters (Munlr et al., 1983). T-HCH 1s typically 65% a. Isomer, 7%
B, 17% y, 4% e and small amounts of 10 other Isomers Including 6.
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The teratogenlc effects of T-HCH have not been Investigated. Nlgam et
al. (1979) and ShTvanandappa and Krlshnakumarl (1981, 1983) have shown that
orally-administered T-HCH causes testlcular atrophy 1n rats and mice (>800
ppm, rats; 500 ppm, mice).
Long-term oral administration of T-HCH has been shown to cause adverse
effects on the liver (Fltzhugh et al., 1950; Barros and Sallba, 1978; Barros
et al., 1982; Shlvanandappa and Krlshnakumarl, 1981; Nlgam et al., 1982,
1984a,b; Munlr and Bhlde, 1984), kidney (Fltzhugh et al., 1950, Barros and
Sallba, 1978; Barros et al., 1982; Shlvanandappa and Krlshnakumarl, 1981),
adrenal cortex (Shlvanandappa and Krlshnakumarl, 1981; Shlvanandappa et al.,
1982) and CNS (Shlvanandappa and Krlshnakumarl, 1981; Kashyap et al., 1979).
Kashyap et al. (1979) also reported that long-term oral exposure to T-HCH
was associated with Increased cornea! opacity.
A large body of evidence Indicates that the nonneoplastlc changes In the
liver associated with exposure to Vsomers of HCH or to T-HCH are associated
with neoplastlc development. The nonneoplastlc changes support the qualita-
tive estimation of cancer of the T-HCH mixture and the Isomers of HCH that
have tested positive. A clear progression of hepatic changes that ulti-
mately lead to the development of malignant tumors has been observed at
gross, histologlcal and ultrastructural levels of examination. These non-
neoplastlc changes were proportional to dose and duration of HCH treatment.
These liver effects are reversible only at the stages before the development
of nodular hyperplasla. The exact stage at which the liver changes become
Irreversible has not been clearly defined (Ito et al., 1975, 1976; Schulte-
Hermann and Parzefall, 1981; Munlr et al., 1983; Munlr and Bhlde, 1984;
Nlgam et al., 1982, 1984a; Suglhara et al., 1975). Although nodular hyper-
plasla may appear to regress shortly after HCH treatment 1s discontinued, 1f
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the observation period Is extended, the development of hepatocellular
carcinoma becomes apparent (Suglhara et al., 1975). Suglhara et al. (1975)
postulated that surviving cells from areas of nodular hyperplasla ultimately
progress to hepatocellular carcinoma.
A q.j* of 6.34 (mg/kg/day)'1 was derived for a-HCH, based on the
combined Incidences of benign and malignant liver tumors In male mice fed 0,
100, 250 and 500 ppm a-HCH In the diet In the Ito et al. (1973a) study.
Corresponding concentrations of a-HCH 1n water associated with Increased
cancer risk levels of 10"5, 10"« and 10~7 are 5.52xlO~5, 5.52xlO"«
and 5.52xlO~7 mg/l.
A 1/ED-iQ (F factor) of 69.5 was derived based on data for benign and
malignant liver tumors In male mice fed a-HCH (Ito et al., 1973a). This F
factor places a-HCH 1n potency Group 3 and, with an EPA classification of
B2, results In a MEDIUM hazard ranking under CERCLA. A chronic toxldty-
based RQ of 1000 was estimated for a-HCH, based on early mortality of rats
1n a chronic feeding study (FHzhugh et al., 1950).
A q.j* of 1.8 (mg/kg/day)"1, originally derived for B-HCH by the U.S.
EPA (1982a), Is the recommended value for this Isomer. This q,* 1s based
on the combined Incidence of benign and malignant liver tumors 1n male mice
fed 0 or 200 ppm B-HCH 1n the diet for up to 110 weeks 1n the study by
Thorpe and Walker (1973). Corresponding concentrations of B-HCH In water
associated with Increased cancer risk levels of 10"5, 10~6 and 10"7
are 1.90xlO~«, 1.90xlO~5 and 1.90x10"* mg/l.
A l/EDlfl (F factor) of 10.7 was derived from the data for benign and
malignant liver tumors In male mice fed B-HCH (Thorpe and Walker, 1973).
xvll
-------
This F factor places B-HCH In Potency Group 2 and with an EPA classification
of C, results In -a LOW hazard ranking under CERCLA. A chronic toxlclty-
based RQ of 1000 was based on early mortality of rats In a chronic feeding
study with B-HCH (Mtzhugh et al., 1950).
A q * of 1.3 {mg/kg/day)"1, which was derived for y-HCH by the
U.S. EPA (1980a), remains the recommended value. This q * Is based on the
combined Incidence of benign and malignant liver tumors In male mice fed 0
or 400 ppm y-HCH 1n the diet for 110 weeks 1n a study by Thorpe and Walker
(1973). Corresponding concentrations of y-HCH 'n water associated with
Increased cancer risks of 10~5, 10~6 and 10"7 are 2.64xlO~4,
2.64xlO"s and 2.64x10"' mg/l.
A 1/EQ-iQ (F factor) of 7.4 was derived from the data for benign and
malignant liver tumors 1n male mice fed y-HCH (Thorpe and Walker, 1973).
This F factor places y-HCH In Potency Group 3 and, with an EPA classifica-
tion between 82 and C, results In a MEBIUH to LOW hazard ranking under
CERCLA. The chronic toxldty-based RQ for y-HCH, based on degenerative
changes 1n the kidneys of rats 1n a subchronlc oral study (Research and
Consulting Co., Ltd., 1983), Is 100.
Pertinent data for the derivation of an RfD or RQ or for assessing
carclnogenldty were not available for 6- or c-HCH. Both these Isomers
are given EPA classifications of C. Since It was not possible to derive a
potency estimate, a default potency group of 2 1s assigned. A Group C
we1ght-of-ev1dence combined with a Group 2 potency results In a LOW hazard
ranking under CERCLA.
A q * of 1.76 (mg/kg/day)'1 was derived for T-HCH from the combined
Incidences of benign and malignant liver tumors In male mice Fed 0, 125 and
250 ppm T-HCH In the diet from 8-10 weeks of age until 15-17 months of age
XV111
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(Hunlr et al., 1983). Corresponding concentrations of T-HCH In water asso-
ciated with Increased cancer risk levels of 10~s, 10~6 and 10~7 are
1.99xlO~4, 1.99xlO"5 and 1.99xlO~6 mg/l.
A 1/ED-iQ (F factor) of 8.1 was calculated from the data for benign and
malignant liver tumors 1n male mice fed T-HCH as noted above (Munlr et al.,
1983). The animal evidence for T-HCH 1s sufficient, thus an EPA Group 82
welght-of-evidence classification. A chronic tox1c1ty-based RQ of 100 was
estimated for T-HCH on the basis of hlstologlcal and hlstochemlcal adrenal
changes Indicative of steroldogenlc Inhibition 1n rats In a subchronlc oral
study (Shlvanandappa et al., 1982).
xlx
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
1.1. STRUCTURE AND CAS NUMBER 1-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1-1
1.3. PRODUCTION DATA 1-3
1.4. USE DATA 1-5
1.5. SUMMARY 1-5
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 2-1
2.1. HATER 2-1
2.1.1. Hydrolysis 2-1
2.1.2. Oxidation 2-1
2.1.3. Photolysis 2-2
2.1.4. Mlcroblal Degradation 2-2
2.1.5. Miscellaneous Processes 2-3
2.1.6. Transport 2-3
2.1.7. Persistence 2-6
2.2. AIR 2-6
2.2.1. Chemical Removal Processes 2-6
2.2.2. Physical Removal Processes 2-7
2.3. SOIL 2-7
2.3.1. Mlcroblal Degradation 2-7
2.3.2. Photolysis 2-9
2.3.3. Adsorption-Leaching 2-9
2.3.4. Volatilization 2-10
2.4. SUMMARY 2-11
3. EXPOSURE 3-1
3.1. WATER 3-1
3.2. FOOD 3-3
3.3. AIR 3-5
3.4. MISCELLANEOUS EXPOSURE 3-5
3.5. SUMMARY 3-6
4. PHARMACOKINETCS 4-1
4.1. ABSORPTION 4-1
4.2. DISTRIBUTION 4-2
4.3. METABOLISM 4-4
4.4. EXCRETION 4-5
4.5. SUMMARY 4-7
xx
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TABLE OF CONTENTS (cont.)
Page
5. EFFECTS 5-1
5.1. CARCINOGENICITY 5-1
5.1.1. a-HCH 5-1
5.1.2. B-HCH 5-1
5.1.3. T-HCH 5-5
5.1.4. i-HCH 5-6
5.1.5. c-HCH 5-6
5.1.6. T-HCH 5-6
5.1.7. General Comments 5-10
5.2. MUTAGENICITY 5-10
5.3. TERATOGENICITY 5-14
5.4. OTHER REPRODUCTIVE EFFECTS 5-19
5.4.1. Testlcular Effects 5-19
5.5. CHRONIC AND SUBCHRONIC TOXICITY 5-20
5.5.1. a-HCH 5-20
5.5.2. B-HCH 5-22
5.5.3. T-HCH 5-24
5.5.4. 6-HCH 5-30
5.5.5. c-HCH 5-30
5.5.6. T-HCH ..... 5-30
5.6. OTHER RELEVANT INFORMATION 5-36
5.7. SUMMARY 5-36
5.7.1. a-HCH 5-36
5.7.2. B-HCH 5-36
5.7.3. T-HCH 5-38
5.7.4. 4-HCH 5-40
5.7.5. c-HCH 5-40
5.7.6. T-HCH 5-40
6. AQUATIC TOXICITY 6-1
6.1. ACUTE 6-1
6.2. CHRONIC 6-15
6.3. PLANTS 6-15
6.4. RESIDUES 6-15
6.5. SUMMARY 6-29
7. EXISTING GUIDELINES AND STANDARDS 7-1
7.1. HUMAN 7-1
7.2. AQUATIC 7-1
xx1
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TABLE OF CONTENTS (cont.)
8. RISK ASSESSMENT 8-1
8.1. a-HCH 8-1
8.2. B-HCH 8-5
8.3. Y-HCH 8-7
8.4. 4-HCH 8-12
8.5. e-HCH 8-12
8.6. T-HCH 8-12
9. REPORTABLE QUANTITIES 9-1
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
TOXICITY 9-1
9.1.1. a-HCH 9-1
9.1.2. B-HCH 9-3
9.1.3. Y-HCH 9-6
9.1.4. T-HCH 9-8
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED10)
FOR CARCINOGENICITY 9-10
9.2.1. a-HCH 9-10
9.2.2. B-HCH 9-20
9.2.3. Y-HCH 9-24
9.2.4. 6-HCH 9-31
9.2.5. c-HCH 9-31
9.2.6. T-HCH 9-32
9.3. SUMMARY OF ALL HCH CANCER DATA 9-41
10. REFERENCES 10-1
APPENDIX: LITERATURE SEARCHED A-l
xx11
-------
LIST OF TABLES
No. - Title J>aqe
1-1 CAS Numbers and Physical Properties of HCH Isomers 1-2
1-2 Production Data for HCH 1-4
5-1 Summary of Oral Cancer Studies Conducted with a-HCH 5-2
5-2 Summary of Oral Cancer Studies Conducted with B-HCH 5-4
5-3 Summary of Oral Cancer Studies Conducted with y-HCH
(Llndane) 5-7
5-4 Summary of Oral Cancer Studies Conducted with 4-HCH 5-9
5-5 Summary of Oral Cancer Studies Conducted with T-HCH 5-11
5-6 Summary of Mutagenldty Data 5-15
5-7 Oral Toxlclty Summary for a-HCH 5-21
5-8 Oral Toxlclty Summary for B-HCH 5-23
5-9 Oral Toxlclty Summary for y-HCH 5-25
5-10 Oral Toxlclty Summary for 6-HCH 5-31
5-11 Oral Toxlclty Summary for T-HCH 5-32
5-12 Oral LD50 Values for Isomers of HCH 5-37
6-1 Acute Toxlclty of Llndane to Freshwater Vertebrates 6-2
6-2 Acute Toxlclty of Other HCH Isomers to Freshwater
Vertebrates 6-5
6-3 Acute Toxlclty of HCH to Marine Fishes 6-8
6-4 Acute Toxlclty of Llndane to Aquatic Invertebrates 6-11
6-5 Acute Toxlclty of Other HCH Isomers to Aquatic
Invertebrates 6-14
6-6 Chronic Toxlclty of HCH to Aquatic Organisms 6-16
6-7 Effects of HCH on Aquatic Plants 6-17
6-8 HCH Uptake and Elimination by Aquatic Organisms 6-19
6-9 HCH Residues In Tissues of Aquatic Organisms 6-24
XX111
-------
LIST OF TABLES (cont.)
No. " Title Page
6-10 Maximum and Mean Wet Weight and Llpld Weight Residue
Concentrations of a-HCH and Llndane from Whole F1sh
Samples Collected from 107 Stations In the United States. . . 6-28
7-1 Ambient Water Quality Criteria for the Protection
of Human Health 7-2
8-1 Summary of Pertinent Data for q-|* for a-HCH 8-2
8-2 Derivation of a q-j* for a-HCH 8-4
8-3 Derivation of a q-|* for a-HCH 8-6
8-4 Summary of Pertinent Data for q-|* for B-HCH 8-8
8-5 Summary of Pertinent Data for q-j* for y-HCH 8-11
8-6 Summary of Pertinent Data for q-|* for T-HCH . 8-14
8-7 Derivation of a q^* for T-HCH 8-16
8-8 Derivation of the q-|* for T-HCH Recommended as the Best
Estimate of Cancer Potency for T-HCH 8-17
9-1 Oral Composite Scores for HCH 9-2 .
9-2 a-HCH: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 9-4
9-3 B-HCH: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 9-5
9-4 f-HCH: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 9-9
9-5 T-HCH: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 9-11
9-6 Incidence of Liver Neoplasms In Male DDY Mice Fed a-HCH
(>99X pure) In the Diet 9-12
9-7 Incidence of Hepatic Neoplasms In Mice fed a-HCH
for 24 Weeks 9-13
9-8 Incidence of Liver Neoplasms 1n Male dd Mice Fed a-HCH
(>99X pure) In the Diet for 24 weeks 9-15
9-9 Incidence of Liver Neoplasms In Male dd Mice Fed a-HCH
(>99% pure) In the Diet for 24 weeks 9-16
xxlv
-------
LIST OF TABLES (cont.)
No. - Title Page
9-10 Incidences of Hepatomas In dd Mice Fed a-HCH In the Diet
for 32 Weeks 9-17
9-11 Incidences of Liver Neoplasms In Male Wlstar Rats Fed a-HCH
(>99% pure) 1n the Diet 9-18
9-12 Incidences of Liver Neoplasms In Female Wlstar Rats
Exposed to a-HCH (99.5% pure) 9-19
9-13 Derivation of Potency Factor (F) for a-HCH 9-21
9-14 Incidence of Liver Neoplasms 1n CF1 Mice Fed B-HCH
(>99X pure) In the Diet for up to 110 Weeks 9-22
9-15 Derivation of Potency Factor (F) for B-HCH 9-25
9-16 Incidence of Hepatomas 1n dd Mice Fed y-HCH In the Diet
for 32 Weeks and Examined After 37-38 Weeks 9-27
9-17 Incidence of Liver Neoplasms In CF1 Mice Fed y-HCH
{>99.5% pure) In the Diet for up to 110 Weeks . 9-28
9-18 Derivation of the Potency Factor (F) for Y-HCH 9-30
9-19 Incidence of Hepatomas 1n dd Mice Fed T-HCH 1n the Diet
for 32 Weeks and Examined After 5-6 Weeks Posttreatment . . . 9-33
9-20 Incidence of Liver Neoplasms 1n Male dd Mice Fed T-HCH
1n the Diet for 24 weeks 9-34
9-21 Incidence of Tumors In Swiss Mice Exposed Orally to T-HCH
for 80 Weeks 9-35
9-22 Incidence of Liver Neoplasms In Male Swiss Mice Fed T-HCH
1n the Diet 9-36
9-23 Incidence of Liver Neoplasms 1n Male Swiss Mice Fed T-HCH
1n the Diet from 8-10 Weeks of Age up to 22 Months of Age . . 9-37
9-24 Incidence of Liver Tumors 1n Mice Fed T-HCH 1n the Diet from
8-10 Weeks of Exposure up to 20 Months of Exposure 9-38
9-25 Derivation of Potency Factor (F) for T-HCH 9-40
9-26 Summary of the CardnogenlcHy Evaluation for
Hexachlorocyclohexanes of Environmental Concern 9-42
xxv
-------
LIST OF ABBREVIATIONS
AchE ' Acetylchollnesterase
ADI Acceptable dally Intake
ATP Adenoslne trlphosphate
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
DNA DeoxyMbonuclelc add
ECso Concentration effective to 50% of recipients
EEG Electroencephalogram
PEL Frank-effect level
HCH Hexachlorocyclohexane
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
LD5Q Dose lethal to SOX of recipients
LOAEL Lowest-observed-adverse-effect level
MATC Maximum acceptable toxicant concentration
MED Minium effective dose
MTD Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
xxvl
-------
LIST OF ABBREVIATIONS (cont.)
PCB PolychloMnated blphenyls
ppb Parts per billion
ppm Parts per million
ppt Parts per thousand
RBC Red blood cell
RNA R1bonucle1c add
RQ Reportable quantity
RVj Dose-rating value
RVe Effect-rating value
SDH Succlnlc dehydrogenase
T-HCH Technical grade HCH
TWA Time-weighted average
UDP Ur1d1ne dlphosphate
UV Ultraviolet
xxvll
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The structure of HCH 1s depicted below.
Cl
Molecular weight: 290.7
Empirical formula: C,H,C1,
00 0
The orientations of the various Isomers discussed In this document are
given below. The CAS numbers of the possible HCH Isomers are listed 1n
Table 1-1.
Orientation of
Cl Atoms on Ring
Isomer
Percent of Isomer
1n Technical HCH
AAEEEE
EEEEEE
AAAEEE
AEEEEE
AEEAEE
a
3
Y
(Undane)
6
t
60-70
5-12
10-15
6-10
3-4
1.2. PHYSICAL AND CHEMICAL PROPERTIES
The Isomers of HCH are white or yellowish powders or flakes, depending
on the Isomer. The odor also depends on the Isomer. The Isomers are
soluble In 100% alcohol, chloroform or ether (Hawley, 1981). Selected
physical properties are listed In Table 1-1.
HCH Isomers can be decomposed by alkaline substances (Hawley, 1981), and
can undergo reactions typical of alkyl halldes. Including hydrolysis and
dehydrohalogenatlon (Morrison and Boyd, 1973).
0816p
1-1
10/21/86
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0816p
1-2
06/27/86
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1.3. PRODUCTION DATA
Production data from the 1977 TSCA Inventory (U.S. EPA, 1977) are
presented In Table 1-2.
T-HCH (65:7:14:4:10; a, 8, Y» e, other Isomers) 1s produced by the
action of visible or UV light. X-rays or gamma rays on a mixture of benzene
and chlorine 1n the presence of free radical Initiators. Batch or continu-
ous methods In stirred tank type reactors or tubular reactors are used.
Typically, benzene 1n excess Is chlorinated at 15-25°C at 1 atm In a glass
reactor. Oxygen and substitution catalysts such as Iron must be excluded.
Part of the benzene Is removed at ambient pressure with the remaining
benzene being removed at reduced pressure. The molten product 1s then steam
stripped to remove residual traces of benzene (Colson, 1979).
Llndane, which 1s >99% y-HCH, Is produced commercially by the super-
saturation process or the fluid classification process. After a-HCH Is
supersaturated In a lower primary alcohol such as methanol, leaving most of
the Y-HCH undlssolved, the alcohol 1s removed, and the y-HCH-r1ch mate-
rial 1s then dissolved 1n carbon tetrachlorlde or a parafflnlc hydrocarbon.
A y-HCH rich concentrate Is precipitated from this preparation. The
concentrate from which the very pure y-HCH 1s finally Isolated contains a
number of Impurities Including a-, 8- and
-------
TABLE 1-2
Production Data for HCH*
Isomer
Y-HCH
a-HCH
B-HCH
4-HCH
c-HCH
Company/Location
Steuber Co. , Inc.
New York, NY
Napp Chemicals, Inc.
Lod1, NJ
Hooker Chemicals i Plastics
Niagara Falls, NY
Hooker Chemicals & Plastics
Niagara Falls, NY
Hooker Chemicals & Plastics
Niagara Falls. NY
Hooker Chemicals & Plastics
Niagara Falls, NY
Hooker Chemicals & Plastics
Niagara Falls, NY
Importer/
Manufacturer
Importer
Importer
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Production
(Ibs)
10,000-100
1,000-10,
NR
NR
NR
NR
NR
Range
,000
000
*Source: U.S. EPA, 1977
NR = Not reported
0816p
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08/07/86
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1.4. USE DATA
y-HCH Is used as an Insecticide on hardwood logs and lumber, seeds
(such as wheat, oats and rye, corn, sorghum, lentils, dry peas), vegetables
and fruits (such as avocados, pineapples, curcubHs, pecans), woody orna-
mentals (such as Christmas trees), hardwood forests, livestock and pets
(external parasite control) and existing structures (control for woodborlng
beetles and termites) (Federal Register, 1983). Pertinent data regarding
uses of the remaining Isomers 1n a pure state could not be located 1n the
available literature as cited 1n the Appendix. The technical form of HCH
contains all the Isomers, however, and has been used as an Insecticide In
the past. It Is no longer used as such 1n the United States (Colson, 1979).
1.5. SUMMARY
The Isomers of HCH are white or yellowish powders or flakes, with
differing odors depending on the Isomer. The Isomers are soluble to varying
degrees In a variety of organic solvents Including ethyl alcohol, chloro-
form, acetone, dloxane, ether and others (Colson, 1979). HCHs can be decom-
posed by alkaline substances and are expected to undergo reactions typical
of alkyl halldes Including hydrolysis and dehydrohalogenatlon (Morrison and
Boyd, 1973).
T-HCH, a 65:7:17:4:10 mixture of a, B, y, c and other Isomers of
HCH, respectively, 1s produced by the photochem1cally-1nduced reaction
between benzene and chlorine In the presence of a free radical Initiator. A
variety of physical separation methods are used to purify y-HCH to 99.9%
from T-HCH for use as an Insecticide (llndane) (Colson, 1979).
0816p 1-5 08/07/86
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y-HCH 1s used as an Insecticide on hardwood logs and lumber, a variety
of seeds, vegetables and fruits, woody ornamentals Including Christmas
trees, hardwood forests, livestock and pets (external parasite control) and
existing structures (control of woodborlng beetles and termites) (Federal
Register, 1983). Pertinent data regarding uses of the other Isomers 1n the
pure state could not be located 1n the available literature as cited 1n the
Appendix. The technical product has been used as an Insecticide In the past
but Is no longer used as such (Colson, 1979).
0816p 1-6 08/07/86
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
2.1. WATER
2.1.1. Hydrolysis. Hydrolysis rate constants at 25°C of 7.5xlO"3,
8.99xlO~* and l.OTxlO"3 hour'1 were determined for Y-HCH In surface
water samples from a eutrophlc pond In Texas (pH 9.3), a dystrophlc
reservoir 1n Louisiana (pH 7.3) and an ol1gotroph1c rock quarry In Indiana
(pH 7.8), respectively (Saleh et al., 1982). The corresponding hydrolysis
half-lives are 92, 771 and 648 hours. Hydrolysis rates of 7.4xlO"«,
1.6xlO"4 and 7.3xlO"3 hour"1 at pH values of 5, 7 and 9, respectively,
were observed for y-HCH 1n M1111-Q water at 25°C (Saleh et al., 1982).
The hydrolysis reactions followed first-order kinetics. Hydrolysis 1n
addle or neutral waters 1s not expected to be a significant fate process
for Y-HCH, although alkaline hydrolysis may be Important.
Pertinent data regarding the rate of hydrolysis of a-HCH could not be
located 1n the available literature as cited In the Appendix. Hydrolysis of
Y-HCH has been observed, however, and based on the relatively greater
stability of o-HCH Imparted by Its greater number of equatorial chlorines,
1t may hydrolyze more slowly than Y-HCH.
Pertinent data regarding the hydrolysis of any of the other Isomers of
HCH could not be located 1n the available literature as cited 1n the
Appendix. 6-. «- and e-HCH, however, have more equatorial chlorines
than Y-HCH, and since equatorial bonds are generally more stable than
axial bonds, H 1s expected that these Isomers will be more resistant to
hydrolysis than Y-HCH.
2.1.2. Oxidation. Pertinent data regarding the oxidation of any of the
Isomers of HCH could not be located 1n the available JHerature as cited In
the Appendix.
0817p 2-1 06/10/86
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2.1.3. Photolysis. First-order photolysis of y-HCH was observed In
direct sunlight photolysis experiments 1n water samples from a eutrophlc
pond In Texas, a dystrophlc reservoir In Louisiana and an ollgotrophic rock
quarry In Indiana (Saleh et a!., 1982). The photolysis rate constants were
4.1xlO~3 (Texas), 3.9xlO"« (Louisiana) and 4.5xlO~4 (Indiana)
hour"1, which correspond to photolysis half-lives of 169, 1791 and 1540
hours, respectively. The relatively low half-life value observed 1n the
Texas water samples was attributed to the higher pH since the products of
hydrolysis, which were presumably In equilibrium with y-HCH, were reported
to be more susceptible to photolysis than y-HCH. A dark control was used
In these studies (Saleh et al., 1982). After 50 days exposure to sunlight,
the concentration of y-HCH In purified water dropped from -9300 to -7600
vg/mi, and the concentration of a-HCH dropped from -1480 to -1130
vg/mi (Mala1yand1 et al., 1982). Since y-HCH and a-HCH have no
conjugated unsaturated systems, 1t Is difficult to explain these apparent
photolyses. It 1s expected, however, that direct photolysis will not be a
predominant fate mechanism for y-HCH or a-HCH 1n the environment.
Pertinent data regarding the photolysis of any of the other Isomers of
HCH could not be located In the available literature as cited 1n the
Appendix. These compounds are not expected to absorb radiation of wave-
lengths present In sunlight since they do not have conjugated unsaturated
systems. They should not, therefore, directly photolyze 1n the environment.
2.1.4. N1crob1a1 Degradation. Of the y-HCH added to unsterilized
natural waters 1n capped bottles, <30X remained after 16 weeks (Sharom et
al., 1980). The authors concluded that blodegradatlon was responsible for
this result, although It was unclear to what extent hydrolysis may have been
0817p 2-2 06/27/86
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Involved. About 25X of y-HCH In raw wastewater from Cincinnati was
removed during aerobic blodegradatlon In a wastewater treatment plant
(Petrasek et al., 1983). Aqueous blodegradatlon data were not available for
any of the other Isomers of HCH.
2.1.5. Miscellaneous Processes. The 1somer1zat1on of y-HCH to a-HCH
by sunlight has been reported (Mala1yand1 et al., 1982). Only a small
amount of y-HCH 1s affected by this transformation, however, so H Is not
expected to be a major environmental fate process.
Deo et al. (1980) observed the formation of a-, y- and 6-HCH by
the reaction of B-HCH with water at 25°C. Only a small portion (not quanti-
fied) of the B-HCH was transformed, however, so the process 1s not a major
fate process for fl-HCH. Instantaneous dechlorlnatlon of B-HCH was also
observed (Deo et al., 1980).
2.1.6. Transport.
2.1.6.1. VOLATILIZATION — Assuming a depth of 1 m, .the volatiliza-
tion half-life of y-HCH from water has been estimated to be 115 days
(Lyman et al., 1982) and 191 days (Mackay and Lelnonen, 1975). From a depth
of 4.5 cm, a volatilization half-life of 3.2 days was determined for y-HCH
In still, pure water at 24°C, while with stirring, the half-life was 1.5
days (Chlou et al., 1980). Using an equation relating water depth to vola-
tilization half-life (Chlou et al., 1980), the experimental volatilization
half-life of 3.2 days was used to calculate a half-life of 692 days for a
depth of 1 m. Since this figure 1s of the same order of magnitude as the
estimated half-lives of 115 and 191 days for volatilization from 1 m, these
figures are considered to be valid estimates of the tendency of Undane to
volatilize.
0817p 2-3 06/27/86
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Measured values of the water solubilities and vapor pressures of the HCH
Isomers (except e-HCH) were used to estimate the Henry's Law constants of
the Isomers that are presented In Table 1-1. Because no experimental data
were available for e-HCH, the Henry's Law constant for {-HCH, the Isomer
which most closely resembles e-HCH, Is given In Table 1-1 as an estimate
of the c-HCH Henry's Law constant. Based on these values, all the Isomers
of HCH are expected to volatilize from water at a rate dependent upon the
rate of diffusion through the air (Lyman et al., 1982).
2.1.6.2. ADSORPTION — A mean K of 1080.9 was obtained for
oc
Y-HCH from K determinations on three soils with an average organic
content of 13X (Rao and Davidson, 1982). Based on this moderate K value
oc
and a water solubility of 7.5 ppm (U.S. EPA, 1981), Y-HCH Is expected to
leach slowly to groundwater. The leaching of y-HCH from Gezlra soil
(38.8X sand, 34.7X silt, 26.2X clay and 4.6X organic carbon) from the Sudan
was slow; after 45 days, <50X of the applied y-HCH had leached from the
soil (El Belt et al., 1981). The fate of Y-HCH has been studied 1n a
field scale experiment (01 Toro and Paquln, 1984). After 100 days, 75% of
the applied Y-HCH was found In the water column and sediment layer of the
rock quarry; the water column contained >75X of this amount. The role of
particle transport In the transfer of y-HCH to the sediment was found to
be small compared with diffusion (D1 Toro and Paquln, 1984). Saleh et al.
(1982) determined Freundllch constants for Y-HCH sorptlon and desorptlon
for four systems: montmorlllonlte clay-distilled water, 1258.9 for both
sorptlon and desorptlon; Roselawn Cemetery water-sediment. 354.8 and 4.26;
Cross Lake water-sediment, 56.2 and 11,220.2; and Indiana Quarry water-
sediment, 2238.7 and 4.26 for sorptlon and desorptlorv, respectively. Saleh
et al. (1982) reported that the high desorptlon constant for the Cross Lake
system suggested a strong Interaction between y-HCH and the organic
0817p 2-4 06/10/86
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material 1n the samples, although the organic contents of the two sediment
samples were similar (Roselawn Cemetery, 1.34X and Cross Lake, 1.33%).
Using a measured water solubility of 2.0 mg/l (U.S. EPA, 1981), a
K of 6463 was estimated for o-HCH (Lyman et a!., 1982). According to
Kenaga (1980), a K of >1000 Indicates such strong adsorption to organic
matter In soil that the compound Is considered Immobile. The K value of
a-HCH and Its low water solubility, therefore, suggest that a-HCH will
bind tightly to soil and leach slowly to groundwater.
A log K value of 3.46 was determined for B-HCH (Schwarzenbach and
Westall, 1981). The water solubility of B-HCH 1s 0.24 mg/l (U.S. EPA,
1981). and combined with the log K of 3.46, B-HCH 1s expected to bind
tightly to soil (Kenaga, 1980) and leach slowly to groundwater.
Using a measured water solubility of 31.4 mg/j. (U.S. EPA, 1981), a
KQC of 1394.3 was estimated for a-HCH (Lyman et al.. 1982). The
moderate water solubility and K of 4-HCH suggest that the Isomer will
bind less tightly than the previous Isomers, but still tightly enough to
prevent rapid Infiltration to groundwater.
Since a measured water solubility for c-HCH was not available, the
measured K of i-HCH, the Isomer that most resembles c-HCH, was used
to estimate a water solubility of 17.4 mg/l for c-HCH, which was then
used to estimate a K value of 1950. The estimated water solubility and
KQC values suggest that e-HCH will bind fairly tightly to soil and will
slowly leach to groundwater.
2.1.6.3. BIOACCUMULATION — Direct Introduction of y-HCH to water
along with the primary food organism (yeast) resulted 1n a BCF of 183 In
brine shrimp, while Introduction of y-HCH onto sand Resulted In a BCF In
the shrimp of 95. Exposure of northern brook sllverslde fish to y-HCH
residues .on sand resulted In a BCF of 1613 (Matsumura and Benezet, 1973).
0817p 2-5 06/10/86
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An average BCF of 319 for Y-HCH was observed 1n Sal mo qalrdnerl Richardson
fry (Ramamoorthy, 1985). BCF factors of 1246 1n topmouth gudgeons
(Kanazawa, 1983), 560 In the fish, Gambusla afflnls (Schlmmel et al., 1977)
and 456 In the snail, Physa (Hetcalf et al., 1973) were observed. Mean BCF
values of 84, 218, 63 and 490 were determined for pink shrimp, plnflsh,
grass shrimp and sheepshead minnows, respectively (Schlmmel et al., 1977).
A BCF of 697 was observed for y-HCH In short-necked clams (Yamoto et al.,
1983).
BCFs of 161 In short-necked clams (Yamato et al., 1983), 706 1n gupples
(Yamato et al., 1983), 216 1n the golden orfe, 588 In gupples, 330 1n carp
and 605 In brown trout {Suglura et al., 1979) were reported for a-HCH.
Yamato et al. (1983) observed BCFs of 1043 and 127 for B-HCH and 648 and 272
for 6-HCH 1n gupples and short-necked clams, respectively.
Pertinent data regarding the bloconcentratlon of e-HCH could not be
located In the available literature as cited In the Appendix. It Is
expected, however, that c-HCH will bloconcentrate to a similar extent as
6-HCH because the two Isomers are similar. Bloconcentratlon Is not
expected to be significant for any of the Isomers of HCH.
2.1.7. Persistence. Based on degradation data, the persistence half-
lives for y-HCH In river, lake and groundwater were estimated to be 3-30,
30-300 and >300 days, respectively (Zoeteman et al., 1980). Pertinent data
regarding the persistence of the other HCH Isomers could not be located In
the available literature as cited In the Appendix.
2.2. AIR
2.2.1. Chemical Removal Processes. The half-life of the reaction of HCH
(unspecified Isomer) with hydroxyl radicals In the atmosphere was estimated
to be 1.63 days (U.S. EPA. 1985a).
0817p 2-6 06/27/86
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2.2.2. Physical Removal Processes. The removal rates of Y-HCH from the
atmosphere by rainfall and dry deposition are 2.5 and 3.3X per week, respec-
tively, and the estimated residence time of Y-HCH 1n the atmosphere 1s 17
weeks (Lewis and Lee, 1976). Pertinent data regarding the removal of the
other Isomers of HCH could not be located 1n the available literature as
cited In the Appendix.
2.3. SOIL
2.3.1. M1crob1al Degradation. As the sole carbon source, y-HCH was
found to support the growth of 71/147 microorganisms Isolated from loamy
sand (Tu, 1976). Chloride Ion formation was noted In these cultures. The
extent of blodegradatlon In these pure culture studies was not given.
Metabolites Isolated from 13 of the 71 microorganisms Included
Y-2,3,4,5,6-pentachloro-l-cyclohexene, a-, B- and y-3,4,5,6-tetra-
chloro-1-cyclohexene and pentachlorobenzene (Tu, 1976). From moist aerated
soil, 62X of the applied Y-HCH was recovered and 3X of the applied 14C
was released after 105 days. After 140 days, 17.8X of the applied 14C was
released from submerged soil. The loss of Y-HCH from submerged anaerobic
soil measured by gas-liquid chromatography was nearly quantitative, with
only 45t of the applied y-HCH recoverable (Kohnen et al., 1975). Mathur
and Saha (1975) reported that 1,2,4-tr1chlorobenzene, 1,2,3,4-tetrachloro-
benzene, Y-2,3,4,5,6-pentachlorocyclohex-l-ene and Y-3,4,5,6-tetra-
chloroclohexane were detected by gas chromatography In the soil 6 weeks
after It was treated with Y-HCH and submerged. The absence of these
products from sterilized soil treated with Y-HCH was cited as evidence
that the compounds were metabolic products from Y-HCH blodegradatlon.
Incubation of aerobic and anaerobic soil suspensions .of Y-HCH for 3 weeks
resulted In the disappearance of zero and 63.8X of the applied Y-HCH,
0817p 2-7 06/10/86
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respectively (Uchtensteln et al., 1971), Indicating that anaerobic degrada-
tion of y-HCH Is more extensive than aerobic degradation. A Clostrldlum
sp. Isolated from y-HCH-amended son was observed to degrade 87X of added
Y-HCH In 24 hours under anaerobic conditions (Sethunathan and Yoshlda,
1973). Blodegradatlon of y-HCH In thick anaerobic digested wastewater
sludge at 35°C was rapid, with <1054 of the added 10 and 1 ppm y-HCH
remaining after 2 and 4 days, respectively (Hill and McCarty, 1967). When
y-HCH was added to an anaerobic preparation of CUrobacter Freundll.
Clostrldlum butyrlcum. Clostrldlum pasteuManum or mixed soil flora, 91.5,
98.3, 91.0 and 78.OX of the organic 3SC1 was released as 35C1 1on
(Haider, 1979). Several studies have shown that anaerobic mlcroblal action
can transform y-HCH Into a-HCH (Vonk and Qu1r1jns, 1979; Engst et al.,
1979). This conversion Is not extensive, however, and 1s not expected to be
of major Importance In the fate of y-HCH.
After 2 weeks 1n unsterlUzed submerged Caslguran sandy loam, the
concentration of a-HCH declined from -16 to <1 ppm compared with a decline
from -18 to 15 ppm In a sterilized preparation (Castro and Yoshlda, 1974).
In another experiment, Incubation of aerobic and anaerobic soil suspensions
of a-HCH for 3 weeks resulted In the disappearance of 11.0 and 26.2% of
the added a-HCH. respectively (MacRae et al., 1984). Indicating that
anaerobic degradation Is more extensive than aerobic blodegradatlon.
Anaerobic pure cultures, probably Clostrldlum sp., degraded suspensions of
a-HCH 1n flooded soils, although no Information on rates was given (Ohlsa
and Yamaguchl, 1978). When a-HCH was added to an anaerobic preparation of
C. freund11. C. butyrlcum. C. pasteurlanum or mixed soil flora, 13.9, 97.4,
53.2 and 6.5X of the organic **C1 was released ds "Cl 1on (Haider,
0817p 2-8 06/27/86
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1979). After 20 weeks of aerobic and anaerobic Incubation of soil samples
polluted with a-HCH, 55 and 35% of the Initial amount of a-HCH had
blodegraded (Doelman et al., 1985).
When B-HCH and 5-HCH were added to an anaerobic preparation of C.
freundl.1, C_. butyrlcum. C_. pasteurlanum or mixed soil flora, 15.3, 23.8,
10.1 and 7.434 (B-HCH), respectively, and 2.8, 38.5, 5.0 and 1.6% (5-HCH),
respectively, of the organic 3SC1 was released as 35C1 Ion (Haider,
1979). Pertinent data regarding" the blodegradatlon of c-HCH could not be
located In the available literature as cited 1n the Appendix.
2.3.2. Photolysis. Pertinent data regarding the photolysis of HCH
Isomers In soil could not be located 1n the available literature as dted In
the Appendix. Although some data suggest that y-HCH 1s subject to
photolysis In water (Saleh et al., 1982), because the lack of a conjugated
unsaturated system Indicates that little or no absorption of light should
occur 1n the environment, soil photolysis Is not expected to be significant.
2.3.3. Adsorption-Leaching. A mean K of 1080.9 was obtained from
K determinations on three soils with an average organic content of 13%
(Rao and Davidson, 1982). Based on this moderate K value and a water
solubility of 7.5 ppm (U.S. EPA, 1981), y-HCH 1s expected to leach slowly
to groundwater. The leaching of y-HCH from Gezlra soil (38.8% sand, 26.2%
clay and 4.6% organic carbon) from the Sudan was slow; after 45 days, <50%
of the applied r-HCH had leached from the soil (El Belt et al., 1981).
Fifteen years following the application of technical HCH to a sandy loam
soil In Nova Scotia, Canada, 4, 44, 10 and 14% of the applied a-. B-,
Y- and 4-HCH remained 1n the soil, respectively. Of this amount, -92,
92.1, 94.7 and 95.1% of the a-, B-. Y- and 4-HCH was found within a
depth of 0-20 cm, Indicating minimal leaching of the Isomers. The soil was
0817p 2-9 06/10/86
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cultivated yearly throughout the 15-year period, Increasing the likelihood
that volatilization may have occurred (Stewart and Chlsholm, 1971).
Using a measured water solubility of 2.0 mg/l (U.S. EPA, 1981), a
K of 6463 was estimated for o-HCH (Lyman et al., 1982). According to
Kenaga (1980), a K of >1000 Indicates such strong adsorption to organic
matter In soil that the compound 1s considered Immobile. The K value of
a-HCH and Us low water solubility, therefore, suggest that o-HCH will
bind tightly to soil and leach slowly to groundwater.
Schwarzenbach and Westall (1981) determined a log K value of 3.46
for B-HCH. Using the water solubility for 3-HCH of 0.24 mg/l (U.S. EPA,
1981) and the log KQC of 3.46. B-HCH 1s expected to bind tightly to soil
(Kenaga, 1980) and leach slowly to groundwater.
Using a measured water solubility of 31.4 mg/l (U.S. EPA, 1981), a
K of 1394.3 was estimated for i-HCH (Lyman et a!., 1982). The
moderate water solubility and K suggest that the Isomer will bind less
tightly than the previous Isomers, but still tightly enough to prevent rapid
Infiltration to groundwater.
Since a measured water solubility for c-HCH was not available, the
measured K for 4-HCH, the Isomer that most resembles c-HCH, was used
to estimate a water solubility of 17.4 mg/l for e-HCH, which was then
used to estimate a K value of 1950. The water solubility and K
oc oc
values suggest that e-HCH will bind fairly tightly to soil and will slowly
leach to groundwater.
2.3.4. Volatilization. After 50 hours. 26 and 100% of surface applied
Y-HCH remained on Hatboro silt loam and Norfolk sandy loam, respectively
(Glotfelty et al., 1984). The authors concluded •that Y-HCH did not
volatilize on the sandy loam because of the dryness of the soil. From a
0817p 2-10 06/27/86
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moist soil surface, the y-HCH content decreased to 50 and 10% of the
amount applied after 6 hours and 6 days, respectively, while 50 hours after
the application of y-HCH to dry soil, 88X of the applied compound remained
(Glotfelty et al., 1984). The y-HCH content of fallow soil 1n a mlcro-
agroecosystem chamber declined to 12% of that applied after 11 days (Nash,
1983).
Pertinent data regarding volatilization of the other HCH Isomers could
not be located 1n the available literature as cited 1n the Appendix. The
estimated Henry's Law constants, K s and measured water solubilities (see
Table 1-1) suggest that the Isomers win bind fairly tightly to soil and
will have little tendency to volatilize from dry soils. Volatilization from
moist soils, however, may be significant.
2.4. SUMMARY
Half-lives of f-HCH In water at 25°C were reported to be 92, 771 and
648 hours In natural water samples from a eutrophlc pond 1n Texas (pH 9.3),
a dystrophlc reservoir In Louisiana (pH 7.3) and an ollgotrophlc rock quarry
In Indiana (pH 7.8), respectively (Saleh et al., 1982). Hydrolysis experi-
ments In M1111-Q water at pH values of 5, 7 and 9 yielded half-lives of 936,
4331 and 95 hours, respectively (Saleh et al., 1982). Therefore, hydrolysis
at alkaline pH values 1s expected to be Important In the fate of y-HCH,
while hydrolysis at acidic and neutral pH values Is not. Pertinent data
regarding the hydrolysis of the other Isomers of HCH could not be located In
the available literature; however, all these Isomers contain more equatorial
bonds than y-HCH, and since these bonds are generally more stable than
axial bonds, It 1s expected that the remaining Isomers will be more stable
to hydrolysis than f-HCH.
0817p 2-11 06/10/86
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First-order photolysis half-lives for Y-HCH of 169. 1791 and 1540
hours were observed In natural water samples from a eutrophlc pond 1n Texas,
a dystrophlc reservoir 1n Louisiana and an ollgotrophlc rock quarry In
Indiana, respectively (Saleh et al., 1982). The relatively short photolysis
half-life observed 1n the Texas sample was attributed to the alkaline pH
that, H was concluded, generated hydrolysis products more susceptible to
photolysis than y-HCH (Saleh et al., 1982). After 50 days exposure to
sunlight, the concentrations of y- and <*-HCH 1n purified water dropped
from -9300 to -7600 yg/mj, and from 1480 to -1130 yg/mi, respectively
(Mala1yand1 et al., 1982). Pertinent data regarding the photolysis of the
other HCH Isomers could not be located 1n the available literature as dted
In the Appendix. Direct photolysis, however. Is not expected to be a major
fate process for any of the HCH Isomers since they do not have conjugated
unsaturated systems.
Of the Y-HCH added to unsterlUzed natural waters "1n capped bottles,
<30X remained after 16 weeks (Sharom et al., 1980). About 25% of the
Y-HCH In raw wastewater from Cincinnati was removed during aerobic
blodegradatlon In a wastewater treatment plant (Petrasek et al., 1983).
Pertinent data regarding the aqueous blodegradatlon of the other HCH Isomers
could not be located In the available literature as dted In the Appendix.
Mala1yand1 et al. (1982) reported that a small amount of Y-HCH
1somer1zed to a-HCH upon exposure to sunlight. B-HCH reacts with water at
2S°C to form small amounts of a-, 6- and Y-HCH, and Instantaneous
dechlorlnatlon of B-HCH In water was observed to a small degree (Deo et al.,
1980). None of these processes are expected to contribute significantly to
the degradation of the HCH Isomers In the environment. '
0817p 2-12 06/27/86
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The volatilization half-life of y-HCH has been estimated to be 115
days (Lyman et al., 1982) and 191 days (Mackay and Lelnonen, 1975), assuming
a depth of 1 m. Volatilization half-lives of 3.2 and 1.5 days were observed
for T-HCH from still and stirred water 4.5 cm deep (Chlou et al., 1980).
The measured volatilization half-life of 3.2 days was used to estimate a
half-life of 692 days from water 1 m deep. Since the half-lives of 115 and
191 days are of the same order of magnitude as the half-life estimated from
experimental data, the former values are considered to be accurate estimates
of the tendency of q-HCH to volatilize. Henry's Law constant values for the
other Isomers have been estimated and suggest that volatilization of all HCH
Isomers occurs at a rate dependent upon the rate of diffusion through the
air (Lyman et al., 1982). Volatilization of HCH Isomers In water Is not
expected to be significant In the environment.
A mean K for y-HCH of 1080.9 was obtained from K determlna-
oc ' oc
tlons on three soils (Rao and Davidson, 1982). Base-d on this K and a
low water solubility of 7.5 ppm (U.S. EPA, 1981), y-HCH Is expected to
leach slowly to groundwater. K values for the remaining HCH Isomers
were estimated (Lyman et al., 1982), and combined with the fairly low water
solubilities of the Isomers suggest that they are expected to bind fairly
tightly to soil and to leach slowly to groundwater. Fifteen years following
the application of technical HCH to a sandy loam soil 1n Canada, >90% of the
applied a-, B-, ?- and 6-HCH remained In the upper 20 cm of soil,
Indicating minimal leaching had taken place (Stewart and Chlsholm, 1971).
BCFs for Y-. «-t B- and &-HCH 1n a variety of species ranged from
63-1613 (Matsumura and Benezet, 1973; Ramamoorthy, 1985; Kanazawa, 1983;
Schlmmel et al., 1977; Metcalf et al., 1973; Yamato et>al., 1983; Suglura et
al., 1979). No BCF values were available for e-HCH, but 1s expected to
0817p 2-13 06/27/86
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bloaccumulate similarly to 6-HCH, to which n bears a close structural
similarity. None of the HCH Isomers are expected to bloconcentrate signifi-
cantly In aquatic organisms.
Based on degradation data, the persistence half-lives for y-HCH In
river, lake and groundwater were estimated to be 3-30, 30-300 and >300 days,
respectively (Zoeteman et al., 1980). Pertinent data regarding the persis-
tence of the other Isomers could not be located 1n the available literature
as cited In the Appendix.
Anaerobic soil preparations were found to readily degrade Y-HCH
(Kohnen et al., 1975; Mathur and Sana, 1975; L1chtenste1n et al., 1971;
Sethunathan and Yoshlda, 1973; Haider, 1979). Degradation of a-HCH by
anaerobic soils has also been observed (Castro and Yoshlda, 1974; MacRae et
al., 1984; Haider, 1979). Doelman et al. (1985) observed greater aerobic
than anaerobic degradation of a-HCH In polluted soil. Anaerobic degrada-
tion of- a-, B- and S-HCH by several organisms has been observed (Haider,
1979). Pertinent data regarding the blodegradatlon of c-HCH could not be
located 1n the available literature as cited In the Appendix.
After 50 hours, 26 and 100X of the surface applied y-HCH remained on
Hatboro silt loam and Norfolk sandy loam, respectively (Glotfelty et al.,
1984). The low volatility of the y-HCH was attributed to the dryness of
the sandy loam. From a moist soil surface, the y-HCH content decreased to
50 and 10X of the amount applied after 6 hours and 6 days, respectively.
while 50 hours after the application of y-HCH to dry soil, 88X of the
applied compound remained (Glotfelty et al., 1984). Pertinent data regard-
Ing the volatilization of the other HCH Isomers could not be located In the
available literature as dted In the Appendix. The 'estimated Henry's Law
constants, K and measured water solubility values suggest that the
oc
0817p 2-14 06/27/86
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Isomers will bind fairly tightly to soil and will have little tendency to
volatilize from dry soils. Volatilization from moist soils, however, may be
s Ignlfleant.
0817p 2-15 06/10/86
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3. EXPOSURE
3.1. WATER
Y-HCH has been detected at 0.01 ppb In Cincinnati, OH, drinking water
(Keith et al., 1976). Rural potable water samples 1n Hampton County, SC,
ranged from not detected (<10 ppt) to 319 ppt, with a median concentration
of 10 ppt, and 1n Chesterfield County, SC, from not detected to 193 ppt,
with a median concentration of 10 ppt. Median y-HCH concentrations 1n
closed wells 1n Chesterfield and Hampton Counties were 16 and 163 ppt,
respectively, and In Hampton County open wells, was 98 ppt (Sandhu et al.,
1978). Potable water samples from Oahu, HI, contained 0.06-0.4 ppt y-HCH,
with a mean concentration of 0.2 ppt (Bevenue et al., 1972). Tap water from
Ottawa, Ontario contained 1.3 vgA y-HCH (Krayblll, 1977). Using
2 i as the average amount of water consumed dally, the average dally
Intake of y-HCH from water consumption ranges from 0.02-0.638 yg, based
on the monitoring data (excluding the data from Ottawa) above; based on the
concentration of y-HCH 1n the Ontario tap water, the average dally Intake
Is 2.6 pg. Since the monitored value of the y-HCH concentration Is so
high relative to all the other values, this Intake value Is considered to be
nonrepresentatlve. Residues of y-HCH In whole samples of Oregon river
water (Includes dissolved and suspended y-HCH) ranged from <0.001-0.002
yg/l (U.S. EPA, 1985a). Surface water from N1agara-on-the-Lake (Oliver
and Charlton, 1984). Washington, DC and Denver, CO (Cole et al., 1984),
Virginia (Saleh et al., 1982), South Carolina (Sandhu et al., 1978), Hawaii
(Bevenue et al., 1972) and New Jersey (Page, 1981) contained measurable
quantities of y-HCH. Parts per trillion concentrations of y-HCH have
been detected 1n rain or snow samples from the Great* Lakes (Canadian side)
0818p 3-1 06/10/86
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(Strachan and Huneault, 1979), Portland, OR (Pankow et al., 1984), Canada
(12 sites) (Brooksbank, 1983) and two sites In Lake .Superior (Caribou Island
and Isle Royale) (Strachan, 1985).
a-HCH has been detected at 2.7-20.3 and 0.45-9.7 ppt 1n municipal
drinking water samples collected 1n the winter and summer, respectively,
from 12 sites 1n Canada (Williams et al., 1982) and at 17 vq/i In tap
water collected In Ottawa, Ontario, Canada (KraybUl, 1977). An average
dally Intake of a-HCH of 0.90-40.6 ng was calculated (excluding the Ottawa
result), assuming an average water consumption of 2 I/day. Based on the
high a-HCH content of tap water from Ontario, an average dally Intake of
34 jig was estimated. The relatively high value of a-HCH In the Ottawa
sample 1s thought to be nonrepresentatlve. Dissolved residues of a-HCH 1n
water ranged from 0.019-0.14 yg/l, with a mean concentration of 0.06025
vg/l (U.S. EPA, 1985a). Surface water from N1agara-on-the-Lake (Kuntz
and Warry, 1983), New Jersey (Page, 1981), Washington, DC and Denver, CO
(Cole et al., 1984) contained measurable amounts of a-HCH. Parts per
trillion concentrations have been detected 1n rain or snow samples from the
Great Lakes (Canadian side) (Strachan and Huneault, 1979). the Great Lakes
ecosystem (Elsenrelch et al., 1981), Portland, OR (Pankow et al., 1984),
Canada (12 sites) (Brooksbank. 1983) and two sites In Lake Superior (Caribou
Island and Isle Royale) (Strachan, 1985).
The concentration of B-HCH ranged from 3-50 ng/i, with a mean
concentration of 17.75 ng/i 1n three rivers; from 2-45 ng/i, with a mean
concentration of 13.3 ng/t In freshwater regions of the Rotterdam; and
from 1 40 ng/l (no mean given) In estuarlne regions In the Netherlands
(Oulnker and Hlllebrand, 1979). Suspended and dissolved B-HCH ranged from
0-1.0 and 0.1-0.2 jig/I, respectively. The mean concentrations were 0.75
0818p 3-2 06/27/86
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and 0.1725 u9/l. respectively (U.S. EPA, 1985a). Pertinent monitoring
data for 5- or e-HCH could not be located In the available literature as
cited 1n the Appendix.
3.2. FOOD
A wide variety of foodstuffs, Including meats, dairy products (except
milk) and vegetables analyzed from 1971-1976, contained y-HCH at ppb
concentrations (Ouggan et al., 1983). The average dally Intake of y-HCH
based on these studies averaged over 1971-1976 1s 0.27 g. Market basket
surveys conducted 1n 1977-1978 revealed the presence of ppb concentrations
In lunch meats, processed cheese, butter, frankfurters, pork chops,
hamburger and round steak (Podrebarac, 1984). Based on these figures, the
average dally Intakes of y-HCH 1n 1977 and 1978 were 3.8 and 2.4 ng/kg
bw/day. Domestic fish samples were 0.7X positive for y-HCH, with an
average concentration of 0.2 ppb, and Imported samples were 6.4% positive,
with an average concentration of 1 ppb In samples taken from 1969-1976.
Imported shellfish analyzed In the same time period contained a mean concen-
tration of y-HCH of 0.4 ppb In 2.1% of the samples (Duggan et al., 1983).
The concentration of y-HCH In a variety of fish collected across the
United States contained <0.01-0.2 ppm y-HCH (Schmltt et al., 1985).
Residues of y-HCH 1n 5026 dried samples of shellfish ranged from 5-100
ppb, with a mean of 7.703 ppm. and 1n 368 samples of shellfish, ranged from
0.001-44.0 ppb with a mean of 1.347 ppb (U.S. EPA, 1985a). Domestic samples
of milk were 2.0% positive for y-HCH, with a mean concentration of 2 ppb
(Ouggan et al., 1983).
Market basket surveys conducted 1n 1977-1978 Indicated ppb concentra-
tions of a-HCH 1n a variety of meats, cottage and .processed cheese. Ice
cream, fish fillets and canned fish, lunch meat and frankfurters
0818p 3-3 06/27/86
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(Podrebarac, 1984). Based on these figures, the average dally Intakes of
a-HCH In 1977 and 1978 were 10.5 and 9.1 ng/kg bw/day. The concentration
of a-HCH In a variety of fish collected across the United States contained
from <0.01-0.2 ppm a-HCH (Schmltt et a1., 1985). Residues of a-HCH In
384 shellfish samples ranged from 0.005-63.0 ppm (wet weight), with a mean
of 1.815 ppm (U.S. EPA, 1985a).
Residues of B-HCH in 375 shellfish samples ranged from 1.0-38.0 ppm (wet
weight), with a mean concentration of 1.940 ppm, and a-HCH ranged from
1.0-10.0 ppm. with a mean of 1.408 ppm 1n 375 shellfish samples (wet weight)
(U.S. EPA, 1985a). Specific data for 8-, «- or e-HCH were not located
In the available literature. A variety of foodstuffs, Including meats,
dairy products (except milk) and vegetables analyzed from 1971-1976,
contained ppb amounts of a-, B- and 4-HCH (combined residues) (Duggan et
al., 1983). Based on these studies, the average dally Intake of the
combined a-, B- and a-HCH residues 1s 0.67 g. The mean concentrations
of combined a-, B- and a-HCH Isomers 1n 13.IX of domestic and 33.1% of
Imported fish samples were 48 and 1 ppb, respectively. The mean concentra-
tions of the Isomers In 8.1% of domestic and 22.6% of Imported shellfish
samples were 1 and 66 ppb, respectively (Ouggan et al., 1983). In a 10-year
study of chlorinated hydrocarbons In bovine milk 1n Illinois, the percent
positive samples for all the Isomers of HCH combined ranged from 68.6-91.8%,
with average residues of 0.01-0.02 ppm. In 1980 and 1981, only 28.3-31% of
the samples were positive, with average concentrations of trace (<0.001 ppm)
to 0.01 ppm (Steffey et al., 1984). Mean concentrations of combined Isomers
of HCH In a variety of Imported spices ranged from <0.005-0.51 ppm
(Sullivan, 1980).
0818p 3-4 06/27/86
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3.3. AIR
Monitoring during the years 1970-1972 revealed a mean concentration of
Y-HCH In ambient air of 0.6 ng/m3 for all years and all states combined.
There were 67.7% positive samples with a mean concentration of 0.9 ng/m3
and a maximum value of 11.7 ng/m3 (Kutz et al., 1976). Y-HCH was also
detected 1n measurable quantities 1n Jackson, MS; Fort Collins, CO (Kutz et
al., 1976); StonevUle, MS (Arthur et al., 1976); Baltimore, MD; Iowa CHy,
IA; Salt Lake CHy, UT (Stanley et al., 1971); and Miami, FL (Lewis and Lee,
1976). Assuming an average Intake of 20 m3 of air/day, the average dally
Intake of y-HCH by Inhalation Is 18 ng, based on the monitoring data given
above.
Monitoring during the years 1970-1972 revealed a mean a-HCH concentra-
tion 1n ambient air of 1.2 ng/ma In 87.37X of the samples for all states
and years combined (Kutz et al., 1976). Measurable quantities of a-HCH
were detected In the air of the Great Lakes ecosystem (Elsenrelch et al.,
1981); Baltimore, MD; Salt Lake CHy, UT, and Iowa CHy, IA (Stanley et al.,
1971). Assuming a normal dally Intake of 20 m3 of air, the average dally
Intake of a-HCH, based on these monitoring data, Is 24 ng. Pertinent
monitoring data regarding the other Isomers of HCH could not be located 1n
the available literature as cited 1n the Appendix.
3.4. MISCELLANEOUS EXPOSURE
Transfer of unspecified amounts of a- and Y-HCH to smoke from
pesticide-treated tobacco has been observed (Ceschlnl and Chauchalx, 1980);
Rao-Kovvall et al. (1980) reported that Indian tobacco contains unspecified
amounts of HCH Isomers. Occupational exposure to q-HCH occurs 1n personnel
operating commercial seed-treating equipment (Grey et, al., 1983). The a-,
B-, Y- and 4 Isomers of HCH have been detected at ppb concentrations In
0818p 3-5 06/10/86
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raw wastewater from coal mining, aluminum forming, foundries and nonferrous
metals manufacturing (U.S. EPA, 1981). Raw wastewater from organic
chemicals manufacturing/plastics Industries contains ppb amounts of a-,
Y- and 6-HCH. The y- and
-------
from Ottawa, an average dally Intake of 34 pg was estimated. Because of
the relatively high value of a-HCH In the Ottawa sample, this value 1s
thought to be nonrepresentatlve. Samples of surface water and precipitation
(rain and snow) from a variety of locations contained a-HCH (U.S. EPA,
1985a; Kuntz and Warry, 1983; Page, 1981; Cole et al., 1984; Strachan and
Huneault, 1979; Elsenrelch et al., 1981; Pankow et al., 1984; Brooksbank,
1983; Strachan, 1985). In the Netherlands, B-HCH was found 1n ng quantities
In a variety of locations (Dulnker and Hlllebrand, 1979). Samples of
surface water In the United States contained a mean B-HCH concentration of
0.1725 yg/l (U.S. EPA, 1985a). Pertinent monitoring data for 5- or
e-HCH could not be located 1n the available literature as dted 1n the
Appendix.
A wide variety of foodstuffs, Including dairy products, meat, vege-
tables, fruits and seafood, contain one or more HCH Isomers (Duggan et al.,
1983; Steffey et al., 1984; Podrebarac, 1984; Schmltt et al., 19.85; U.S.
EPA, 1985a). The average dally Intake of y-HCH was estimated to be 0.27
vg, based on the y-HCH content 1n foods from 1971-1976, and that of
a-HCH was estimated to be 10.5 and 9.1 ng/kg bw/day, based on 1977 and
1978 data, respectively. Since monitoring data 1n foods are available only
for mixtures of the Isomers, B-, 6- and e-HCH, 1t 1s not possible to
estimate the average dally Intakes of Individual Isomers.
The mean concentration of y-HCH 1n positive samples of ambient air 1n
the United States In 1970-1972 was 0.9 ng/m3 (Kutz et al., 1976). Based
on this value and assuming an average Intake of 20 m3 air/day, the average
dally Intake of y-HCH Is 18 ng. Monitoring data during the years
1970-1972 revealed a mean a-HCH concentration 1n« ambient air of 1.2
ng/m» In the positive samples collected across the United States (Kutz et
0818p 3-7 06/10/86
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al., 1976). Assuming an average dally Intake of 20 m3 of air, this figure
1s equivalent to an average dally Intake of 24 ng. Pertinent monitoring
data regarding the other Isomers of HCH could not be located 1n the avail-
able literature as dted In the Appendix.
There are several miscellaneous sources of exposure to HCH Isomers
Including burning of tobacco (Cesch1n1 and Chauchalx, 1980) and the opera-
tion of commercial seed-treatment equipment (Grey et al., 1983). Isomers
of HCH were detected In wastewater from coal mining, aluminum forming,
foundries, nonferrous metals manufacturing, paint and Ink formulation,
petroleum refining, metal finishing and organic chemicals manufacturing/
plastics Industries (U.S. EPA, 1981).
0818p 3-8 06/10/86
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4. PHARMACOKINETICS
4.1. ABSORPTION
Two studies provide direct evidence that y-HCH 1s absorbed from the
gastrointestinal tract. Turner and Shanks (1980) showed that 29.6-42.6X and
42.3-53.OX of 0.05 and 0.1 pmol of Y-HCH (dissolved In rat bile),
respectively, were absorbed Into the blood from Injected Intestinal loops of
male Wlstar rats. Ahdaya et al. (1981) administered radlolabeled T-HCH (1
mg/kg In Emulphor:ethanol:water, 1:1:8) to fasted ICR mice by stomach needle
and monitored the appearance of radioactivity In the gastrointestinal tract
(minus contents), blood, liver and carcass and the disappearance of radio-
activity from the gastrointestinal tract contents for up to 60 minutes after
administration. Radioactivity 1n the gastrointestinal tract (minus con-
tents) reached a maximum of 17X of the administered dose at -8 minutes after
treatment, then declined to 9X for the duration of the study. The amount of
radioactivity In the blood reached a maximum of 2.2X of the administered
dose within 15 minutes and then declined slightly (to -1.5X) for the
remainder of the study. Radioactivity In the liver reached a maximum of 8X
within 15 minutes and declined to 5X by 60 minutes. By 60 minutes after
treatment, 70.7X of the administered radioactivity was absorbed. The time
for 50X absorption was estimated at 14.2±0.6 minutes, using an unspecified
model that gave the best linearization.
In a study designed to Investigate the possibility of 1somer1zat1on,
Elchler et al. (1983) administered either o-HCH (15 mg/kg/day) or T-HCH
(15 mg/kg/day males; 10 mg/kg/day females) by stomach tube to male and
female rats for 56 days. The concentration of o-HCH peaked 1n the blood
within 28 days of exposure (13-14 mg/kg blood) and remained at that level
through 56 days of treatment. Peak levels of Y-HCH were also observed
0819p 4-1 06/27/86
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within 28 days of treatment (2.1 mg/kg blood), but then declined to 0.9
mg/kg blood by day 56 of treatment. Using methods with a detection limit of
0.001 mg/kg blood or tissue, Elchler et al. (1983) found no evidence of
1somer1zat1on of a- or y-HCH.
The appearance of B-HCH In the brain and adipose tissue of rats and
mlnlplgs after dietary administration of this Isomer (11 weeks, rats; 37
weeks, mlnlplgs) Indicates that 0-HCH 1s absorbed by the gastrointestinal
tract (Altmann et al., 1983). No other details were given.
Muralldhara et al. (1979) demonstrated that the acute tox1c1ty of
y-HCH 1s proportional to the solubility of y-HCH In the carrier and
suggested that poor solubility results In reduced absorption 1n the small
Intestine. Herbst and Bodensteln (1972) suggested that I1p1d-med1ated
carriers enhance the rapidity with which y-HCH 1s absorbed.
4.2. DISTRIBUTION
In general, Isomers of HCH tend to accumulate 1n fatty tissue. In a
comparative study, Elchler et al. (1983) gavaged male and female rats with
either a-HCH (15 mg/kg/day) or r-HCH (15 mg/kg/day, males; 10 mg/kg/day,
females after 15 days of 15 mg/kg/day) for 56 days. Both Isomers were
present In higher concentrations In the tissues studied (brain, liver,
kidney and fat) than 1n the blood; levels 1n the fat were especially high.
a-HCH accumulated 1n the fat and brain to a greater extent than did
f-HCH. Furthermore, the retention of a-HCH 1n the tissues was 10-20
times greater than that of y-HCH. Tissue concentrations of y-HCH
decreased markedly during the 15 days after the termination of exposure. In
contrast, concentrations of a-HCH remained high, particularly In the fat,
even 15 days posttreatment. In other dietary and gavage studies In rats.
0819p 4-2 06/27/86
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Isomers of HCH were shown to accumulate In fatty tissues (Chand and Rama-
chandran, 1980; Lakshmanan et al., 1979; Chadwlck et al., 1978a; Altmann et
al., 1983).
Chadwlck et al. (1978a) and Lakshmanan et al. (1979) demonstrated that
dietary factors can affect the retention of y-HCH In the tissues.
Chadwlck et al. (1978a) found that rats fed a high-fiber diet for 28 days
before dosing retained a significantly greater amount of radioactivity from
i«C-(y-HCH) In the brain, liver, kidney, stomach and muscle than did
rats fed a low-fiber diet. Retention was measured 24 hours after adminis-
tration of a single oral dose of 2.87 mg 14C-(Y-HCH). Lakshmanan et al.
(1979) varied fat content In the diet of rats and found that rats maintained
on a low-fat diet had significantly less y-HCH 1n adipose tissue than did
rats fed a high-fat diet. y-HCH content of the brain was not affected by
diet.
Human studies have shown that y-HCH and other Isomers of HCH accumu-
late In the fatty tissues (Baumann et al., 1980; S1dd1qu1 et al., 1981a;
Szymczynskl and Wallszewskl, 1981a). Investigators have also shown that
y-HCH accumulates 1n human milk and Is able to cross the placenta
(Slddlqul et al.. 1981b; Poradovsky et al., 1977; Saxena et al., 1981; Welch
and Ftndlay, 1981). Isomers of HCH (a, B, y,
-------
4.3. METABOLISM
The metabolism of HCH Isomers primarily Involves dehydrogenat1on,
dehydrochloMnatlon and dechlorlnatlon. Conjugation reactions with sulfuMc
and glucuronlc acid and glutathlone are also Important (Macholz et al.,
1982a; Engst et al., 1976, 1979; Chadwlck et al., 1975; Grover and Sims,
1965; Freal and Chadwlck, 1973; Chadwlck and Freal, 1972; Allsup and Walsh,
1982; Kurlhara et al., 1979). In mammals, Including humans, common metabo-
lites of HCHs Include chlorinated phenols, chlorinated benzenes and penta-
chlorocyclohexenes (Angerer et al., 1983; Kujwa et al., 1977; Grover and
Sims, 1965; Freal and Chadwlck, 1973; Chadwlck and Freal, 1972; Engst et
al., 1976; Chadwlck et al., 1975, 1978a). These metabolites are excreted 1n
the urine and have also been Identified In the blood, liver, kidney, spleen,
heart and brain of rats fed y-HCH {Engst et al., 1976).
Chadwlck et al. (1975) demonstrated that 1n rats y-HCH Is metabolized
to hexachlorocyclohexene, which 1s then degraded to 2,3,4,5,6-pentachloro-
2-cyclohexene-l-ol, two tetrachlorophenols and three trlchlorophenols.
Macholz et al. (1982a) demonstrated that rats fed a-HCH In the diet for 30
days excreted all Isomers of tMchlorophenol and tetrachlorophenol In the
urine. Similar results were obtained when rats were fed B-HCH In the same
manner {Macholz et al., 1982b). Pentachlorocyclohexene was also Identified
as a metabolite of a-HCH but was not excreted 1n the urine.
A number of In vUro studies have shown that the metabolism of HCHs In
mammals Is probably mediated to a great extent by oxldatlve processes In
hepatic mlcrosomes (Gopalaswamy and A1yar, 1984; Yamamoto et al., 1983;
FHzloff et al., 1982; FHzloff and Pan, 1984; Baker et al., 1985; Tanaka et
al., 1979; Portlg et al., 1973).
0819p 4-4 10/27/86
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Dietary factors have been shown to influence the metabolism and excre-
tion of Y-HCH. Chadwlck et al. (1978c) pretreated male Wlstar rats with
cadmium and then exposed them to 14C-(Y-HCH). Cadmium-exposed rats
excreted less radioactivity 1n the urine than did controls. Exposure to
cadmium also Inhibited the dehydrogenatlon of y-HCH to hexachlorocyclo-
hexene and altered the distribution of neutral to polar metabolites.
Chadwlck et al. (1978a) also demonstrated that rats fed high-fiber diets for
28 days before oral administration of y-HCH, dehydrogenated and dechlorl-
nated y-HCH to a greater extent than did rats fed a low fiber diet.
Studies conducted by L1u (1982) suggested that metabolism of y-HCH
varies with the genetic strain of the animal studied. Long-term administra-
tion of y-HCH resulted 1n lower levels of 2,4,6-trlchlorophenol and
2,3,4,6-tetrachlorophenol 1n the blood of DBA/2 mice than 1n C57B1/6 mice.
Subsequently, however, levels of 2,3,4,6-tetrachlorophenol 1n DBA/2 mice
exceeded those In C57B1/6 mice. DBA/2 mice also had higher concentrations
of 2,4,6-trlchlorophenol 1n the liver, kidney and spleen.
4.4. EXCRETION
U.S. EPA (1980a, 1985a) concluded that even after prolonged administra-
tion, y-HCH and Us metabolites are completely excreted after application
1s terminated. Frawley and Fltzhugh (1949) demonstrated that y-HCH con-
centration In the fatty tissue of rats dropped from 102 ppm to undetectable
levels (sensitivity of method not reported) within 1 week after administra-
tion of r-NCH was discontinued. Lehman (1952a,b) demonstrated a similar
reduction (281 ppm to undetectable) within 2 weeks of discontinuation of
exposure. KHamura et al. (1970) observed that after 20 days of feeding
Y-HCH at 10 ppm In the diet, no residues of y-HCH 'could be detected In
the bodies of rats within 1 day of return to the control diet. After 20
0819p 4-5 06/27/86
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days of feeding a-HCH at 100 ppm 1n the diet, residues In the body
declined to 0.1 ppm by 3 days after return to the control diet (KHamura et
al., 1970).
In a comparative study, KHamura et al. (1970) demonstrated that the
disappearance of y-HCH from the bodies of mice given a single oral dose
(500 yg) was more rapid than that of B-HCH under Identical experimental
conditions.
Y-HCH was eliminated more rapidly from fat than was a-HCH 1n a
longer-term oral study (Elchler et al., 1983). In this study, Y-HCH
levels In fat declined from a maximum of 385 to 15 ppm by 15 days after the
termination of 56 days of oral administration of 10-15 mg/kg/day of y-HCH
to rats. In contrast, a-HCH accumulated to a maximum of 4255 ppm In fat
and then declined to 1947 ppm by 15 days after the termination of 56 days of
oral administration of 15 mg/kg/day of a-HCH to rats.
The principle route of excretion for Y-HCH and metabolites 1s urinary.
When U-14C-(Y-HCH) was administered orally to rats or IntrapeMtoneally
to mice, radioactivity was excreted primarily In the urine (Chadwlck et al.,
1978a; Engst et al., 1979). Following oral administration of
U-14C-[Y-HCH] to rats, lesser amounts of radioactivity appeared 1n the
feces than In the urine (Chadwlck et al., 1978a) and trace amounts (as
14CO?) appeared 1n the expired air (Adhaya et al., 1981; Chadwlck et
al., 1978a).
Very little Y-HCH Is excreted unaltered according to U.S. EPA (1980a,
1985a). Laug (1948) recovered only 4% of the administered dose of Y-HCH
(not specified) as parent compound In the urine of rats fed Y-HCH. Egnst
et al. (1976), however, reported that substantial amounts of free Y-HCH
were excreted In the urine of rats administered 8 mg/kg/day of Y-HCH 1n
0819p 4-6 10/27/86
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sunflower oil by gavage for 19 days. Metabolites were also found In the
urine. In the feces, only unaltered y-HCH was detected. Excretion of
urinary metabolites of Y-HCH, primarily 1n conjugated forms, has been
reported by Kurlhara et al. (1979), Chadwlck et al. (1975, 1978a,b), Allsup
and Walsh (1982), Zesch et al. (1982), Angerer et al. (1981) and Stein et
al. (1980). Urinary excretion of a-HCH metabolites was reported by
Macholz et al. (1982a).
In feeding studies, Chadwlck et al. (1978a) demonstrated that dietary
fiber can Influence the metabolism and excretion of Y-HCH In rats given a
single oral dose of 2.87 mg of U-14C-(Y-HCH).
The feeding of high fiber diets (Purina Lab Chow or a low fiber diet
supplemented with pectin) for 28 days before administration of y-HCH was
shown to cause significant Increases 1n the excretion of radioactivity (as X
of dose) 1n the urine (9.70-13.00X for high fiber diets vs. 7.85% for low
fiber diet) and feces (3.55-4.12X for high fiber diets vs. 0.72X for low
fiber diet) and significant Increases In the amounts of conjugated chloro-
phenols and polar metabolites excreted In the urine.
Isomers of HCH are excreted 1n human milk (Herbst and Bodensteln, 1972;
Welch and Flndlay, 1981) and semen (Szymczynskl and Wallszewskl, 1981a,b).
8-HCH accounts for 9OX of the HCH found 1n human milk, while a- and
Y-HCH accounts for the remaining 10X. All five Isomers have been found In
human semen.
4.5. SUMMARY
Two studies provide direct evidence that y-HCH 1s absorbed from the
gastrointestinal tract (Turner and Shanks, 1980; Ahdaya et al., 1981). The
appearance of a-HCH and 8-HCH In the blood and tissues after oral adminis-
tration Is also Indicative of gastrointestinal absorption (Elchler et al.,
1983; Altmann et al., 1983; Macholz et al., 1982a,b).
0819p 4-7 08/07/86
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In general, Isomers of HCH and their metabolites tend to accumulate In
fatty tissue (Elchler et al., 1983; Chand and Ramachandran, 1980; Lakshmanan
et al., 1979; Chadwlck et al., 1978a; Altmann et al., 1983; Baumann et al.,
1980; S1dd1qu1 et al., I981a; Szymczynsk! and Wallszewskl, 1981a,b). In a
comparative study where a-HCH or y-HCH was fed to rats In the diet for
56 days, Elchler et al. (1983) found that a-HCH accumulated In the fat and
brain to a greater extent than did y-HCH. Furthermore, the retention of
a-HCH In the tissues (fat, brain, liver, kidney) was 10-20 times greater
than that of y-HCH. Tissue concentrations of y-HCH declined to a much
greater extent than did tissue levels of a-HCH during the 15 days follow-
ing termination of exposure.
The metabolism of HCH Isomers primarily Involves dehydrogenatlon,
dehydrochloMnatlon and dechlorlnatlon. Conjugation reactions with sulfurlc
and glucuronlc add are also Important (Macholz et al., 1982a; Engst et al.,
1976, 1979; Chadwlck et al., 1975; Grover and Sims, 1965; Freal and Chad-
wick, 1973; Chadwlck and Freal, 1972; Allsup and Walsh, 1982). In mammals,
Including humans, common metabolites of HCH Include chlorinated phenols,
chlorinated benzenes and pentachlorocyclohexenes. These metabolites are
usually excreted In conjugated form (or a degradation product of a previ-
ously conjugated form) In the urine, and have also been detected In blood,
liver, kidney, spleen, heart and brain (Engst et al., 1976; Chadwlck et al.,
1975, 1978a; Freal and Chadwlck, 1973; Chadwlck and Freal, 1972; Angerer et
al., 1983; Kujwa et al., 1977; Grover and Sims, 1965). A number of 1n vitro
studies have shown that the metabolism of HCHs In mammals Is mediated to a
great extent by oxldatlve processes 1n hepatic mlcrosomes (Gopalaswamy and
Alyar, 1984; Yamamoto et al., 1983; FHzloff et al., >982; FHzloff and Pan.
1984; Baker et al., 1985; Tanaka et al., 1979; Portlg et al., 1973).
0819p 4-8 08/07/86
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HCH Isomers and metabolites have been recovered 1n the urine and feces
(Ahdaya et al., 1981; KuMhara et al., 1979; Chadwlck et al., 1975, 1978a,b;
Allsup and Walsh, 1982; Zesch et al., 1982; Angerer et al., 1981; Stein et
al., 1980; Macholz et al., 1982a,b), and trace amounts (as 14CO_) have
been detected In expired air (Ahdaya et al., 1981; Chadwlck et al., 1978a).
In comparative studies, KHamura et al. (1970) and Elchler et al. (1983)
demonstrated that the disappearance of y-HCH from the bodies of mice given
a single oral dose or rats given repeated oral doses was more rapid than
that of B-HCH or «-HCH administered 1n the same manner. Isomers of HCH
are known to be excreted 1n human milk (Herbst and Bodensteln, 1972; Welch
and Flndlay, 1981) and semen (Szymczynskl and Wallszewskl, 1981a,b).
Chadwlck et al. (1978a,c) and lakshmanan et al. (1979) have demonstrated
that dietary factors (cadmium, fiber and fat) can alter the retention,
metabolism and excretion of y-HCH. Herbst and Bodensteln (1972) have
suggested that I1p1d-med1ated carriers enhance the absorption of y-HCH.
L1u (1982) suggested that the metabolism of y-HCH might vary with the
strain of animal used 1n the study.
0819p 4-9 08/07/86
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. 5. EFFECTS
5.1. CARCINOGENICITY
5.1.1. a-HCH. Dietary a-HCH has been shown to cause Increased
Incidences of liver tumors In five strains of mice (Ito et al., 1973a,b,
1976; Nagasaki et al., 1972a, 1975; Hanada et al., 1973; Goto et al., 1972)
and In Wlstar rats (Ito et al., 1975; Schulte-Hermann and Parzefall, 1981)
(Table 5-1). None of the tests In mice were negative. However, the
cardnogenlclty In Wlstar rats In these studies was either marginal or
negative, Indicating a greater sensitivity of the mouse to this compound.
Goto et al. (1972) reported that when control diet or diet containing
600 ppm of T-HCH, a-HCH, B-HCH, y-HCH or a mixture of 4- and c-HCH
or 300 ppm Y-HCH was fed to ICR-JCL mice for 26 weeks, grossly observable
hepatic nodules occurred 1n all mice fed T-HCH or a-HCH, In 5/10 mice fed
Y-HCH and In 10/10 mice fed 4- and e-HCH. By Implication, no grossly
observable .hepatic nodules were seen 1n mice treated with 600 ppm B-HCH, 300
ppm y-HCH or control diet. The report, written 1n German, Indicates that
hlstologlcal examination revealed benign hepatomas 1n all groups treated
with 600 ppm HCH as above and that malignant hepatomas were frequently found
In the groups treated with a-HCH or 6- and e-HCH. The report does not
explicitly state the Incidences of hlstologlcally confirmed benign or
malignant hepatomas 1n any group.
5.1.2. B-HCH. Table 5-2 summarizes the available oral cardnogenlclty
studies on B-HCH. Dietary B-HCH has been shown to cause Increased Inci-
dences of liver tumors only 1n CF1 mice with marginal Increases In ICR-JCL
mice (Thorpe and Walker, 1973; Goto et al., 1972) but no Increased Incidence
1n dd mice (Ito et al., 1973a,b; Hanada et al., 1973; Nagasaki et al.,
1972a) or In Wlstar rats (Ito et al., 1975; FHzhugh et al.. 1950).
0820p 5-1 10/27/86
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The studies with negative results, however, were of short Duration
(Hanada et al., 1973; Ito et al., 1973a,b; Nagasaki et al., 1972a), used
small numbers of animals [except Thorpe and Walker (1973)], or failed to
examine all the experimental animals (Fltzhugh et al., 1950; Nagasaki et
al., 1972a; Hanada et al., 1973). These studies that were observed to be
negative for B-HCH might have been expected to yield negative results
because of study design limitations and, therefore, are only of limited
utility.
5.1.3. f-HCH. Dietary f-HCH was shown In one study to cause an
Increased Incidence of liver tumors 1n male CF1 mice fed 400 ppm for 110
weeks (Thorpe and Walker, 1973). Marginal results were observed In male
ICR-JCL mice fed 600 ppm for 26 weeks (Goto et al., 1972). The Thorpe and
Walker (1973) study was the only full-term study In mice since the other
studies 1n mice were terminated at shorter than lifetime testing durations
(24, 24, 32. 26 and 24 weeks). Only the most potent carcinogens would
display clear results In these shorter duration studies. For example, no
liver tumors were observed 1n dd mice fed up to 500 ppm for 24 weeks (Ito et
al., 1973a.b; Nagasaki et al.. 1972a) or 1n Wlstar rats fed 500 ppm for up
to 48 weeks (Ito et al., 1975). Significant compound-related development of
tumors of any type was not observed In NHRI mice (Herbst et al., 1975;
Welsse and Herbst. 1977). B6C3F1 mice (NCI, 1977) Osborne-Hendel rats (NCI,
1977) or Wlstar rats (Fltzhugh et al., 1950). The rat study conducted by
NCI (1977) has been criticized for poor survival, changes- In- dosing regime
and the possibility that male rats did not receive HTDs (IARC. 1979).
Reuber (1979) also disputed the negative findings of NCI (1977) and reported
that an Independent Interpretation of the hUtologlcal data leads to the
conclusion that y-HCH 1s carcinogenic 1n both rats and mice. The validity
of this assessment Is uncertain. The negative findings of Fltzhugh et-al.
0820p 5-5 04/22/88
-------
(1950), Ito et al. (1973a,b, 1975) and Nagasaki et al. (1972a) are
attributed 1n part to small numbers of animals, short duration or failure to
examine all animals In the study. Table 5-3 summarizes these oral carclno-
genldty studies. A metabolite of y-HCH, 2,4,6-trlchlorophenol, 1s
carcinogenic 1n rats and mice and has been classified as a "probable" human
carcinogen (Group B2). This metabolite has been Identified 1n rodents and
humans.
5.1.4. 4-HCH. Oral cardnogenldty data for a-HCH are presented In
Table 5-4. Dietary 4-HCH did not cause neoplastlc or nonneoplastlc
changes 1n the livers of male dd mice (Ito et al., 1973a; Nagasaki et al.,
1972a) or male Hlstar rats (Ito et al., 1975). However, these negative
studies are of limited utility. These studies used small numbers of animals
and were only conducted for 24 weeks. Furthermore, Nagasaki et al. (1972a)
failed to examine all the mice started on the test.
Goto et al. (1972) reported that a mixture of 6-HCH and e-HCH caused
Increased Incidences of benign and malignant hepatomas 1n ICR-JCL mice after
26 weeks of dietary administration, but the Individual Isomers were not
tested 1n the study (see Section 5.1.1.).
5.1.5. e-HCH. No direct cancer data exist for e-HCH. Goto et al.
(1972) reported that a mixture of 4-HCH and c-HCH caused an Increased
Incidence of benign and malignant hepatomas 1n ICR-JCL mice after 26 weeks
of dietary administration, but the Individual Isomers were not tested In the
study (see Section 5.1.1.). Additional pertinent data regarding the
cardnogenlclty of c-HCH could not be located 1n the available literature
as cited 1n the Appendix.
5.1.6. T-HCH. The T-HCH mixture has been shown to cause Increased
Incidences of liver neoplasms In four strains of mice (Hanada et al., 1973;
Goto et al., 1972; Kashyap et al., 1979; N1gam et al., 1984a; Bhatt et at.,
0820p 5-6 04/22/88
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1981; Munlr et al., 1983; Nagasaki et al., 1971, 1972b; Nagasaki, 1973;
Munlr and Bhlde, 1984). However, cardnogenlclty was not observed In Hlstar
rats (Munlr et al., 1983) nor 1n Syrian Golden hamsters (Munlr et al., 1983)
(Table 5-5).
5.1.7. General Comments. All but six of the cardnogenlclty studies
[Fltzhugh et al., 1950 (a, B, y); Herbst et al., 1975 (Y); Welsse and
Herbst, 1977 (T); Ito et al., 1975 (a, 0, Y. *); NCI, 1977 (Y);
Thorpe and Walker, 1973 (B, Y)] assayed only for hepatic response, I.e., a
full examination of other tissues was not done. A large body of evidence
Indicates that the nonneoplastlc changes In the liver associated with expo-
sure to Isomers of HCH or T-HCH are associated with neoplastlc development.
A clear progression of hepatic changes, which ultimately leads to the
development of malignant tumors has been observed at gross, hlstologlcal and
ultrastructural levels of examination; these changes, proportional to dose
and duration of treatment, are reversible only at the very earliest stages
before the development of nodular hyperplasla. The transition from reversi-
ble to Irreversible change has not been accurately defined, but 1s charac-
teristic of tumor progression which has been widely reported (Ito et al.,
1975, 1976; Schulte-Hermann and Parzefall, 1981; Munlr et al., 1983; Munlr
and Bhlde, 1984; N1gam et al., 1982, 1984a; Suglhara et al., 1975).
5.2. MUTAGENICITY
Y-HCH was not found to be mutagenlc 1n Ames tests on Salmonella typhl-
murlum with or without S-9 (Lawlor et al., 1979; Probst et al., 1981) or
EscheMchla coll (Probst et al., 1981). Negative results with Y-HCH were
also obtained In an oral dominant lethal test on SPF:THOM rats (Rohrborn,
1977), 1n an 1ntraper1toneal dominant lethal test on mice (U.S. EPA, 1973)
and 1n a recessive lethal test on DrosophUa melanoqaster (Benes and Sram,
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1969). Rohrborn (1977) reported that weakly mutagenlc effects were caused
by Y-HCH 1n a host-mediated assay with S. typhlmurlum. while Buselmaler et
al. (1972) reported negative results for y-HCH 1n host-mediated assays
with £. typhlmurlum and Serratla narcescens. Tests of y-HCH-lnduced geno-
toxldty have yielded both positive and negative results. Chinese hamster
Hbroblasts (Ishldate and Odashlma, 1977) and human peripheral lymphocytes
(Tzoneva-Maneva et al., 1971). In contrast, y-HCH did not cause chromo-
somal aberrations 1n lymphocytes of llndane production workers (Klraly et
al., 1979) or 1n bone marrow from Chinese hamsters (Rohrborn, 1977), did not
cause unscheduled ONA synthesis 1n SV-40 transformed human flbroblasts
(Ahmed et al., 1977) or human lymphocytes (Rocchl et al., 1980), did not
Increase mlcronucleus formation In epithelial cells from C3H mice
(DeBrabander et al., 1976) or CBA mice (Jenssen and Ramel, 1980), and failed
to Induce DNA repair In primary cultures of rat hepatocytes (Probst et al.,
1981).
a-HCH was not mutagenlc with or without S-9 In reversion assays with
Saccharomyces cerevlslae (Shahln and Von Borstel, 1977) or £. coll (MoMya
et al., 1983), but caused Increased m1tot1c activity 1n A. cepa roots (Nybom
and Knutsson, 1947) and In hepatic parenchymal cells of rats fed 0.06X In
the diet for 3 weeks (Hitachi et al., 1975).
Shlmazu et al. (1976) reported that S-HCH caused chromosomal aberrations
In bone marrow cells taken from LE rats Injected 1.p. with 0.01-10 mH/kg bw
B-HCH. Which dose levels were considered positive were not reported.
T-HCH did not promote mutation 1n an Ames test with S. typhlmurlum
(Anderson and Styles, 1978), but yielded positive results 1n a dominant
lethal test where Swiss mice were fed 500 ppm for 4, 6 or 8 months (Lakkad
et al., 1982). Furthermore, Babu et al. (1981) reported that prolonged
•>
0820p 5-13 03/18/88
-------
dietary exposure (5-8 months) but not after 3 months to 500 ppm T-HCH
Inhibited melotlc division In the testes but not mltotlc division 1n the
bone marrow of Swiss mice. Bone marrow metaphases did not Indicate an
Increase In chromosome aberrations.
A mixture of <»-, B- and y-UCH was not mutagenlc In a rec assay with
Bacillus subtlUs or In reversion assays with E_. coll or S. typhlmurlum
(Shlrasu et al., 1976). y-HCH has been shown to cause mltotlc arrest at
metaphase In All 1 urn cepa (Nybom and Knutsson, 1947) and P1sum satlvum
(Baquar and Khan, 1971; Sharma and Gosh, 1969), and caused chromosome
aberrations 1n A. cepa roots (Sax and Sax, 1968). Additional Information
for the above studies 1s given 1n Table 5-6.
5.3. TERATOGENICITY
A majority of the studies available suggest that y-HCH Is not
teratogenlc.
Khera et al. (1979) administered 0, 6.25, 12.5 or 25 mg y-HCH/kg bw by
gavage (vehicle = corn oil) to groups of 20 female Wlstar rats on days 6-15
of gestation. On day 22 of gestation, there were no differences between
control and y-HCH-treated rats 1n terms of numbers of pregnancies,
abortions, corpora lutea/pregnancy, live fetuses/pregnancy, dead or resorbed
fetuses, anomalous fetuses/number examined or Utters with anomalous
fetuses/number of Utters examined. Furthermore, there were no compound-
related effects on fetal body weight.
Palmer et al. (1978a) conducted a 3-generat1on reproduction study on CD
rats. Groups of 10 male and 20 female weanling rats were fed 0, 25, 50 or
100 ppm y-HCH 1n the diet for 60 days before mating, and were then mated
to produce two Utters. A similar protocol was used for the F. and F_
generations. Mating performance, pup mortality, number of viable offspring
0820p 5-14 03/18/88
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and examination for external and Internal malformations (at 21 days of age)
was conducted for all generations. Ten males and 10 females 1n each group
of the F_ generation were examined for skeletal defects; organ weights
were measured on an additional 10 pups/sex/group, and hlstologlcal examina-
tion of major organs was conducted on 10 pups/sex from the high-dose groups.
There were no compound-related effects on reproduction and no compound-
related teratogenlc effects 1n any generation. A dose-related Increase 1n
liver weight was observed, and enlarged hepatocytes were observed In some
controls and treated males and females of the F0. generation. Palmer et
3b
al. (1978a) considered the latter findings to be of doubtful Importance when
compared with the lack of effects on growth and reproductive performance.
Palmer et al. (1978b) did not observe compound-related teratogenlc
effects 1n CFY rats gavaged with 0, 5, 10 or 15 mg y-HCH/kg on days 6-16
of gestation, or 1n New Zealand White rabbits gavaged similarly on days 6-18
of gestation.
In an effort to screen compounds to recommend for teratology testing,
Chernoff and Kavlock (1983) and Gray and Kavlock (1984) monitored the growth
and viability of progeny from CD-I mice gavaged with 25 mg y-HCH/kg on
days 8-12 of gestation. There were no effects on Incidence of pregnant
females (-25/group tested), maternal mortality or body weight. There were
no significant compound-related effects on the growth and viability of
progeny observed for up to 250 days.
In contrast to the negative findings, Dz1erzawsk1 (1977) reported a
2- to 20-fold Increase 1n the number of resorbed fetuses In hamsters given
(route not specified) 40 mg y-HCH/kg on day 8 of gestation, 1n rabbits
given 40 or 60 mg y-HCH/kg on day 9 of gestation. In rats given 50 or 100
mg y-HCH/kg on day 9 of gestation and In rats given 40 mg y-HCH/kg on
days 6, 8 and 10 of gestation.
0820p 5-18 03/18/88
-------
Pertinent data regarding the teratogenldty of other Isomers of HCH
could not be located 1n the available literature as cited 1n the Appendix.
5.4. OTHER REPRODUCTIVE EFFECTS
Palmer et al. (1978a) failed to observe adverse effects on reproduction
In three generations of CD rats fed up to 100 ppm y-HCH 1n the diet (see
Section 5.3.). In contrast, Shtenberg and Mametkullev (1976) reported that
rats exposed orally to 5 mg/kg/day y-HCH for 5 months had reduced mating
and pregnancy Indices, regardless of whether females were mated to treated
or control males. Administration of 0.05 mg/kg for 9 months had no adverse
effects on the gonads. Other details, such as whether 5 mg/kg and 0.05
mg/kg represent dietary concentrations or actual doses were not reported.
Other studies suggest that low doses of i-HCH given to rats and rabbits
for several generations causes adverse effects on reproduction and on the
developing fetus (Khamldov, 1984; Petescu et al., 1974); however, these
studies were available only as abstracts and details were limited.
Saxena et al. (1980) and Wassermann et al. (1982) studied the possible
association between body levels of organochlorlne pesticides and premature
labor In humans. Although premature labor was correlated with Increased
levels of Y-HCH In the blood, other organochlorlne pesticides were also
present at elevated concentrations.
Pertinent data regarding other reproductive effects of other Isomers of
HCH could not be located 1n the available literature as cited 1n the
Appendix.
5.4.1. Testlcular Effects. Testlcular atrophy has been observed 1n rats
and mice fed T-HCH and In rats gavaged with y-HCH. In general, the
atrophy was characterized by degenerative changes 1n the seminiferous
epithelium, reduction In number of spermatocytes and the appearance of
multlnucleated giant cells.
0820p 5-19 03/18/88
-------
Shlvanandappa and KMshnakumaM (1981, 1983) fed 0, 100, 750 and 1500
ppm T-HCH (equivalent to 0, 80, 625 and 1174 mg/rat/90 days) to groups of 10
weanling male Wlstar rats for 90 days. Significant effects Including
mortality (two deaths at 8 weeks), reductions In body weight and food
consumption (7-13 weeks), decreases In testlcular weight, seminiferous
tubule diameter, Leydlg cell diameter and testlcular enzyme activities, and
Increases In total llpld and total cholesterol content of the testes were
observed only among rats fed 1500 ppm T-HCH.
Nlgam et al. (1979) fed 0 or 500 ppm T-HCH to male Swiss mice for up to
10 months. Groups of six mice were killed each month and the testes were
weighed and examined hlstologlcally. Mice exposed to T-HCH had hlstologlcal
evidence of testlcular atrophy and Increased testlcular weight at >3 months
of treatment. This study provided few details.
Dlkshlth and Datta (1977) and DlkshHh et al. (1978) reported testlcular
atrophy 1n adult ITRC rats gavaged with 17.6 mg y-HCH/kg bw (1n peanut
oil) for 90 days.
5.5. CHRONIC AND SUBCHRONIC TOXICITY
5.5.1. o-HCH. The available chronic and subchronlc oral studies on
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FHzhugh et al. (I960) conducted a lifetime feeding study on Wlstar
rats, In which groups of 10 rats/sex were fed 0, 50, 100 or 800 ppm a-HCH
In the diet until they died or were killed when moribund. Growth rate, food
consumption, mortality, organ weights, and gross and microscopic pathology
were examined. Microscopic analysis, however, was not performed on all rats
(only on 8-15 rats/treatment) and detailed sections were not always prepared
for those that were examined. There was no evidence of compound-Induced
development of tumors. Compared with controls, high-dose rats had signifi-
cantly reduced survival, reduced growth rate, Increased liver weight and
hlstologlcal evidence of slight to moderate kidney damage and moderate liver
damage. Increased liver weights were also observed 1n rats fed 50 and 100
ppm, but no significant changes In liver histology were observed at these
concentrations. No effects were observed among rats fed 10 ppm a-HCH. In
a similar study, Ito et al. (1975) observed neoplastlc changes 1n the livers
of Hlstar rats only at dietary levels >1000 ppm a-HCH.
5.5.2. B-HCH. Chronic and subchronlc oral studies on B-HCH are summa-
rized 1n Table 5-8. Three of the five studies (Ito et al., 1973a,b, 1975)
were designed to Investigate and characterize hepatic carcinogenic response
1n male Wlstar rats and dd mice. Neoplastlc changes were not observed 1n
these studies, but Increases In absolute and relative liver weight were
observed at doses >250 ppm. Nonneoplastlc hlstologlcal changes were not
observed. These studies were conducted only for 24-72 weeks.
In a 110-week dietary study on CF1 mice. Thorpe and Walker (1973)
observed enlargement of the liver, but this effect was probably related to
the development of tumors. No other significant compound-related effects
were observed.
0820p 5-22 10/21/86
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-------
In a lifetime study, Fltzhugh et al. (1950) observed early mortality
(average llfespan = 4.4*1.3 weeks), histologlcal evidence of liver damage
and Increased relative liver weight 1n Wlstar rats fed 800 ppm 13-HCH.
Significantly reduced body weight. Increased relative liver weight and
hlstologlcal evidence of liver damage were observed among rats fed 100 ppm;
Increased relative liver weight was the only effect observed at 10 ppm. No
tumors were observed at any level of treatment; however, only 5-14 rats/
level of treatment were examined microscopically, and detailed examinations
were not always prepared for those that were examined.
5.5.3. Y-HCH. Long-term oral studies on the toxldty of y-MCH have
been conducted on rats (DlkshHh and Datta, 1977; 01ksh1th et al., 1978;
NCI, 1977; Ito et al., 1975; Fltzhugh et al., 1950; Research and Consulting
Co., Ltd., 1983; Oesch et al., 1982), mice (Oesch et al., 1982; Thorpe and
Walker, 1973; Ito et al.. 1973a.b), dogs (Rlvett et al., 1978; Earl et al.,
1970; Lehman, 1965) and monkeys (SantolucHo, 1975) (Table 5-9). The
studies conducted by NCI (1977) on rats and mice, by Ito et al. (1975) on
rats and by Ito et al. (1973a,b) on mice were designed to Investigate
oncogenlclty, but nonneoplastlc effects were also Investigated.
A number of long-term oral studies report that y-HCH can cause hepatic
hypertrophy, Induce mlcrosomal enzyme activity and cause nonneoplastlc
hepatic changes In the absence of neoplastlc changes (DlkshHh et al., 1978;
Fltzhugh et al., 1950; Research and Consulting Co., Ltd., 1983; Oesch et
al., 1982; Ito et al., 1973a; Rlvett et al., 1978). If these studies,
however, had used larger number of animals and were conducted for longer-
periods of time, It Is possible that a carcinogenic response would have been
observed, especially since y-HCH has been shown to cause liver tumors 1n
CF1 and dd mice (Thorpe and Walker, 1973; Hanada et al., 1973; Goto et al.,
0820p 5-24 TO/21/86
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1972) and since the nonneoplastic changes have been associated with the
development of tumors in rats and mice exposed to a-HCH and T-HCH (Ito et
al., 1975, 1976; Schulte-Hermann and Parzefall, 1981; Munir et al., 1983;
Nigam et al., 1982; 1984b). Although negative results were found for
oncogenicity in the Fitzhugh et al. (1950) and NCI (1977) lifetime studies,
Fitzhugh et al. (1950) examined only a portion of the treated rats in the
study (criteria for selection not reported), and the NCI (1977) study
yielded negative results for both neoplastic and nonneoplastlc effects.
Two studies have reported that y-HCH adversely affects the kidney.
Fitzhugh et al. (1950) reported gross and histological evidence of slight to
moderate kidney damage (focal nephritis, hyaline granular degeneration,
pitted kidneys) In rats fed 800 ppm Y-HCH as powder mixed in the diet for
life but not in rats treated similarly with 800 or 1600 ppm dietary Y-HCH
dissolved in corn oil. The Research and Consulting Co., Ltd., (1983)
observed tubular degeneration, hyaline droplets, tubular casts, tubular
distension, interstitial nephritis and basophlUc tubules in Wlstar KFM-HAN
SPF rats fed 20 or 100 ppm Y-HCH (1.55 or 7.25 mg/kg/day) for 12 weeks,
but not 1n rats exposed similarly to 0.2, 0.8 or 4 ppm Y-HCH.
Olkshith and Oatta (1977) and 01ksh1th et al. (1978) demonstrated that
Y-HCH (17.6 mg/kg/day in peanut oil for 90 days) can cause testlcular
atrophy in ITRC rats.
Fitzhugh et al. (1950) observed nervous symptoms and convulsions in rats
fed 800 or 1600 ppm Y-HCH for life. Dlkshlth et al. (1978) reported
significant decreases In AchE activity in the blood and brains of ITRC rats
given 17.6 mq y-HCH/kg/day 1n peanut oil for 90 days. Shorter-term
studies also suggested that Y-HCH causes neurotoxic effects. Des1 (1974)
reported that the number of lever presses In an operant conditioning box
0820p 5-28 10/21/86
-------
were significantly Increased 1n Wlstar rats exposed orally to 25 mg
Y-HCH/kg/day for 40 days; an Increased number of errors In maze-running
and Increased maze-running times were observed 1n rats treated similarly at
doses >5 mg/kg/day. Muller et al. (1981) reported significantly reduced
conduction velocity 1n Hlstar rats fed 25 mg Y-HCH/kg/day for 30 days.
Czegledl-Janko and Avar (1970) reported that male workers 1n a ferti-
lizer plant with "mild but definite" symptoms of neurotox1c1ty (clinical
exam and EEG) had >0.02 ppm y-HCH In their blood; however, 22 of the 37
men 1n the study had been exposed to aldrln 2 years before their examina-
tion. Examinations of these men before Y-HCH exposure revealed a strong
association between exposure to aldrln and neurotoxlc effects.
Hematologlcal effects resulting from exposure to y-HCH have also been
reported. Earl et al. (1970) reported that adverse hematologlcal effects
(decreased numbers of retlculocytes and platelets, crenated RBCs and a
myelo1d:erythro1d ratio >750:1) occurred In dogs fed 225 mg Y-HCH/kg/day
In the diet for 24 weeks. These effects were not reported for dogs fed 7.5
or 15.0 mg/kg/day. A case-report (Morgan et al., 1980) also suggests that
anemia may result from prolonged exposure to Y-HCH; severe but reversible
hypoplastlc anemia was observed In a 2.5-year-old boy who was exposed to
Y-HCH since birth through use of a vaporizer 1n his home. Other family
members were not affected.
Short-term studies suggest that Y-HCH may cause Immunosupresslon. A
dose-related decrease In Immunological tlters was observed 1n rabbits
gavaged with 1.5-12 mg Y-HCH/kg/day, 5 days/week for 5-6 weeks, then
challenged with S. typhlrourlum (Desl et al., 1978). Similar results were
reported In rats exposed orally to either 6.25 or 24 mg Y-HCH/kg In olive
oil on alternate days for 35 days (Dewan et al.. 1980).
0820p 5-29 10/21/86
-------
5.5.4. 6-HCH. Long-term oral studies on 6-HCH are summarized In
Table 5-10. Significant compound-related changes were not observed In male
Wlstar rats fed 500 or 1000 ppm 6-HCH for up to 48 months (Ito et al.,
1975). Ito et al. (1973a) observed significant elevation In relative and
absolute liver weights among male dd mice fed 500 ppm 6-HCH for 24 weeks;
however, no hlstologlcal or ultrastructural changes were observed 1n the
livers of these mice. No effects on the liver were observed In mice fed 100
or 250 ppm 6-HCH for 24 weeks.
5.5.5. e-HCH. Pertinent data regarding the chronic toxlclty of e-HCH
could not be located In the available literature as dted In the Appendix.
5.5.6. T-HCH. Long-term oral studies on the toxlclty of T-HCH have been
conducted on rats (Fltzhugh et al., 1950; Barros and Sallba, 1978; Barros et
al., 1982; Shlvanandappa and KrlshnakumaM, 1981, 1983; Shlvanandappa et
al., 1982) and mice (Nlgam et al.. 1979, 1982, 1984a,b; Munlr and BMde,
1984; Kashyap et al., 1979). These studies are summarized In Table 5-11.
A number of these studies have shown that T-HCH has adverse effects upon
the liver (Fltzhugh et al., 1950; Barros and Sallba, 1978; Barros et al.,
1982; Shlvanandappa and Krlshnakumarl, 1981; Nlgam et al., 1982, 1984a,b;
Munlr and Bhlde, 1984). These effects Include Increased relative and
absolute weight of the liver and hlstologlcal (cellular alterations, degen-
erative and prollferatlve changes, glycogen accumulation), ultrastructural
and hlstochemlcal changes. Barros and Sallba (1978) reported T-HCH-lnduced
changes In the livers of Wlstar rats exposed to as little as 0.9 ppm for 90
days. In general, these changes Increased 1n Incidence and severity 1n
proportion to dose and duration of treatment. Nlgam et al. (1982, 1984a,b)
and Munlr and Bhlde (1984) demonstrated that the progression of hepatic
0820p 5-30 1.0/2T/86
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changes caused by T-HCH leads ultimately to the development of tumors and
are reversible only If exposure ceases at the very earliest stages sometime
before tumor formation.
High doses of T-HCH have been shown to cause kidney damage 1n Wlstar
rats. FHzhugh et al. (1950) reported focal nephritis (tubular atrophy and
hyaline cast formation), brown pigmentation and basal vacuollzatlon In the
kidneys of rats fed 800 ppm T-HCH for life. Barros and Sallba (1978) also
reported hyaline degeneration 1n the kidneys of rats exposed to 900 ppm for
90 days. Barros et al. (1982) reported a 40% reduction In renal alkaline
phosphatase activity after 90 days of exposure. Shivanandappa and KMsh-
nakumarl (1981) observed Increased relative kidney weight but no hlstologl-
cal changes In male CFT-Wlstar rats fed 750 or 1500 ppm T-HCH for 90 days.
Dietary T-HCH has been shown to cause testlcular atrophy 1n rats and
mice. These effects were observed In rats fed 1500 ppm for 90 days
(Shlvanandappa and KrlshnakumaM, 1981, 1983) or 800 ppm for life (FHzhugh
et al., 1950), and In mice fed 500 ppm for up to 10 months (N1gam et al.,
1979). Testlcular effects were not seen 1n rats fed 10, 100 or 750 ppm;
lower concentrations were not tested 1n mice.
In two separate studies, Shlvanandappa and KrlshnakamuM (1981) and
Shlvanandappa et al. (1982) observed Increased adrenal weight and hlstologl-
cal and hlstochemlcal evidence of steroldogenlc Inhibition In the adrenal
cortex of male CFT-W1star rats fed >750 ppm T-HCH for 90 days. Adrenal
changes were not observed In rats fed <250 ppm.
Two oral studies suggest that T-HCH may cause neurotoxlc effects. In a
90-day study, Shlvanandappa and KMshnakumarl (1981) reported 100% mortality
1n male CFT-Wlstar rats fed 3000 ppm which was accompanied by signs of CNS
stimulation; signs of CNS stimulation were not reported 1n rats fed <1500
0820p 5-35 10/21/86
-------
ppm. Hlstologlcal or ultrastructural changes in the nervous system were not
examined. Kashyap et al. (1979) observed convulsions and a "tendency to
circle in one direction with drooping ears" among Swiss mice fed 100 ppm 1n
the diet or gavaged with 10 mg/kg/day for 100 weeks. These signs of Intoxi-
cation were said to be "not prominent." Kashyap et al. (1979) also reported
unl- and bilateral corneal opacity In the T-HCH-exposed mice.
5.6. OTHER RELEVANT INFORMATION
Oral LD5Qs for Isomers of HCH are summarized In Table 5-12.
5.7. SUMMARY
5.7.1. a-HCH. Dietary a-HCH has been shown to cause Increased Inci-
dences of liver tumors In five strains of mice (Ito et al., 1973a,b, 1976;
Nagasaki et al., 1972a, 1975; Hanada et al., 1973; Goto et al., 1972) and 1n
Wlstar rats (Ito et al., 1975; Schulte-Hermann and Parzefall, 1981). The
teratogenlc and reproductive effects of a-HCH have not been Investigated.
Nonneoplastlc hepatic changes have been observed in rats and mice fed
a-HCH (Schulte-Hermann and Parzefall, 1981; Ito et al., 1973a,b, 1975,
1976; Fltzhugh et al., 1950).
5.7.2. B-HCH. Dietary B-HCH has been shown to cause definite Increased
Incidences of liver tumors In CF1 mice (benign and malignant) and possibly a
marginal Increase In ICR-JCL mice (hepatomas) (Thorpe and Walker, 1973; Goto
et al., 1972) but clearly not In dd mice (Ito et al., 1973a,b; Hanada et
al., 1973; Nagasaki et al., 1972a) nor In Hlstar rats (Ito et al., 1975;
Fltzhugh et al., 1950). The reproductive and teratogenlc effects of B-HCH
have not been Investigated. Nonneoplastlc and neoplastlc hlstologlcal
changes In the liver were not observed In studies that were designed to
Investigate hepatic carcinogenic response (Ito et al., 1973a,b, 1975);
Increases In absolute and relative liver weight were observed at dietary
0820p 5-36 TO/27/86
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Oral
TABLE 5-12
Values for Isomers of HCH*
Isomer
Species
"SO
(mg/kg)
a-HCH
B-HCH
Y-HCH
4-HCH
Mixture of Isomers
(proportions not reported)
mouse
rat
mouse
rat
mouse
rat
rabbit
guinea pig
rat
rat
mouse
1000
500-1700
1500
2000
86
124-230
60-200
100-127
750-1000
600-1250
700
'Source: WHO, 1969
0820p
5-37
10/21/86
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concentrations >250 ppm. FHzhugh et at. (1950) observed Increases In liver
weight accompanied" by hlstologlcal changes In rats fed >100 ppm S-HCH;
Increased relative Hver weight was the only effect observed at 10 ppm.
Early mortality was also observed among rats fed 800 ppm. No tumors were
observed 1n this study; however, not all of the rats started on the test
were examined h1stolog1cally (no criterion for selection was given). No
other chronic effects were reported.
5.7.3. Y-HCH (Llndane). Dietary y-HCH was shown to cause an
Increased Incidence of liver tumors In male CF1 mice fed 400 ppm for 110
weeks (Thorpe and Walker, 1973), a marginal response In male dd mice fed 600
ppm for 32 weeks and then examined 5-6 weeks posttreatment (Hanada et al.,
1973), and a marginal response 1n male ICR-JCL mice fed 600 ppm for 26 weeks
(Goto et al., 1972). No liver tumors were observed 1n dd mice fed up to 500
ppm for 24 weeks (Ho et al., 1973a,b; Nagasaki et al., 1972a) or In Wlstar
rats fed 500 ppm for up to 48 weeks (Ito et al., 1975). Significant
compound-related development of tumors of any type was not observed In NMRI
mice treated with Y-HCH for 80 weeks (Herbst et al.. 1975; Welsse and
Herbst, 1977), B6C3F1 mice also treated for 50 weeks (NCI, 1977), Osborne-
Mendel rats (NCI, 1977) or Wlstar rats {FHzhugh et al., 1950). The study
conducted by NCI (1977) has been criticized for poor survival of rats,
changes 1n dosing regimen and the possibility that male rats did not receive
MTDs (IARC, 1979). The negative findings of FHzhugh et al. (1950) are also
Inconclusive since only small numbers of animals were examined hlstologl-
cally. The negative findings of Ito et al. (1973a,b), Nagasaki et al.
(1972a) and Ito et al. (1975) might be attributed to small numbers of
animals and short duration. A metabolite of Undane, 2,4,6-trlchlorophenol,
has been Identified 1n exposed rodents and humans and 1s considered to have
a we1ght-of-ev1dence for human cardnogenlclty of Group 62.
0820p 5-38 03/18/88
-------
Orally-administered f-HCH was not found to be teratogenic or fetotoxlc
1n Wlstar rats (Khera et a"!., 1979), CD rats (Palmer et al., 1978a), CFY
rats (Palmer et al., 1978b), New Zealand White rabbits (Palmer et al.,
1978b) or CD-I mice (Chernoff and Kavlock, 1983; Gray and Kavlock, 1984).
In contrast, a study by Dz1erzawsk1 (1977) reported Increased numbers of
resorbed fetuses In hamsters (40 mg/kg on day 9 of gestation), rabbits (40
or 60 mg/kg on day 9 of gestation) and rats (40, 50 or 100 mg/kg on various
days of gestation). Maternal toxldty was not reported. These doses are
higher than any of those tested 1n the negative studies of y-HCH, though
Chernoff and Kavlock (1983) reported that 25 mg/kg/day was the maximum dose
that was not toxic to maternal CD-I mice.
Palmer et al. (1978a) failed to observe adverse effects on reproduction
In three generations of CD rats fed up to 100 ppm y-HCH In the diet.
Dlkshlth and Datta (1977) and Dlkshlth et al. (1978), however, observed
testlcular atrophy 1n ITRC rats gavaged with 17.6 mg y-HCH/kg 1n peanut
oil for 90 days, suggesting that f-HCH might have adverse effects upon
reproduction.
Long-term oral studies have associated exposure to HCH with nonneoplas-
t1c liver changes (Dlkshlth et al., 1978; FHzhugh et al., 1950); Research
and Consulting Co., Ltd., 1983; Oesch et al., 1982; Ito et al., 1973a,
Rlvett et al.. 1978), kidney changes (FHzhugh et al., 1950; Research and
Consulting Co., Ltd., 1983), hematologlcal effects (Earl et al., 1970;
Morgan et al., 1980) and neurotoxldty (FHzhugh et al., 1950; Czegledl-
Janko and Avar, 1980). Short-term studies suggest that y-HCH may cause
Immunosupresslon (Dewan et al., 1980; Des1 et al., 1978).
0820p 5-39 VO/21/86
-------
5.7.4. 6-HCH. Dietary s-HCH did not cause neoplastlc or nonneoplas-
t1c changes 1n the livers of male dd mice (Ito et al., 1973a; Nagasaki et
al., 1972a) or male Wlstar rats (Ito et al., 1975). These studies used
small numbers of animals and were only conducted for 24 weeks. A mixture of
6- and e-HCH caused benign and malignant hepatomas 1n male ICR-JCL mice
when fed In the diet at 600 ppm for 26 weeks (Goto et al., 1972). Other
pertinent data regarding the teratogenlc, reproductive or chronic effects of
4-HCH could not be located In the available literature as cited 1n the
Appendix.
5.7.5. e-HCH. A mixture of 5- and e-HCH caused benign and
malignant hepatomas In male ICR-JCL mice when fed In the diet at 600 ppm for
26 weeks (Goto et al., 1972). Other pertinent data regarding the health
effects associated with exposure to c-HCH could not be located 1n the
available literature as cited In the Appendix.
5.7.6. T-HCH. T-HCH has been shown to cause Increased Incidences of
liver neoplasms 1n four strains of mice (Hanada et al., 1973; Goto et al.,
1972; Kashyap et al., 1979; N1gam et al., 1984a; Bhatt et al., 1981; Munlr
et al., 1983; Nagasaki et al., 1971, 1972b; Nagasaki, 1973; Munlr and Bhlde,
1984) but not 1n Wlstar rats (Munlr et al., 1983) or Syrian golden hamsters
(Munlr et al., 1983).
The teratogenlc effects of T-HCH have not been Investigated. N1gam et
al. (1979) and Shlvanandappa and KMshnakumarl (1981. 1983) have shown that
orally-administered T-HCH causes testlcular atrophy 1n rats and mice (>800
ppm, rats; 500 ppm, mice).
Long-term oral administration of T-HCH has been shown to cause adverse
effects on the liver (Fltzhugh et al., 1950; Barros and Sallba, 1978; Barros
et al.. 1982; Shlvanandappa and Krlshnakumarl, 1981; N1gam et al., 1982,
0820p 5-40 10/21/86
-------
1984a.b; Hunir and Bhide, 1984), kidney (FHzhugh et al., 1950, Barros and
Sallba, 1978; Barros et al., 1982; ShWanandappa and KrlshnakumaM, 1981),
adrenal cortex (Shlvanandappa and Krlshnakumarl, 1981; ShWanandappa et al.,
1982) and CMS (Shivanandappa and Krlshnakumarl, 1981; Kashyap et al., 1979).
Kashyap et al. (1979) also reported that long-term oral exposure to T-HCH
was associated with Increased corneal opacity.
It has been proposed that In sensitive species/strains the nonneoplastlc
changes In the liver associated with exposure to certain Isomers of HCH or
to T-HCH are associated with neoplastlc development. In some studies, clear
progression of hepatic changes that ultimately lead to the development of
malignant tumors has been observed at gross, hlstologlcal and ultra-
structural levels of examination. These changes are proportional to dose
and duration of treatment and appear to be reversible only at the very
earliest stages sometime before the development of nodular hyperplasla (Ito
et al., 1975, 1976; Schulte-Hermann and Parzefall, 1981; Munlr et al., 1983;
Munlr and Bhlde, 1984; N1gam et al., 1982, 1984a; Suglhara et al., 1975).
Although nodular hyperplasla may appear to regress shortly after HCH treat-
ment 1s discontinued, If the observation period Is extended, the development
of hepatocellular carcinoma becomes apparent {Suglhara et al., 1975) (see
Tables 1n Sections 5.1. and 9.2.). Suglhara et al. (1975) postulated that
surviving cells from areas of nodular hyperplasla ultimately progress to
hepatocellular carcinoma. As such, tissues affected by HCH would have
"memory" to later respond In a recurrent manner to further HCH treatment or
to another tumor progressor producing an additive cardnogenlclty testing
with cancer-positive HCH Isomers.
0820p 5-41 10/21/86
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6. AQUATIC TOXICITY
T-HCH Is a mixture of the five HCH Isomers 1n the following ranges:
a-, 55-70%; B-, 6-8%; Y-. 10-18%; 4-, 3-4%; and trace amounts of the
c-lsomer. The y-lsomer has Insectlddal properties and preparations
containing at least 99% y-HCH are called Undane. The y-^omer Is
considered to be the most Important since H 1s the most toxic to aquatic
organisms (U.S. EPA, 1980b).
6.1. ACUTE
Since there Is a large volume of Information dealing with acute toxlclty
of HCH to freshwater animals, only acute toxlclty data pertinent to fish and
Invertebrate species found 1n North American waters will be presented.
Exceptions may be made 1f data for other species provide general Information
regarding HCH toxlclty (relative toxlclty of the various Isomers).
Information concerning toxlclty of Undane to freshwater fish and
amphibians Is shown 1n Table 6-1. The most sensitive species was the brown
trout, Salmo trutta. which had a 96-hour LCrn of 1.7 ^g/8, (Johnson and
iu
Flnley, 1980), the lowest reported acutely toxic concentration. The data In
Table 6-1 Indicate that salmonlds generally are more sensitive to Undane
than other species.
Data concerning the acute toxlclty of HCH Isomers other than Undane
(y-HCH) to freshwater fishes and amphibians are shown In Table 6-2.
Sufficient Information Is not available to draw conclusions about the
relative toxlclty of other HCH Isomers, but they appear to be less toxic
than Undane. The mixture of Isomers referred to as HCH 1s much less toxic
than Undane. This Is not only due to a lower y-HCH content than pure
Undane; 1t Is possible that the other Isomers either reduce the solubility
of y-HCH or somehow antagonize Us toxlclty (U.S. EPA, 1980b).
0821p 6-1 06/27/86
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Data concerning the acute toxldty of HCH to marine fishes are shown In
Table 6-3. The" lowest reported lethal concentration was 7.3
Undane, the 96-hour LC5Q for the striped bass, Horone saxatnis (Korn and
Earnest, 1974). The only data for HCH compounds other than Undane Indicat-
ed that HCH was less toxic than Undane to the plnflsh, Lagodon rhomboldes.
with 96-hour LC£ values of 86.4 yg/j. for HCH and 30.6 vg/l for
Undane (Schlmmel et al., 1977).
Acute toxldty of HCH to fishes 1s not greatly Influenced by temperature
or water hardness. In experiments where temperature effects have been
demonstrated, the results are conflicting. Undane LC™ values for
rainbow trout decreased 2.3 times over the temperature range of 2-18°C, but
blueglll LC5Q values Increased 2.6 times over the range of 7-29°C (Johnson
and Flnley, 1980). Macek et al. (1969) also reported that Undane toxldty
to bluegllls Increased slightly with Increasing temperature, with 96-hour
LC values of 54 yg/8. at 12.7°C and 37 vg/i at 23.8°C. Acute
toxlclty to eels, Anglulla anglulla. decreased slightly at higher tempera-
tures (48-hour LC5Q = 600 yg/i at 11.5°C and 1000 vg/l at 22.5°C),
which was attributed to Increased mucus production at the higher tempera-
ture, thereby Inhibiting pesticide uptake (Foulquler et al., 1971).
Variations 1n water hardness have been found to have little or no effect on
toxlclty of Undane or HCH to fishes (Henderson et al . , 1959; Johnson and
Flnley, 1980).
It 1s likely that Insecticide-resistant populations of aquatic organisms
can develop 1n areas where organochlorlde pesticides have been used for long
periods. Culley and Ferguson (1969) studied this phenomenon In mosquito-
fish, Gambusla aff 1n1s. populations 1n Mississippi. They conducted acute
bloassays using fish from an area with no history of Insecticide application
0821p 6-7 06/27/86
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and compared the results with those obtained using fish from a population
with a history of exposure to different Insecticides. For Undane, they
found that the fish from the contaminated area were 42 times more resistant
to Undane. The 48-hour LC values were 3104 and 74 yg/8,, respec-
tively. Development of such resistant populations may be the result of
selection for resistant Individuals over several generations of exposure, or
may also be due to Induction of detoxification mechanisms In previously-
exposed fish.
Table 6-4 contains Information about the acute toxlclty of Undane to
freshwater Invertebrates. Cladocerans generally seem to be the most resis-
tant freshwater species, while other crustaceans and Insects are among the
most sensitive (U.S. EPA, 1980b). The lowest reported acutely toxic concen-
tration was 1 yg/l, the 96-hour LC for stonefHes, Pteronarcys sp.
(Cope, 1965; Snow, 1958). Although Undane 1s used as an Insecticide, the
most sensitive Invertebrate species are only slightly more sensitive than
the most sensitive fishes (U.S. EPA, 1976).
Among saltwater Invertebrates, crustaceans were more sensitive to
Undane than mollusks or annelids (see Table 6-4). The most sensitive
saltwater Invertebrate was the pink shrimp, Penaeus duorarum. with a 96-hour
LC of 0.17 vg/l Undane (Schlmmel et al., 1977).
Data concerning effects of HCH compounds other than Undane on fresh-
water and saltwater Invertebrates are found In Table 6-5. Llndane appears
to be more toxic than other HCH compounds. The species most sensitive to
HCH compounds was still the stonefly, Pteronarcys sp., with a 96-hour LC5Q
of <18 vg/i HCH (Johnson and Flnley, 1980) and the pink shrimp, with a
96-hour LC5Q of 0.34 yg/i HCH (Schlmmel et al., 1977).
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6.2. CHRONIC
The available Information concerning long-term effects of HCH compounds
on freshwater organisms Is shown In Table 6-6. No data for saltwater
species were available. The lowest concentration reported to cause chronic
toxldty was 3.3 jig/9. Undane, which was a chronic value for the midge,
Chlronomus tentans (Macek et a!., 1976). Acute toxldty, however, has been
reported at lower concentrations 1n more sensitive species, such as brown
trout and stonefHes. Data for these most sensitive species are needed
before the chronic toxldty of Undane can be fully evaluated. The avail-
able data for other HCH compounds are Insufficient to draw any conclusions
about their chronic toxldty relative to Undane.
6.3. PLANTS
Table 6-7 contains the available Information regarding effects of HCH on
aquatic plants. Aquatic plants are less sensitive to HCH compounds than
fish and Invertebrates (U.S. EPA, 1980b). The lowest concentration reported
to cause toxic effects was 80 yg/l HCH, which Inhibited growth and DNA
synthesis In the blue-green algae, Anabaena aphanlzomenoldes and Anabaenop-
sls radborskll (Das and Singh, 1977). Most reported toxic concentrations
for freshwater and marine plant species were >1000 (see Table 6-7).
6.4. RESIDUES
There are several studies available concerning the kinetics of uptake
and elimination of HCH compounds by aquatic organisms (Table 6-8). Because
several of these studies were of short duration, the BCFs that were deter-
mined do not represent steady-state values; however, the steady-state BCFs
that have been determined Indicate that HCH compounds do not bloaccumulate
to the same extent as organochlorlne compounds such as PCBs and DDT (U.S.
EPA, 1980b). BCFs for HCH compounds are generally <1000 (see Table 6-8),
0821p 6-15 06/27/86
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probably becasue a- and y-HCH are less UpophHlc than most other
organochlorlnes (Rlckard and Dulley, 1983). Like other organochlorlnes,
however, the primary site of HCH accumulation Is also fat (Suglura et al.,
1979).
Some studies have addressed the relative Importance of uptake from water
vs. uptake from food 1n determining levels of HCH accumulation. Hansen
(1980) found that Undane uptake from water by Daphnla magna and stickle-
backs, Gasterosteus aculeatus. was very rapid, while uptake from food was
relatively slow and dependent on the duration of exposure and feeding rate.
In a study In which fish, Goblo goblo. were exposed to Undane In water and
fed contaminated or uncontamlnated diets for 433 hours, uptake from food
appeared to be less Important than uptake from water (Harcelle and Thome,
1984). Since the difference 1n Undane content between "contaminated" and
"uncontamlnated" food, however, was only 2-fold (100 ppm vs. 50 ppb), these
results are of questionable validity. In a similar study (Canton et al.,
1975), Daphnla magna and rainbow trout, Salmo qalrdnerl. exposed to a-HCH
In food and water, accumulated slightly higher residues than animals exposed
to a-HCH 1n water alone. Rainbow trout receiving a-HCH only 1n food
were found to have concentration ratios (I.e., ppm 1n fat/ppm In diet) of
0.1-0.7. Great Lakes coho salmon, Oncorhynchus klsutch, fed natural diets
containing organochlorlne compounds were found to accumulate a-HCH, B-HCH
and Undane 1n proportion to dietary concentrations (Leatherland and
Sonstegard, 1982). Concentration ratios 1n this study ranged from 0.4-0.8
In Lake Ontario fish, the only fish found to have detectable HCH residues In
the diet and their tissues.
HCH compounds are generally eliminated more rapidly than other organo-
chlorlne compounds such as DOT and dleldrln (Tooby and Durbln, 1975), which
0821p 6-22 06/27/86
-------
could also contribute to the relatively low steady-state BCF values. Elimi-
nation half-times for HCH compounds 1n various species range from 10
years. Llndane Hself was detected only occasionally 1n fishes, but a-HCH
was found rather frequently. Concentrations of a-HCH 1n Intestinal fat
samples were 740 ppb 1n goldeye, Hlodon alosoldes, from the Saskatchewan
River, but were -100 ppb or less In other species and In other areas.
0821p 6-23 10/27/86
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Occurrence of the other organochlorlne compounds was widespread 1n all
species at low concentrations, despite the fact that they were no longer
used. This observation Is consistent with the high BCFs and long half-lives
of these compounds 1n fish tissues. Relative to these other organochlo-
rlnes, HCH does not accumulate appreciably In fish (Chovelan et al., 1984).
These and other monitoring data 1n Table 6-9 Indicate that HCH compounds
do not undergo ecological magnification to a great extent. HCH concentra-
tions 1n carnivorous fish species are comparable to those 1n herbivorous
fish species (Sackmauerova et al., 1977). In addition, laboratory studies
with experimental food chains also Indicate that HCH 1s not blomagnlfled to
a great extent (Strelt, 1979), especially compared with other organo-
chlorlnes.
Schmltt et al. (1985) reported the results of a monitoring study of fish
tissue residues from 107 freshwater stations In the United States (Table
6-10), and concluded that HCH was relatively short-lived compared with other
organochlorlnes. A decline 1n tissue concentration and occurrence of
detectable HCH residues In fish tissues were observed from 1976-1981. In
the 1980-1981 sampling period, whole-body Undane residues were >10 ng/g
only at one station In Hawaii, where levels were 20-30 ng/g. Tissue concen-
trations of a-HCH were generally higher than Undane, and the highest
concentrations (30-40 ng/g) were found 1n fish from stations 1n the south-
west and midwest.
In a monitoring study of marine species, Tanabe et al. (1984) found that
the primary form of HCH 1n seawater, zooplankton, squid, Todarodes
padflcus, and myctophlds, Dlaphys suborbUalls. was a-HCH. In a marine
mammal, the striped dolphin, Stenello coeruleoalba. >50% of the total HCH
concentration was B-HCH (Tanabe et al., 1983, 1984).
0821p 6-27 06/27/86
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Tanabe et al. (1983, 1984) presented Information concerning HCH residues
In marine mammals of the Pacific Ocean. Blubber of these species contained
the highest reported HCH residues. The highest concentration, 13,000-15,000
ng/g, was found In blubber of the Pacific white-sided dolphin, Lagenorhyn-
chus obUquldence. which Inhabits northern temperate waters that contain
high levels of organochlorlnes relative to other areas. Species from Arctic
and Antarctic waters contained lower HCH residues. Tanabe et al. (1983)
concluded that because of their long Hfespans and their position as
top-level carnivores, marine mammals are likely to accumulate high levels of
organochlorlnes Including HCH.
6.5. SUMMARY
There 1s a large volume of Information available concerning effects of
HCH on aquatic organisms. Llndane (f-HCH) 1s generally more toxic to
freshwater and saltwater fish and Invertebrates than other HCH Isomers or
mixtures (U.S. EPA, 1980b). The lowest reported acutely toxic concentra-
tions for freshwater species were 1.7 yg/i Undane, which was a 96-hour
LC5Q for brown trout (Johnson and Flnley, 1980) and 1 yg/8, Undane,
which was a 96-hour LC5Q for stonefHes (Cope, 1965, Snow, 1958). The
lowest reported acutely toxic Undane concentrations for marine fish and
Invertebrates, respectively, were 7.3 yg/l, a 96-hour IC__ for striped
bass (Korn and Earnest, 1974), and 0.17 vg/l, a 96-hour LC Q for pink
shrimp (Schlmmel et al., 1977). Among the freshwater fishes, salmonlds
appeared to be more sensitive than other species. Crustaceans other than
cladocerans were generally the most sensitive Invertebrate species both In
freshwater and saltwater (U.S. EPA, 1980b). Fish and Invertebrates appeared
to be about equally sensitive to HCH.
0821p 6-29 06/27/86
-------
In chronic toxldty studies, no adverse effects were reported at concen-
trations lower than the acutely toxic levels for the most sensitive species;
however, chronic toxldty data for the most acutely sensitive species were
generally unavailable.
The available Information Indicated that aquatic plants were much less
sensitive to HCH than fish or Invertebrates.
HCH accumulates In aquatic biota primarily 1n fatty tissue; however, HCH
Is less UpophlUc and less persistent than other organochlorlnes and there-
fore 1s not bloaccumulated or b1omagn1f1ed to a great extent.
0821p 6-30 06/12/86
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The existing guidelines for human exposure to HCH from ambient water are
based on cancer data. These values, summarized 1n Table 7-1, were derived
by the U.S. EPA (1980a, 1982b). The q^ for y-HCH (Undane) reported In
Table 7-1 1s also reported In a Health Effects Assessment (U.S. EPA, 1984a)
and a Drinking Water Criteria Document {U.S. EPA, 1985a). Values were not
available for either 6- or e-HCH.
In addition, an RfD for oral exposure to y-HCH has been estimated and
verified by the U.S. EPA (1985a, 1986a). This ADI of 0.023 mg/day (0.0003
mg/kg/day) for a 70 kg human was based on a rat subchronlc oral NOAEL of
0.33 mg/day (Research and Consulting Co., Ltd., 1983) and an uncertainty
factor of 1000.
OSHA (1985) and ACGIH (1985-1986) recommend a TWA of 0.5 mg/m3 for
Undane (y-HCH) and Indicate that dermal exposure may be substantial.
7.2. AQUATIC
U.S. EPA (1980b) derived an ambient water quality criterion for Undane
for the protection of aquatic life. For the protection of freshwater
species, the concentration of Undane should be <0.8 ug/fc as a 24-hour
average and should be <2.0 yg/j. at any time. For saltwater species, the
Undane concentrations should be <0.16 yg/i at any time. No criteria
were derived for other HCH Isomers or BHC, but U.S. EPA (1980b) noted that
acute toxldty to freshwater and saltwater species occurred at concentra-
tions as low as 100 and 0.34 yg/l HCH, respectively, and would occur at
lower concentrations In species more sensitive than those tested.
U.S. EPA (1976) recommended criteria of 0.01 yg/l to protect
freshwater organisms and 0.04 yg/8. to protect saltwater organisms.
0822p 7-1 03/18/88
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8. RISK ASSESSMENT
8.1. a-HCH
Dietary a-HCH has been shown to cause an Increased Incidence of liver
tumors 1n five strains of mice (Ito et al., 1973a,b, 1976; Nagasaki et a!.,
1972a, 1975; Hanada et al., 1973; Goto et al., 1972) and In Wlstar rats (Ito
et al., 1975; Schulte-Hermann and Parzefall, 1981). The teratogenlc and
reproductive effects of a-HCH have not been Investigated. Nonneoplastlc
hepatic changes have occurred 1n rats and mice fed a-HCH (Shulte-Hermann
and Parzefall, 1981; Ito et al., 1973a,b, 1975, 1976; FHzhugh et al., 1950).
According to EPA criteria, there 1s sufficient evidence to conclude that
a-HCH 1s carcinogenic to animals. A past assessment for a-HCH (U.S.
EPA, 1982b) derived a q * for humans of 11.1 (mg/kg/day)'1 on the basis
of an Increased Incidence of liver neoplasms 1n male DDY mice fed 250 and
500 ppm a-HCH 1n the diet for 24 weeks (Nagasaki et al., 1972a). The data
from the past assessment of the U.S. EPA (1982b) to estimate the a-HCH
q,* are presented 1n Table 8-1.
There are, however, a number of problems with these two data sets.
Nagasaki et al. (1972a) reported only the Incidences of macroscopic liver
nodules 1n groups of mice fed 0, 100 ppm (13 mg/kg/day), 250 ppm (37.5
mg/kg/day) or 500 ppm (65.0 mg/kg/day) of a-HCH 1n the diet. Although
Nagasaki et al. (1972a) mentioned that hlstologlcal examination revealed
benign and malignant hepatomas 1n the livers of mice fed 250 or 500 ppm
a-HCH, they did not report Incidences of h1stolog1cally verified tumors
and did not Indicate whether the livers of mice fed 0 or 100 ppm of a-HCH
were examined histologlcally. Hence, the Incidence data used In the past by
U.S. EPA (1982b) to estimate a q * 1s for grossly observable liver nodules
0823p 8-1 03/18/88
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TABLE 8-1
Summary of Pertinent Data for q-j* for a-HCHa
The water quality criterion for a-HCH 1s derived from the oncogenlc
effects observed In the livers of male dd mice fed 0, 250 or 500 ppm a-HCH
In the diet for 24 weeks. These dietary levels correspond to TWA doses of
0, 37.5 or 65 mg/kg/day, respectively. The criterion was calculated from
the following parameters without the 13 mg/kg/day dose:
Incidence of Grossly
Dose Observable Liver Nodules^
(mq/kg/day) (No. responding/No, tested)
0 0/20
13.0 0/20
37.5 9/20
65.0 20/20
le = 24 weeks w = 0.030 kg
LE = 24 weeks
L = 90 weeks
With these parameters the carcinogenic potency factor for humans, q-|*,
Is 11.12 (mg/kg/day)~1C.
aSource: Nagasaki et a!., 1972a
bThese tumors are not hepatocellular carcinomas nor do they appear to be
hepatomas, but rather are swellings leading "nodules."
cWhen dose-response data for the lowest dosage group (dose = 13 mg/kg/day,
Incidence = 0/20) Is Included In the analysis, the q-|* for humans 1s 3.03
(mg/kg/day)"1 for L = 90 weeks or 4.68 (mg/kg/day)'1 for L = 104 weeks:
Animal q-|* = 4.335761xlO"3 (mg/kg/day)'1
Human q-|* = 3.03 (mg/kg/day)"1 = animal q-|* x (70/0.03)1/3 x (90/24)3
Human q-j* = 4.68 (mg/kg/day)"1 = animal q-)* x (70/0.03)1/3 x (104/24)'
0823p 8-2 10/24/86
-------
only, and omits the Incidence 1n the lowest dosage group. If the dose-
response for this previously omitted group (dose = 13 mg/kg/day; Incidence =
0/20) 1s Included In the q^* derivation, the resulting q^ Is 3.03
(mg/kg/day)'1 with a mouse Hfespan of 90 weeks, or 4.68 (mg/kg/day)'1
when the Hfespan of the mice 1s assumed to be 104 weeks, a time correction
consistent with current methodology (U.S. EPA, 1985b).
Ito et al. (1973a) performed a similar study on male dd mice using the
same dietary levels and duration (but a larger 250 ppm group) and obtained
similar results. The Ito et al. (1973a) study, however, provides combined
Incidence data for hlstologlcally confirmed liver tumors (nodular hyper-
plasla and hepatocellular carcinoma). The data of Ito et al. (1973a),
summarized In Table 8-2, yield a q * for humans of 6.3 (mg/kg/day)'1
when the Hfespan of the mice 1s assumed to be 104 weeks, consistent with
current methodology (U.S. EPA, 1985b). The q * of 6.3 (mg/kg/day)"1 Is
recommended as the best estimate of the carcinogenic potency of a-HCH.
The corresponding water levels associated with maximum Increased lifetime
cancer risks for humans of 10~5, 10~6 and 10~7 are 5.52xlO~5,
5.52xlO"6 and 5.52xlO"7, respectively. The Ito estimate [6.34 (mg/kg/
day)"1] of cancer potency does not vary greatly from the above-reviewed
Nagasaki estimate [4.6 (mg/kg/day)"1].
A q * was also derived from the only available oral study that
Involved chronic administration (I.e., >24-32 weeks of the other studies) of
o-HCH and that reported combined Incidences of benign and malignant liver
tumors (Section 9.2.1.). In the 26-month study by Schulte-Hermann and
Parzefall (1981), the combined Incidence of hepatic neoplastlc nodules and
hepatocellular carcinomas 1n Wlstar rats was 6/6 In female Wlstar rats fed
-20 mg/kg/day of a-HCH for 20-26 months vs. 1/6 1n controls (p=0.008,
0823p 8-3 03/18/88
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TABLE 8-2
Derivation of a q-|* for a-HCH
Reference: Ito et al., 1973a
Specles/straln/sex: mouse/dd/male
Route/vehicle: oral/diet
Tumor site and type: liver, nodular hyperplasla3 and hepatocellular
carcinoma
le = 24 weeks
LE = 24 weeks
L = 104 weeks
bw = 0.03 kg (assumed)
Exposure
(ppm)
0
100
250
500
Transformed Dose"
(mq/kq/day)
0
13.0
37.5
65.0
Incidence
0/20
0/20
10/38
20/20
aThe hyperplasla was considered to be a precursor to tumor development In
this experiment and as such was added Into the tumor counts.
^Dose was transformed by multiplying dietary ppm by a food factor of 0.13
to obtain doses 1n mg/kg/day.
Animal qi* = 5.870060xlO"3 (mg/kg/day)'1
Human q-|* = 6.34 (mg/kg/day)"1 = animal qi* x (70/0.03)1/3 x (104/24)3
0823p 8-4 10/24/86
-------
Fisher Exact test). Because Global 82 will not converge when there are only
two groups (control and exposed) with 100% response 1n one of the groups, H
was necessary to reduce the Incidence to a value <100% and to adjust the
dose proportionally (Table 8-3). The adjusted data yield a q,* for humans
of 1.3 (mg/kg/day)'1, which Is only somewhat smaller, but of the same
order of magnitude as the q * derived for a-HCH from the much shorter
(24-week) study by Ito et al. (1973a). Such relative agreement may be
fortuitous but does suggest that the true upper limit estimate Is likely to
He 1n the 1.33-6.38 (mg/kg/day)"1 range.
8.2. B-HCH
Dietary B-HCH has been shown to cause an Increased Incidence of liver
tumors 1n CF1 mice (Thorpe and Walker, 1973). Tumors were not Increased In
dd mice (Ito et al., 1973a,b; Hanada et al., 1973; Nagasaki et al., 1972a)
or Wlstar rats (Ho et al., 1975; FHzhugh et al., 1950). The Thorpe and
Walker (1973) study Is the only positive cancer study for B-HCH. As previ-
ously discussed (see Section 5.1.1.), an additional report (Goto et al.,
1972) Indicates that mice fed 600 ppm of B-HCH had no grossly observable
liver nodules but had hlstologlcal evidence of benign hepatomas at an
unspecified Incidence, which Is considered to be marginal evidence at best.
The reproductive and teratogenlc effects of B-HCH have not been Investi-
gated. Ito et al. (1973a,b, 1975) found neither nonneoplastlc nor neo-
plastlc hlstologlcal changes 1n the livers of mice and rats 1n studies that
were designed to Investigate hepatic carcinogenic response; however.
Increases In absolute and relative liver weight were observed at dietary
concentrations >250 ppm. FHzhugh et al. (1950) observed Increased liver
weight accompanied by hlstologlcal changes 1n rats fed >100 ppm B-HCH;
Increased relative liver weight was the only effect observed at 10 ppm.
0823p 8-5 03/18/88
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TABLE 8-3
Derivation of a q-|* for a-HCH
Reference: Schulte-Hermann and Parzefall, 1981
Spec1es/strain/sex: rat/WIstar/female
Route/vehicle: oral/diet
Tumor site and type: liver, neoplastlc nodules and hepatocellular carcinomas
le = 20-26 months
LE = 20-26 months3
L = 20-26 months3
bw = 0.35 kg (assumed)
Exposure Transformed Dose Incidence
(mq/kq/day) (mq/kq/day)
0 0 1/6
20 16.67 (20)b 5/6 (6/6)b
aAssumed; data are unclear (Section 9.2.1.)
bS1nce GLOBAL 82 will not converge when there are only two groups and when
one of the groups has 100X response, 1t was necessary to reduce the Inci-
dence from 6/6 to 5/6 and to adjust the dose to 5/6 of the original value
(5/6x20 = 16.67).
Animal q-|* = 2.27421068X10"1 (mg/kg/day)"1
Human q-|* = 1.33 (mg/kg/day)'1 = animal q-)* x (70/0.35)1/3
0823p 8-6 06/10/86
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Early mortality was also observed among rats fed 800 ppm. Although no
tumors were observed 1n this study, not all of the rats started on the test
were examined h1stolog1cally (no criterion for selection was given). No
other chronic effects were reported.
According to EPA criteria, there 1s limited evidence that B-HCH 1s
carcinogenic to mice. This limitation 1s based 1n part on only one positive
mouse study (CFI strain), a marginal mouse study (ICR-JCL strain), four
negative mouse tests In 24-week studies (all dd strain mice), and two
negative long duration studies using Wlstar rats. U.S. EPA (1980a) has
previously derived a q,* for humans of 1.84 (mg/kg/day)'1 based on the
Increased combined Incidence of hepatic hyperplastlc nodules and hepato-
cellular carcinomas In male CFI mice fed 200 ppm B-HCH 1n the diet for 110
weeks (Thorpe and Walker, 1973). These data are summarized and quantified
In Table 8-4 and are recommended to best represent any putative carcinogenic
potency of B-HCH, keeping In mind the limitations of the weight of evidence.
No additional studies of the cardnogenldty of B-HCH have been published
since the U.S. EPA (1982a) document. The corresponding water levels asso-
ciated with maximum Increased lifetime cancer risks for humans of 10~5,
10"6 and 10~7 are 1.90xlO~4, 1.90xlO~5 and 1.90xlO"6 mg/l,
respectively.
8.3. Y-HCH (Llndane)
Dietary y-HCH was shown to cause an Increased Incidence of liver
tumors 1n male CFI mice fed 400 ppm for 110 weeks (Thorpe and Walker, 1973).
Marginal cancer responses were also observed In three other studies: 1) In
male dd mice fed 600 ppm for 32 weeks and examined 5-6 weeks after treatment
(Hanada et al., 1973); 2) 1n male ICR-OCL mice fed 600 ppm for 26 weeks
(Goto et al., 1972); and 3) 1n B6C3F1 mice dosed up to 160 ppm, when
0823p 8-7 03/18/88
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TABLE 8-4
Summary of Pertinent Data for q-|* for B-HCH3
The water quality criterion for B-HCH 1s derived from the oncogenlc
effects observed 1n the livers of male CF1 mice fed 200 ppm B-HCH In the
diet for 110 weeks (Thorpe and Walker, 1973). A TWA dose of 26.0 mg/kg/day
was derived from this exposure. The criterion 1s calculated from the
following parameters:
Dose
(mq/kq/day)
0
26.0
Incidence^
(no. responding/no, tested)
11/45
22/24
le = 110 weeks
LE = 110 weeks
L = 110 weeks
w = 0.030 kg
With these parameters the carcinogenic potency factor for humans, q-]*,
1s 1.84 (mg/kg/day)"1.
aSource: U.S. EPA, 1982a
^Combined Incidence of hyperplastlc nodules and hepatocellular carcinomas,
subsequent to the finding of the first tumor 1n any tissue In each group of
mice (Section 9.2.2.)
0823p
8-8
06/27/86
-------
compared with pooled controls at 90 weeks. On the other hand, no liver
tumors were observed In dd mice fed up to 500 ppm for 24 weeks (Ito et al.,
1973a,b; Nagasaki et al., 1972a) or In Wlstar rats fed 500 ppm for up to 48
weeks {Ito et al., 1975). Significant compound-related development of
tumors of any type was not observed 1n NMRI mice (Herbst et al., 1975;
Welsse and Herbst, 1977), B6C3F1 mice (NCI, 1977), Osborne-Hendel rats (NCI,
1977) or Wlstar rats (FHzhugh et al., 1950). The study conducted by NCI
(1977) has been criticized for poor survival of rats, changes 1n dosing
regimen and the possibility that male rats did not receive MTDs (IARC,
1979). The negative findings of FHzhugh et al. (1950) are also Inconclu-
sive since only small numbers of animals were examined hlstologlcally. The
negative findings of Ito et al. (1973a,b), Nagasaki et al. (1972a) and Ito
et al. (1975) 1s likely to be attributable to small numbers of animals and
short duration.
Orally-administered y-HCH was not found to be teratogenlc or fetotoxlc
In Wlstar rats (Khera et al., 1979), CO rats (Palmer et al., 1978a), CFY
rats (Palmer et al., 1978b), New Zealand White rabbits (Palmer et al.,
1978b) or CD-I mice (Chernoff and Kavlock, 1983; Gray and Kavlock, 1984).
In contrast, a study by Dzlerzawskl (1977) reported Increased numbers of
resorbed fetuses 1n hamsters (40 mg/kg on day 9 of gestation), rabbits (40
or 60 mg/kg on day 9 of gestation) or rats (40, 50 or 100 mg/kg on various
days of gestation). Maternal toxldty, 1f any, was not reported. These
doses are higher than any of those tested 1n the negative result studies,
though Chernoff and Kavlock (1983) reported that 25 mg/kg/day was the
maximum dose that was not toxic to maternal CD-I mice.
0823p 8-9 10/24/86
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Palmer et al. (1978a) observed no adverse effects on reproduction In
three generations' of CD rats fed up to 100 ppm y-HCH 1n the diet.
D1ksh1th and Datta (1977) and DlkshHh et al. (1978), however, observed
testlcular atrophy In ITRC rats gavaged with 17.6 mg y-HCH/kg In peanut
oil for 90 days, suggesting that y-HCH might have adverse effects upon
reproduction.
Long-term oral studies have associated exposure to HCH with nonneoplas-
t1c liver changes (DlkshHh et al., 1978; Fltzhugh et al., 1950; Research
and Consulting Co., Ltd., 1983; Oesch et al., 1982; Ito et al., 1973a,
Rlvett et al., 1978), kidney changes (Fltzhugh et al., 1950; Research and
Consulting Co., Ltd., 1983), hematologlcal effects (Earl et al., 1970;
Morgan et al., 1980) and neurotoxlclty (Fltzhugh et al., 1950; Czegledl-
Janko and Avar, 1970). Short-term studies suggest that y-HCH may cause
Immunosupresslon (Dewan et al., 1980; Desl et al., 1978).
According to EPA criteria, there 1s sufficient limited evidence that
Y-HCH Is carcinogenic to animals. U.S. EPA (1980a) has 1n the past
derived a q,* of 1.3 (mg/kg/day)"1 based on the Increased combined
Incidence of hepatic hyperplastlc nodules and hepatocellular carcinomas 1n
male CF1 mice fed 400 ppm y-HCH 1n the diet for 110 weeks (Thorpe and
Walker, 1973). These data are summarized In Table 8-5. There are no more
recent data available that could provide a better estimate of carcinogenic
potency for y-HCH. Corresponding water levels associated with maximum
Increased lifetime cancer risks for humans of 10~5, 10~« and 10~7 are
2.64xlO~4, 2.64xlO"5 and 2.64xlO~« mg/l, respectively.
0823p 8-10 03/18/88
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TABLE 8-5
Summary of Pertinent Data for q-|* for f-HCHa
The water quality criterion for y-HCH 1s derived from the oncogenk
effects observed 1n the livers of male CF1 mice fed 400 ppm y-HCH In the
diet (Thorpe and Walker, 1973). The TWA dose of 52 mg/kg/day was given In
the feed for 110 weeks. The criterion Is calculated from the following
parameters:
Dose Inc1denceb
(mg/kg/day) (no. responding/no, tested)
0 11/45
52 27/28
le = 770 days w = 0.030 kg
LE = 770 days
L = 770 days
With these parameters, the q-|* for humans Is 1.326 (mg/kg/day)"1.
aSource: U.S. EPA, 1980a
''Combined Incidence of hyperplastlc nodules and hepatocellular carcinomas,
subsequent to the finding of the first tumor 1n any tissue 1n each group of
mice (see Section 9.2.3.)
0823p 8-11 06/10/86
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8.4. 4-HCH
Dietary 6-HCH Tlld not cause neoplastlc or nonneoplastlc changes 1n the
Hvers of male dd mice (Ito et al., 1973a; Nagasaki et al., 1972a) or male
Wlstar rats (Ito et al., 1975). These studies used small numbers of
animals, were conducted for only 24 weeks and examined only liver effects.
Goto et al. (1972) reported that a mixture of 6- and e-HCH caused an
Increased Incidence of benign and malignant hepatomas 1n ICR-JCL mice after
26 weeks of dietary administration, but the Individual Isomers were not
tested In this study. This constitutes limited animal evidence and thus Is
In EPA Group C. Other pertinent data regarding the teratogenlc,
reproductive or chronic effects of 6-HCH could not be located 1n the
available literature as dted 1n the Appendix.
8.5. e-HCH
Goto et al. (1972) reported that a mixture of 6- and e-HCH caused an
increased Incidence of benign and malignant hepatomas In ICR-JCL mice after
26 weeks of dietary administration, but the Individual Isomers were not
tested 1n this study. This constitutes limited animal evidence and thus Is
1n EPA Group C. Other pertinent data regarding the health effects
associated with exposure to e-HCH could not be located 1n the available
literature as cited 1n the Appendix.
8.6. T-HCH
T-HCH has been shown to cause Increased Incidences of liver neoplasms In
four strains of mice (Hanada et al., 1973; Goto et al., 1972; Kashyap et
al., 1979; Nlgam et al., 1984a; Bhatt et al., 1981; Munlr et al., 1983;
Nagasaki et al., 1971, 1972b; Nagasaki, 1973; Munlr and Bhlde, 1984) but not
1n Wlstar rats (Munlr et al., 1983) or Syrian golden hamsters (Munlr et al.,
1983).
0823p 8-12 03/18/88
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The teratogenlc effects of T-HCH have not been Investigated. N1gam et
al. (1979) and Shtvanandappa and KrlshnakamuM (1981, 1983) have shown that
orally-administered T-HCH causes testlcular atrophy 1n rats and mice (>800
ppm, rats; 500 ppm, mice).
Long-term oral administration of T-HCH has been shown to cause adverse
effects on the liver (FHzhugh et al., 1950; Barros and Sallba, 1978; Barros
et al., 1982; Shlvanandappa and Kr1shnakamur1, 1981; Nlgam et al., 1982,
1984a,b; Munlr and Bhlde, 1984), kidney (FHzhugh et al., 1950, Barros and
Sallba, 1978; Barros et al., 1982; Shlvanandappa and Kr1shnakamur1, 1981),
adrenal cortex {Shlvanandappa and Kr1shnakamur1, 1981; Shlvanandappa et al.,
1982) and CNS (Shlvanandappa and Krlshnakamurl, 1981; Kashyap et al., 1979).
Kashyap et al. (1979) also reported that long-term oral exposure to T-HCH
was associated with Increased corneal opacity.
According to EPA criteria, there Is sufficient evidence that T-HCH Is
carcinogenic 1n animals (Group B2). U.S. EPA (1982b) 1n the past derived a
q * of 4.7 (mg/kg/day)"1 based on Increased combined Incidences of
hepatic hyperplastlc nodules and hepatomas In male dd mice fed 6.6, 66 and
660 ppm T-HCH for 24 weeks (Nagasaki et al., 1972b) (Table 8-6). However,
this 1s not a malignant tumor endpolnt, but 1t Is assumed that the nodules
would progress to hepatomas and the hepatomas to carcinomas. In estimating
this q.^, the U.S. EPA (1982b) assumed the Hfespan of the mice was 90
weeks. If the Hfespan 1s assumed to be 104 weeks, consistent with current
methodology (U.S. EPA, 1985b), the q for humans Is 7.3 (mg/kg/day)'1.
0823p 8-13 03/18/88
-------
TABLE 8-6
Summary of Pertinent Data for q-[* for T-HCH3
The water quality criterion for T-HCH 1s derived from the oncogenlc
effects observed In the livers of male dd mice fed 6.6, 66 or 660 ppm T-HCH
1n the diet for 24 weeks (Nagasaki et al., 1972b). These dietary levels
correspond to TWA doses of 0.858, 8.58 or 85.8 mg/kg/day, respectively. The
criterion Is calculated from the following parameters:
Dose Incidence**
(mq/kg/day) (no. responding/no, tested)
0 0/14
0.858 0/20
8.58 0/20
85.8 20/20
le = 24 weeks w = 0.036 kg
LE = 24 weeks
L = 90 weeks (104 weeks)c
With these parameters the carcinogenic potency factor for humans, q-j*,
Is 4.75 (mg/kg/day)~ic.
aSource: U.S. EPA, 1982b
^Combined Incidence of hyperplastlc nodules and hepatomas
cUse of an assumed llfespan (L) of 104 weeks, which 1s consistent with
current methodology (U.S. EPA, 1985b), gives a q-|* for humans of 7.35
(mg/kg/day)"1 as follows:
Animal q-|* = 7.232384xlO"3
Human q-|* = 7.35 (mg/kg/day)'1 = animal qi* x (70/0.036)1/3 x (104/24)3
0823p 8-14 11/17/86
-------
There are additional data available from which a q * can be derived.
Munlr et al. (1983) observed a dose- and duration-related Increase 1n the
combined Incidence of hepatic benign nodules and hepatocellular carcinomas
In male Swiss mice fed 0, 125, 250 or 500 ppm T-HCH from 8-10 weeks of age
until either 8-11, 12-14, 15-17 or 18-22 months of age. Once 100% response
was observed at a particular level of treatment, mice were no longer
examined at that level of treatment. Instead, data from age groups that
Include one group with 100% response and response data for more than one
dosage (12-14 months; 15-17 months) were used to calculate q * values.
These data are summarized In Tables 8-7 and 8-8. (Detailed Incidence data
for all groups are provided 1n Section 9.2.6.). A human q * of 1.17
(mg/kg/day)'1 was obtained from data on mice that were killed at 12-14
months of age; a human q,* of 1.76 (mg/kg/day)"1 was obtained from data
on mice that were killed at 15-17 months of age. These values are similar
to, but somewhat lower than, the q * values based on the 24-week study of
Nagasaki et al. (1972b).
The data of Munlr et al. (1983) for mice killed at 15-17 months of age
are recommended as the best basis for a q * [1.76 (mg/kg/day)"1]. This
q * Is considered to be the best estimate because treatment was for a
greater, proportion of the animals' Hfespan and was at a dosage that defined
dose-response relationships more clearly than do the data of Nagasaki et al.
(1972b). Water levels corresponding to the recommended q * of 1.76
(mg/kg/day)'1 and associated with a maximum Increased lifetime cancer risk
for humans of 10"5, 10"* and 10"7 are 1.99xlO~4, 1.99xlO"5 and
1.99xlO~6 mg/l, respectively.
0823p 8-15 10/24/86
-------
TABLE 8-7
Derivation of a q-|* for T-HCH
Reference: Munlr et al., 1983
Species/strain/sex: mouse/Swiss/male
Route/vehicle: oral/diet
Tumor site and type: liver, benign nodules and hepatocellular carcinomas
le = LE = from 8-10 weeks of age to 12-14 months of age (=12 months)
L = 104 weeks (24 months)
bw = 0.03 kg (assumed)
Exposure
(ppm)
0
125
250
500
Transformed Dose3
(mq/kq/day)
0
16.25
32.50
65.00
Incidence
0/16b
0/10
9/12
10/10
aDose was transformed by multiplying concentration In ppm by a food factor
of 0.13.
bControl data are from a similar experiment In male Swiss mice performed
In the same laboratory and reported 1n the same paper.
Animal q-|* = 1.1033241xlO"2 (mg/kg/day)'1
Human qi* = 1.17 (mg/kg/day)"1 = animal q-|* x (70/0.OS)1^ x (24/12)3
0823p 8-16 10/24/86
-------
TABLE 8-8
Derivation of the q-|* for T-HCH
Recommended as the Best Estimate of Cancer Potency for T-HCH
Reference: Munlr et al., 1983
Spec1es/strain/sex: mouse/Swiss/male
Route/vehicle: oral/diet
Tumor site and type: liver, benign nodules and hepatocellular carcinomas
le = LE = from 8-10 weeks of age to 15-17 months of age (-15 months)
L = 104 weeks (24 months)
bw = 0.03 kg (assumed)
Exposure
(ppm)
0
125
250
Transformed Dose3
(mg/kq/day)
0
16.25
32.50
Incidence
2/22c
8/20
12/12
aAn1mals at 500 ppm were not examined at this age since 100% response was
observed at this level among mice that were 12-14 months of age.
''Dose was transformed by multiplying concentration In ppm by a food factor
of 0.13.
cControl data are from a similar experiment 1n male Swiss mice performed
In the same laboratory and reported In the same paper. The controls,
however, were killed at 15-20 months of age.
Animal q-|* = 3.2323128xlO~2 (mg/kg/day)'1
Human q-j* = 1.76 (mg/kg/dayT1 = animal q-!* x (70/0.03)1/3 x (24/15)3
0823p 8-17 10/24/86
-------
9. REPORTABLE QUANTITY
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY
A large body of evidence Indicates that the nonneoplastlc changes In the
liver associated with dietary exposure to Isomers of HCH or T-HCH are asso-
ciated with neoplastlc development. A clear progression of hepatic changes
that ultimately lead to the development of malignant tumors has been
observed at gross, hlstologlcal and ultrastructural levels of examination.
These changes, proportional to dose and duration of treatment, are revers-
ible only at the very earliest stages before development of nodular hyper-
plasla; the transition from reversible to Irreversible change Is not
well-defined (Ito et al., 1975, 1976; Schulte-Hermann and Parzefall, 1981;
Munlr et al., 1983; Munlr and Bhlde, 1984; Nlgam et al., 1982, 19£4a;
Suglhara et al., 1975). Therefore, preneoplastlc hepatic changes were not
considered 1n the derivation of RQs for chronic toxlclty.
CSs for HCH are summarized 1n Table 9-1. Data from which RQs could be
derived were not available for 5- or c-HCH.
9.1.1. a-HCH. Available long-term studies for a-HCH are summarized
1n Table 5-6. All studies used oral routes of exposure; five of the six
studies were designed to Investigate hepatic carcinogenic response (Schulte-
Hermann and Parzefall, 1981; Ito et al., 1973a,b, 1975, 1976). The study
conducted by FUzhugh et al. (1950) was conducted for the Hfespan of the
animal (rats) and examined endpolnts other than liver histology, but not all
animals started on the test were examined. Despite the latter deficiency,
the study by FHzhugh et al. (1950) Is the only study available from which
an RQ can be derived.
0824p 9-1 06/27/86
-------
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-------
A CS of 15 can be derived from the lifetime rat study by FHzhugh et al.
(1950) (Table 9-2"). A PEL of 800 ppm can be defined on the basis of a
significantly reduced llfespan. Assuming that a rat consumes the equivalent
In food of 5X of Its body weight/day, 800 ppm Is equivalent to an animal
dose of 40 mg/kg/day. Multiplying 40 mg/kg/day by the product of the cube
root of the ratio of rat to human body weight and human body weight (70 kg)
yields a human MED of 479 mg/day, which warrants an RV. of 1.5. An RV
of 10 can be assigned on the basis of early mortality. Multiplying the
RV by the RV yields a CS of 15, which corresponds to an RQ for a-HCH
of 1000 (see Table 9-2).
9.1.2. S-HCH. The available long-term studies on B-HCH are summarized In
Table 5-7. Most of these studies were designed to Investigate hepatic
carcinogenic response (Ito et al., 1973a,b, 1975). Thorpe and Walker (1973)
Investigated multiple endpolnts but observed no effects aside from those
related to development of liver tumors. FHzhugh et al. (1950) conducted a
lifetime dietary study on rats and Investigated multiple endpolnts, but did
not examine all animals (rats) that were started on the test. Despite the
latter deficiency, FHzhugh et al. (1950) 1s the only study that provides
appropriate data from which an RQ can be derived (Table 9-3).
The lifetime oral rat study by FHzhugh et al. (1950) provides a FEL of
800 ppm for significantly reduced llfespan and a LOAEL of 100 ppm for
significantly reduced body weight. The highest CS Is obtained from the FEL
1n the following manner. Assuming that a rat consumes the equivalent In
food of 554 of Hs body weight/day, 800 ppm 1s equivalent to an animal dose
of 40 mg/kg/day. Assuming that a rat weighs 0.35 kg, a human MED of 479
mg/day 1s obtained by multiplying the animal dose by the product of the cube
root of the ratio of rat weight to human body weight and by human body
0824p 9-3 06/27/86
-------
TABLE 9-2
a-HCH
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 479 mg/day
Effect: early mortality
Reference: FHzhugh et al., 1950
RVd: 1.5
RVe: 10
Composite Score: 15
RQ: 1000
'Equivalent human dose
0824p 9-4 06/10/86
-------
TABLE 9-3
B-HCH
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 479 mg/day
Effect: early mortality
Reference: FHzhugh et al., 1950
RVd: 1.5
RVe: 10
Composite Score: 15
RQ: 1000
'Equivalent human dose
0824p 9-5 06/10/86
-------
weight (70 kg); this MED warrants an RVd of 1.5. An RVg of 10 can be
assigned on the tasls of early mortality. Multiplying the RV by the
RVg yields a CS of 15, which corresponds to an RQ for 8-HCH of 1000 (see
Table 9-3).
9.1.3. Y-HCH (Llndane). Long-term oral studies on y-HCH have
associated exposure to HCH with nonneoplastlc liver changes (D1ksh1th et
al., 1978; FHzhugh et al., 1950; Research and Consulting Co., Ltd., 1983;
Oesch et al. 1982; Ho et al., 1973a; Rlvett et al., 1978), kidney changes
(FUzhugh et al., 1950; Research and Consulting Co., Ltd., 1983), hemato-
loglcal effects (Earl et al., 1970; Morgan et al., 1980) and neurotoxlclty
(FHzhugh et al., 1950; Czegledl-Janko and Avar, 1970) (see Table 5-8).
Short-term studies suggest that Y-HCH may cause Immunosupresslon (Dewan et
al., 1980; Des1 et al., 1978) (see Section 5.5.).
Orally-administered y-HCH was not found to be teratogenlc or fetotoxlc
In Hlstar rats (Khera et al., 1979). CD rats (Palmer et al., 1978a), CFY
rats (Palmer et al., 1978b), New Zealand White rabbits (Palmer et al.,
1978b) or CD-I mice (Chernoff and Kavlock, 1983; Gray and Kavlock, 1984).
In contrast, a study by Dz1erzawsk1 (1977) reported Increased numbers of
resorbed fetuses 1n hamsters (40 mg/kg on day 9 of gestation), rabbits (40
or 60 mg/kg on day 9 of gestation) and rats (40, 50 or 100 mg/kg on various
days of gestation). Maternal toxlclty was not reported. These doses are
higher than any of those tested In the negative studies, though Chernoff and
Kavlock (1983) reported that 25 mg/kg/day was the maximum dose that was not
toxic to maternal CD-I mice.
Palmer et al. (1978a) observed no adverse effects on reproduction In
three generations of CD rats fed up to 100 ppm Y-HCH In the diet.
0824p 9-6 03/18/88
-------
DlkshHh and Datta (1977) and DlkshHh et al. (1978), however, observed
testlcular atrophy In ITRC rats gavaged with 17.6 mg y-HCH/kg 1n peanut
oil for 90 days, suggesting that y-HCH may have adverse effects on
reproduction.
Studies that provide adequate Information for the derivation of an RQ
for T-HCH are those of DlkshHh et al. (1978), Fltzhugh et al. (1950),
Research and Consulting Co., Ltd. (1983), Earl et al. (1970) and Dz1erzawsk1
(1977).
OlkshHh et al. (1978) observed a LOAEL of 17.6 mg/kg/day for testlcular
atrophy In ITRC rats fed T-HCH for 90 days. Fltzhugh et al. (1950)
observed early mortality, gross and hlstologlcally-deflned kidney damage and
nervous symptoms and convulsions 1n rats fed 800 ppm y-HCH for life. . The
Research and Consulting Co., Ltd. (1983) reported degenerative hlstologlcal
changes In the kidneys of rats fed y-HCH (1.55 mg/kg/day) for 12 weeks.
Earl et al. (1970) reported hematologlcal effects In dogs fed Y-HCH (22.5
mg/kg/day) for 24 weeks. Oz1erzawsk1 (1977) observed Increased numbers of
resorptlons In rats, rabbits and hamsters given 40 mg y-HCH/kg/day on >1
days of gestation.
Although each of these studies has some deficiencies (short duration.
Incomplete examination of animals, small numbers of animals), taken collec-
tively, the studies Indicate that the RQ for y-HCH Is 1000. The study
that provided the highest CS (17) 1s the Research and Consulting Co., Ltd.
(1983) study. The LOAEL of 1.55 mg/kg/day for kidney damage Is assigned an
RV of 6. Dividing 1.55 mg/kg/day by an uncertainty factor of 10 (for
Iess-than-chron1c exposure) then multiplying by the product of the cube root
of the ratio of rat body weight to human body weight (assuming a body weight
of 0.35 kg for rats) and by the human body weight (70 kg), yields a human
0824p 9-7 06/27/86
-------
MED of 1.86 mg/day; this Is equivalent to an RV. of 5.1. Multiplying the
RVd by the RVg yields a CS of 31, which corresponds to an RQ of 100
(Table 9-4).
9.1.4. T-HCH. Long-term oral administration of T-HCH has been shown to
adversely affect the liver (FHzhugh et al., 1950; Barros and Sallba (1978),
Barros et al., 1982; Shlvanandappa and Krlshnakamurl , 1981; N1gam et al.,
1982, 1984a,b; Munlr and Bhlde, 1984), kidney (FHzhugh et al., 1950; Barros
and Sallba, 1978; Barros et al., 1982; Shlvanandappa and Krlshnakamurl,
1981), adrenal cortex (Shlvanandappa and Krlshnakamurl, 1981; Shlvanandappa
et al., 1982) and CNS (Shlvanandappa and Krlshnakamurl, 1981; Kashyap et
al., 1979). Kashyap et al. (1979) also reported that long-term oral
exposure to T-HCH was associated with Increased corneal opacity.
The teratogenlc effects of T-HCH have not been Investigated. N1gam et
al. (1979) and Shlvanandappa and Krlshnakamurl (1981. 1983) have shown that
orally-administered T-HCH causes testlcular atrophy In rats and mice (>800
ppm, rats; 500 ppnt, mice) (see Table 5-10).
Studies that demonstrated adverse effects at the lowest levels of
exposure are those of FHzhugh et al. (1950), Shlvanandappa et al. (1982),
N1gam et al. (1979) and Kashyap et al. (1979). FHzhugh et al. (1950)
observed early mortality and degenerative changes 1n the kidneys and testes
of rats fed 800 ppm y-HCH for life. Shlvanandappa et al. (1982) reported
gross, hlstologlcal and hlstochemlcal changes 1n the adrenal glands of rats
fed 750 ppm Y-HCH (625 mg/rat/90 days) for 90 days. Testlcular atrophy
was observed among mice fed 500 ppm y-HCH for 10 months (N1gam et al.,
1979), and corneal opacity and a slight tendency to convulse were observed
among mice fed 100 ppm y-HCH or gavaged with 10 mg y-HCH/kg/day for 80
weeks (Kashyap et al.. 1979).
0824p 9-8 06/10/86
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TABLE 9-4
Y-HCH
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 1.86 mg/day
Effect: degenerative changes 1n kidney
Reference: Research and Consulting Co., Ltd., 1983
RVd: 5.1
RVe: 6
Composite Score: 31
RQ: 100
'Equivalent human dose
0824p 9-9 06/10/86
-------
The study of Sh1vanandappa et al. (1982) yields the highest composite
score. The animal- dose of 19.8 1s adjusted to a human MED of 24 mg/day In
the following manner. The animal dose 1s first divided by an uncertainty
factor of 10 to account for less than chronic exposure. This yields an
adjusted animal dose of 1.98 mg/kg/day. An MED of 24 Is obtained by multi-
plying 1.98 by the product of the cube root of the ratio of rat body weight
(0.35 kg, assumed) to human body weight (70 kg). An RV. of 3.4 1s
assigned on the basis of the MED. An RV of 7 1s assigned on the basis of
h1stolog1cal and hlstochemlcal adrenal changes Indicative of steroldogenlc
Inhibition. Multiplying the RV. by the RV yields a composite score of
24. The RQ for T-HCH 1s therefore 100 (Table 9-5).
9.2. HEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED1Q) FOR CARCINOGENIC1TY
9.2.1. a-HCH. Dietary a-HCH has been shown to cause an Increased
Incidence of liver tumors 1n five strains of mice (Ito et al., 1973a,b,
1976; Nagasaki et al., 1972a, 1975; Hanada et al., 1973; Goto et al., 1972)
and In Wlstar rats (Ito et al., 1975; Schulte-Hermann and Parzefall, 1981).
The teratogenlc and reproductive effects of a-HCH have not been Investi-
gated. Nonneoplastlc hepatic changes have occurred 1n rats and mice fed
a-HCH (Shulte-Hermann and Parzefall, 1981; Ito et al., 1973a,b, 1975,
1976; FHzhugh et al., 1950).
According to IARC (1979), as well as the EPA Guidelines for Cancer
Assessment (U.S. EPA, 1986b), there 1s sufficient evidence to conclude that
a-HCH 1s carcinogenic to mice. Since there are no human data available,
a-HCH Is placed 1n IARC Group 28 and EPA Group B2, meaning that a-HCH 1s
considered probably carcinogenic to man. Data for the positive studies that
reported Incidences of h1stolog1cally verified tumors are summarized In
Tables 9-6 through 9-12. Positive studies lacking this type of Incidence
0824p 9-10 03/18/88
-------
TABLE 9-5
T-HCH
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 24 mg/day
Effect: hlstologlcal and hlstochemlcal adrenal changes
Indicative of steroldogenlc Inhibition
Reference: Shlvanandappa et al., 1982
RVd: 3.4
RVe: 7
Composite Score: 24
RQ: 100
*Equ1valent human dose
0824p 9-11 06/10/86
-------
TABLE 9-6
Incidence of Liver Neoplasms In Male DDY Mice Fed a-HCH
(>99X pure) In the D1eta
Dose Duration of Exposure
(ppm) (weeks)
Duration of Study
(weeks)
Tumor Incidence0
0
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
NA
16
20
20
20
20
24
24
24
24
24
24
24
36
36
36
36
72
16
20
24
28
32
24
28
32
36
40
48
60
36
48
60
72
0/18
5/21
14/20
8/20
5/20
2/19
20/20
18/19
9/16
7/17
8/16
12/15
14/14
14/14
11/13
12/12
13/13
Strengths of study:
Weakness of study:
Overall adequacy:
Comments:
QUALITY OF EVIDENCE
time-to-tumor Information; comprehensive examination of
the liver
short duration of exposure
adequate
100X response was observed at >24 weeks of exposure.
Hepatocellular carcinoma was the predominant tumor type
60-70 weeks from the beginning of the study.
aSource: Ho et al.. 1976
bComb1ned Incidence of hepatocellular carcinoma and nodular hyperplasla
NA = Not applicable
0824p
9-12
06/10/86
-------
TABLE 9-7
Incidence oT Hepatic Neoplasms In Mice Fed a-HCH for 24 Weeksa-b
Strain
DOY
ICR
DBA/2
C57BL/6
C3H/He
Sex
M
M
M
H
F
F
M
M
F
F
M
M
F
F
H
M
F
F
M
N
F
F
Dose
(ppm)
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
Incidence of
Nodular
Hyperplasla
0/16
20/20
0/20
20/20
0/20
16/20
0/20
18/23
0/19
15/29
0/13
8/16
0/16
5/15
0/22
4/21
0/16
3/18
0/17
13/20
0/18
11/20
Tumors0
Hepatocellular
Carcinoma
0/16
6/20
0/20
13/20
0/20
5/20
0/20
8/23
0/19
6/29
0/13
1/16
0/16
1/15
0/22
0/21
0/16
0/18
0/17
0/20
0/18
2/20
0824p
9-13
06/10/86
-------
TABLE 9-7 (cont.)
QUALITY OF EVIDENCE
five strains and both sexes tested
purity of compound not reported; short duration of
exposure
adequate
Strengths of study:
Weaknesses of study:
Overall adequacy:
aSource: Nagasaki et al.. 1975
DPur1ty not reported
cComb1ned Incidence not reported
0824p
9-14
06/10/86
-------
TABLE 9-8
Incidence of Liver Neoplasms 1n Male dd Mice fed a-HCH
(>99X pure) In the Diet for 24 Weeks3
Dose
(ppm)
0
50
100
250
Duration of Study
(weeks)
24
24
24
24
Incidence
Nodular
Hyperplasla
0/20
0/28
0/26
23/30
of Tumors'5
Hepatocellular
Carcinoma
0/20
0/28
0/26
8/30
Strengths of study:
Weaknesses of study:
Overall adequacy:
QUALITY OF EVIDENCE
three different doses tested; relatively large number
of mice examined/treatment
short duration of exposure; only the liver was exam-
ined microscopically
limited
aSource: Ito et al., 1973b
''Combined Incidence not reported
0824p
9-15
06/10/86
-------
TABLE 9-9
Incidence of Liver Neoplasms In Male dd Mice fed o-HCH
(>99X pure) 1n the Diet for 24 Weeks3
Incidence of Tumors
Dose
(ppm)
0
100
250
500
Duration of Study
(weeks)
24
24
24
24
Nodular
Hyperplasla
0/20
0/20
30/38
20/20
Hepatocellular
Carcinoma
0/20
0/20
10/38
17/20
Comb1nedb
0/20
0/20
30/38
20/20
Strengths of study:
Weaknesses of study:
Overall adequacy:
QUALITY OF EVIDENCE
three doses tested; relatively large number of mice/
treatment
short duration of exposure; only the liver was
examined microscopically
adequate
aSource: Ito et al., 1973a
^Combined Incidence of nodular hyperplasla and hepatocellular carcinoma
0824p
9-16
06/10/86
-------
TABLE 9-10
Incidences of Hepatomas In dd Mice Fed a-HCH 1n the Diet
for 32 Weeks3-b
Sex
M
F
Dose
(ppm)
0
100
300
600
0
100
300
600
Duration of Study
(weeks)
37-38
37-38
37-38
37-38
37-38
37-38
37-38
37-38
Tumor Incidence0
0/14
1/8
7/7
7/7
0/15
0/8
2/3
6/8
QUALITY OF EVIDENCE
Strengths of study: three levels of exposure
Weaknesses of study: small numbers of mice/treatment; only livers were
examined h1stolog1cally; the purity of a-HCH was not
reported
Overall adequacy: limited
aSource: Hanada et al., 1973
^Purity not reported
cNumber of mice started on test was 10-1 I/sex for each treated group and
20-21/sex for controls. Only mice that survived >36 weeks were examined.
0824p 9-17 06/10/86
-------
TABLE 9-11
Incidences of Liver Neoplasms In Male Wlstar Rats
Fed a-HCH (>99X pure) 1n the Diet3
Tumor Incidence15
Dose
(ppm)
0
500
500
1000
1000
1000
1500
Duration of
Treatment
(weeks)
NA
24
48
24
48
72
72
Duration
of Study
(weeks)
72
24
48
24
48
72
72
Nodular
Hyperplasla
0/8
0/6
0/5
0/8
5/12
12/16
10/13
Hepatocellular
Carcinoma
0/8
0/6
0/5 .
0/8
0/12
1/16"
3/13
Strengths of study:
Weakness of study:
Overall adequacy:
QUALITY OF EVIDENCE
three doses used; time-to-tumor Information; all major
organs examined
small numbers of rats/treatment
limited
aSource: Ito et al., 1975
bComb1ned Incidence not reported; rats that died during the experiment
were not examined.
NA = Not applicable
0824p
9-18
06/10/86
-------
TABLE 9-12
Incidences of Liver Neoplasms 1n Female Wlstar Rats
Exposed Orally to e»-HCH (99.5X) pure)3
Vehicle
NA
Diet
Vegetable oil
NA
Vegetable oil
NA
Diet
Vegetable oil
NA
Diet
Vegetable oil
Dose and Duration
0 mg/kg/day
-20 mg/kg/day for 8 months
420 mg/kg every 3rd week for
7 months
0 mg/kg/day
200 mg/kg every 2nd week for
12 months
0 mg/kg/day
-20 mg/kg/day for
13.5-17 months
420 mg/kg every 3rd week for
11 .6-16 months
0 mg/kg/day
-20 mg/kg/day for 20-26 months
420 mg/kg every 3rd week for
Age at
Deathb
(months)
9-10
9-10
9-10
12
12
14-19
14-19
14-19
23-34.5
23-34.5
23-34.5
Tumor
Incidence
0/4
0/3
0/1
0/9
3/8
0/3.
2/4
1/4
1/6
6/6c
7/8d
21.5-33 months
QUALITY OF EVIDENCE
Strengths of study: sufficient duration of exposure; time-to-tumor Infor-
mation
Weaknesses of study: small numbers of rats/group; liver was the only organ
examined
Overall adequacy:
limited
aSource: Schulte-Hermann and Parzefall, 1981
DRats were -1.25-2 months old at start of treatment
cComb1ned Incidences of neoplastlc nodules and hepatocellular carcinomas
done of these tumors was a hepatocellular carcinoma
NA = Not applicable
0824p
9-19
06/27/86
-------
data (Nagasaki et al., 1972a; Goto et al., 1972) and a negative study
(Fltzhugh et al., 1950) are summarized In Table 5-1.
The study that provides the best estimate of carcinogenic potency Is
that of Ito et al. (1973a); an adjusted potency factor of 69.5 (mg/kg/
day)'1 Is based on an Increased Incidence of liver neoplasms In male dd
mice fed 100, 250 and 500 ppm o-HCH for 24 weeks (Table 9-13). The
potency factor was adjusted for body weight and less-than-llfctime exposure
1/3
[unadjusted 1/ED1Q x (70/0.03) ) x (104/24)*]. The currently recom-
mended 1/ED-iQ °f 69.5 (mg/kg/day)'1 Is thus different from the value of
211 reported by U.S. EPA (1984b); the U.S. EPA (1984b) value apparently was
based on the data of Ito et al. (1976). A potency factor of 69.5 (mg/kg/
day)'1 (Potency Group 3) and an EPA Group rating of 82 place <*-HCH 1n
the MEDIUM category of the CERCLA hazard ranking scheme.
9.2.2. B-HCH. Dietary B-HCH has been shown to cause an Increased
Incidence of liver tumors 1n GF1 mice (Thorpe and Walker, 1973) but not 1n
dd mice (Ho et al., 1973a,b; Hanada et al., 1973; Nagasaki et al., 1972b)
or Wlstar rats (Ito et al., 1975; FHzhugh et al., 1950). As previously
discussed (see Section 5.1.1.), an additional report (Goto et al., 1972)
Indicates that mice fed 600 ppm of B-HCH had no grossly observable liver
nodules but had hlstologlcal evidence of benign hepatomas (Incidence not
specified).
According to IARC criteria, and the EPA cancer guidelines (U.S. EPA,
1986b), there 1s limited evidence that B-HCH Is carcinogenic to mice. Since
there were no human data available, B-HCH 1s placed 1n EPA Group C, meaning
B-HCH Is considered a possible human carcinogen. Incidence data for the
only study that provided positive results and actual Incidences (Thorpe and
Walker, 1973) are summarized 1n Table 9-14. Negative studies are summarized
In Table 5-2.
0824p 9-20 03/18/88
-------
TABLE 9-13
Derivation of Potency Factor (F) for a-HCH
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposure (ppm):
Transformed doses (mg/kg/day)a:
Tumor Incidence^:
Unadjusted 1/ED10:
1/ED10 (F Factor):
Ito et al., 1973a
oral
mouse
dd
male
diet
0.03 kg (assumed)
24 weeks
24 weeks
104 weeks
liver
nodular hyperplasla and hepatocellular
carcinoma
0
0
0/20
100
13.0
0/20
250
37.5
10/38
500
65
20/20
0.0644114
69.5 (mg/kg/day)'1
aAssumes a food factor of 0.13
bGLOBAL 82 and GLOBAL 79 will not converge when there are only two levels
of treatment and 100% response 1n one of the groups. It was therefore
necessary to reduce the Incidence to a value <100% and to adjust the dose
proportionally.
0824p
9-21
06/10/86
-------
TABLE 9-14
Incidence of Liver Neoplasms In CF1 Mice Fed B-HCH (>99X pure)
1n the Diet for up to 110 Weeks3
Sex
M
F
F
Duration of Exposure
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)
Adjusted total Incidence6
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)
Adjusted total Incidence6
Dose
(ppm)
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
Tumor Incidence15
(p value, 2x2 Exact Test)
0/4
6/13 (<0.05)
2/18
10/17 (<0.05)
2/25
18/26 (<0.01)
9/20
4/4 (>0.05)
11/45
22/29 (<0.01)
11/45
22/24 (<0.01)
0/4
2/16 (<0.01)
0/11
5/20 (<0.01)
5/30
9/25 (>0.05)
5/14
4/5 (>0.05)
10/44
13/30 (>0.05)
10/44
13/19 (<0.01)
0824p
9-22
06/10/86
-------
TABLE 9-14 (cont.)
QUALITY OF EVIDENCE
Strengths of study: study was conducted over the Hfespan of the animal;
comprehensive hlstologlcal examination was performed;
time-to-tumor Information
Overall adequacy: adequate
aSource: Thorpe and Walker, 1973
bComb1ned Incidence of hyperplastk nodules and hepatocelltrlar carcinoma
cThese are cumulative Incidences for mice that died and were subsequently
examined.
dThe Incidences are for mice killed at the end of the experiment.
elnc1dence subsequent to the finding of the first tumor In any tissue 1n
each group of mice (I.e., excluding mice examined before the first tumor)
0824p 9-23 06/27/86
-------
An adjusted potency factor of 10.7 can be derived on the basis of an
Increased combined Incidence of hepatic hyperplastlc nodules and hepato-
cellular carcinomas 1n male CF1 mice fed 200 ppm B-HCH 1n the diet for 110
weeks (Thorpe and Walker, 1973). This value was obtained by multiplying the
unadjusted potency factor by the cube root of the ratio of human body weight
(70 kg) to mouse body weight (0.03 kg). Adjustment for Iess-than-l1fet1me
exposure was not necessary since the mice were treated for 110 weeks (Table
9-15). The potency factor of 1.7 reported 1n U.S. EPA (1984b) was derived
from the Thorpe and Walker (1973) study, but was based on malignant liver
tumors only. The value of 10.7 1s based on the combined Incidence of benign
and malignant hepatic tumors and 1s therefore the recommended value.
A chemical with a potency factor of 10.7 and a EPA Group C Classifi-
cation has a LOW hazard ranking under CERCLA.
9.2.3. Y-HCH (Llndane). Dietary y-HCH was shown to cause a definite
Increase In the Incidence of liver tumors 1n male CF1 mice fed 400 ppm for
110 weeks (Thorpe and Walker, 1973). Borderline responses were also
observed 1n two other studies 1n male dd mice fed 600 ppm for 32 weeks and
examined 5-6 weeks after treatment (Hanada et al., 1973), and In male
ICR-JCL mice fed 600 ppm for 26 weeks (Goto et al., 1972). No liver tumors
were observed 1n dd mice fed up to 500 ppm for 24 weeks (Ito et al.,
1973a,b; Nagasaki et al., 1972a) or 1n Wlstar rats fed 500 ppm for up to 48
weeks (Ito et al., 1975). Significant compound-related development of
tumors of any type was not observed 1n NHRI mice (Herbst et al., 1975;
Welsse and Herbst, 1977), B6C3F1 mice (NCI. 1977), Osborne-Mendel rats (NCI.
1977) or Wlstar rats (FUzhugh et al., 1950). The study conducted by NCI
(1977) has been criticized for poor survival (rats), changes 1n dosing
regime and the possibility that male rats did not receive MTDs (IARC.
1979). The negative findings of FUzhugh et al. (1950) are also
0824p 9-24 04/22/88
-------
TABLE 9-15
Derivation of Potency Factor (F) for B-HCH
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposure (ppm)
Transformed doses (mg/kg/day)*:
Tumor Incidence:
Unadjusted 1/ED10:
1/EDio (F Factor):
Thorpe and Walker, 1973
oral
mouse
CF1
male
diet
0.03 kg
110 weeks
110 weeks
110 weeks
liver
hyperplastlc nodules and hepato-
cellular carcinoma
0
0
11/45
200
26
22/24
0.804783634
10.7
*Assumes a food factor of 0.13
0824p
9-25
06/10/86
-------
Inconclusive since only small numbers of animals were examined
historically. The negative findings of Ito et al. (1973a,b), Nagasaki et
al. (1972a) and Ito et al. (1975) might be attributed to small numbers of
animals and short duration of study.
Incidence data for the positive studies that reported Incidences of
h1stblog1cally verified tumors are summarized In Tables 9-16 and 9-17. A
positive study lacking this type of Incidence data (Goto et al., 1972) and
negative studies are summarized 1n Table 5-3. According to IARC criteria,
and EPA guidelines (U.S. EPA, 1986b), there 1s sufficient evidence 1n one
study and 1n two borderline studies that give rise to some uncertainty about
the strength of carcinogenic evidence 1n animals. Notably a metabolite of
Undane, 2,4.6-tr1chlorophenol has a Group B2 weight of evidence and this
metabolite has been Identified In both exposed rodents and humans. Since
there are no human data available, f-HCH 1s placed EPA Group B2-C (I.e.,
between Groups B2 and C) (U.S. EPA, 1985a, 1986a). This range reflects some
uncertainty 1n the strength of the animal cardnogenldty data.
The study that provides the best estimate of carcinogenic potency Is
that of Thorpe and Ualker (1973). An adjusted potency factor of 7.4 can be
estimated from this study and 1s based on the Increased combined Incidence
of hyperplastlc nodules and hepatocellular carcinomas 1n male CF1 mice fed
400 ppm T-HCH for 110 weeks (Table 9-18). The adjusted value was obtained
by multiplying the animal value (unadjusted value) by the cube root of the
ratio of human body weight (70 kg) to mouse body weight (0.03 kg). Adjust-
ment for Iess-than-l1fet1me exposure was not necessary since mice were
exposed for 110 weeks. This potency factor of 7.4 differs from the value of
1.7 reported by U.S. EPA (1984b); the U.S. EPA (19845) value was also based
on the data of Thorpe and Ualker (1983) but was estimated on the basis of
0824p 9-26 04/22/88
-------
TABLE 9-16
Incidence of Hepatomas 1n dd Mice Fed y-HCH 1n the Diet for
32 Weeks and Examined After 37-38 Weeks3
Sex
M
F
Dose
(ppm)
0
100
300
600
0
100
300
600
QUALITY OF
Tumor
0/14
0/10
0/9
3/4
0/15
0/8
0/7
1/3
Incidence**
EVIDENCE
Strengths of study:
Weaknesses of study:
Overall adequacy:
three doses tested; organs other than liver examined
short duration; small numbers of mice/treatment;
purity of compound was not specified; survival In 600
ppm group was poor
limited
aSource: Hanada et a!., 1973
bNumber of mice started on test was 10-11/sex for each treated group and
20-21/sex for controls. Only mice that survived >36 weeks were examined.
0824p
9-27
06/10/86
-------
TABLE 9-17
Incidence oT Liver Neoplasms 1n CF1 Mice Fed y-HCH (>99.5% pure)
In the Diet for up to 110 Weeks3
Sex
M
F
F
Duration of Exposure
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)
Adjusted total Incidence6
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)6
Adjusted total Incidence6
Dose
(ppm)
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
Tumor Incidence**
(p value, 2x2 Exact Test)
0/6
6/86 (<0.01)
2/11
14/15 (<0.01)
2/25
23/24 (<0.01)
9/20
4/5
11/45
27/29 (<0.01)
11/45
27/28 (<0.01)
0/4
9/18 (<0.01)
0/11
14/23 (<0.01)
5/30
19/28 (<0.01)
5/14
1/1 (<0.05)
10/44
20/29 (<0.05)
10/44
20/21 (<0.05)
0824p
9-28
06/10/86
-------
TABLE 9-17 (cont.)
QUALITY OF EVIDENCE
Strengths of study: study was conducted over the Hfespan of the animal;
comprehensive hlstologlcal examination was performed;
t1me-to-tumor Information given
Overall adequacy: adequate
aSource: Thorpe and Walker, 1973
^Combined Incidence of hyperplastlc nodules and hepatocellular carcinomas
cThese are cumulative Incidences for mice that died and were subsequently
examined.
dThe Incidences are for mice killed at the end of the experiment.
elnc1dence subsequent to the finding of the first tumor In any tissue In
each group of mice.
0824p 9-29 06/10/86
-------
TABLE 9-18
Derivation of the Potency Factor (F) for y-
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental doses/exposure (ppm)
Transformed doses (mg/kg/day)*:
Tumor Incidence:
Unadjusted l/ED-jo:
1/E010 (F Factor):
Thorpe and Walker, 1973
oral
mouse
CF1
male
diet
0.03 kg
110 weeks
110 weeks
110 weeks
liver
hyperplastlc nodules and hepato-
cellular carcinoma
0
0
11/45
0.557044101
7.4
400
52
27/28
*Assumes a food factor of 0.13
0824p
9-30
10/24/86
-------
malignant liver tumors only. The potency factor of 7.4 Is based on the
combined Inddence'of benign and malignant liver tumors and Is therefore the
recommended value.
A potency factor of 7.4 and a CAG Group rating of B2-C place y-HCH In
the MEDIUM-LOW categories of the CERCLA hazard ranking scheme.
9.2.4. 4-HCH. Dietary s-HCH did not cause neoplastlc or nonneo-
plastlc changes In the livers of male dd mice (Ito et a!., 1973a; Nagasaki
et al., 1972a) or male Wlstar rats (Ito et al., 1975). These studies used
small numbers of animals and were conducted for only 24 weeks. Goto et al.
(1972) reported that a mixture of 6- and c-HCH caused an Increased
Incidence of benign and malignant hepatomas 1n male ICR-JCL mice after 26
weeks of dietary administration, but the Individual Isomers were not tes.ted.
There were no human data available.
According to the EPA cancer guidelines (U.S. EPA, 1980), there 1s
limited evidence that 4-HCH Is carcinogenic In animals. Therefore,
6-HCH 1s placed 1n EPA Group C, but It Is not possible to derive a potency
factor. Accordingly, a default potency category of 2 Is assigned. A
potency Group of 2 and a Group C we1ght-of-evidence result In a LOW hazard
ranking under CERCLA.
9.2.5. c-HCH. Data pertaining to the carcinogenic effects of e-HCH
could not be located In the available literature as cited 1n the Appendix.
Goto et al. (1972) reported that a mixture of 4-HCH and c-HCH caused an
Increased Incidence of benign and malignant hepatomas In male ICR-JCL mice
after 26 weeks of dietary administration, but the Individual Isomers were
not tested.
0824p 9-31 03/18/88
-------
According to the EPA cancer guidelines (U.S. EPA, 1980), there 1s
limited evidence - that e-HCH Is carcinogenic In animals. Therefore,
e-HCH falls Into EPA Group C, and H Is not possible to derive a potency
factor. Accordingly, a default potency category of 2 Is assigned. A
potency Group of 2 and a Group C we1ght-of-evidence result In a LOW hazard
ranking under CERCLA.
9.2.6. T-HCH. T-HCH has been shown to cause Increased Incidences of
liver neoplasms 1n four strains of mice (Hanada et al., 1973; Goto et al.,
1972; Kashyap et al., 1979; N1gam et al., 1984a; Bhatt et al., 1981; Munlr
et al., 1983; Nagasaki et al., 1971, 1972b; Munlr and Bhlde, 1984) but not
In Wlstar rats (Munlr et al., 1983) or Syrian golden hamsters {Munlr et al.,
1983).
According to the EPA cancer guidelines (U.S. EPA, 1986b), there Is
sufficient evidence to conclude that T-HCH Is carcinogenic to animals.
Since there are no human data available, T-HCH Is placed 1n EPA Group 82.
This Is Interpreted to Indicate that T-HCH 1s probably carcinogenic to
humans. Incidence data from the positive studies that reported Incidences
of h1stolog1cally verified tumors are summarized In Tables 9-19 through
9-23. Positive studies lacking this type of data and negative studies are
summarized 1n Table 5-5.
The study that provides the best estimate of carcinogenic potency Is
that of Munlr et al. (1983). An adjusted potency factor of 8.08 Is based on
an Increased Incidence of benign and malignant liver tumors In male Swiss
mice fed 0, 125 or 250 ppm T-HCH from 8-10 weeks of age to 15-17 months of
age (Table 9-24). The potency factor was adjusted for body weight and less-
1/3
than-Hfetlme exposure [unadjusted 1/ED1Q x (70/0.03)"° x (24/15)3]
(Table 9-25).
0824p 9-32 03/18/88
-------
TABLE 9-19
Incidence of Hepatomas In dd Mice Fed T-HCH In the Diet for
32 Weeks and Examined 5-6 Weeks Posttreatment3
Sex
M
F
Dose
(ppm)
0
100
300
600
0
100
300
600
QUALITY OF
Tumor
0/14
0/10
4/4
4/4
0/15
0/8
3/5
5/5
Inc1denceb
EVIDENCE
Strengths of study: three doses tested
Weaknesses of study: small numbers of mice/treatment; short duration of
exposure; 1somer1c composition not specified
Overall adequacy: limited
aSource: Hanada et al., 1973
^Number of mice started on test was 10-1 I/sex for each treated group and
20-21/sex for controls. Only mice that survived >36 weeks were examined.
0824p 9-33 06/27/86
-------
TABLE 9-20
Incidence of Liver Neoplasms In Male dd Mice Fed T-HCH
In the Diet for 24 Heeksa'b
Dose
(ppm)
0
6.6
66
660
Tumor Inc1dencec
0/14
0/20
0/20
20/20
QUALITY OF EVIDENCE
Strengths of study: composition of compound reported; three doses tested;
hlstopathologlcal examinations were performed on major
organs
Weaknesses of study: short duration of exposure
Overall adequacy: adequate
aSource: Nagasaki et al.. 1971, 1972b; Nagasaki, 1973
b66.5X a-HCH, 11.4X B-HCH, 15.2% y-HCH, 6.4X 4-HCH and 0.5X "other"
GComb1ned Incidence of hyperplastlc nodules and hepatomas
0824p 9-34 06/10/86
-------
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0824p
9-35
06/10/86
-------
TABLE 9-22
Incidence of Liver Neoplasms In Male Swiss Mice Fed T-HCH In the Diet*
Dose/Exposure
0 ppm/NA
500 ppm/2 months
500 ppm/2 months
500 ppm/2 months
500 ppm/4 months
500 ppm/4 months
500 ppm/4 months
500 ppm/6 months
500 ppm/6 months
500 ppm/6 months
500 ppm/8 months
500 ppm/8 months
500 ppm/8 months
Duration
of Study
(months)
18
2
6
12
4
8
14
6
10
16
8
12
18
Neoplastlc
Nodules
0/75
0/6
0/6
0/15
0/6
0/6
6/15
4/6
5/6
7/15
2/6
2/6
3/15
Tumor Incidence
Trabecular Cell
Carcinoma
0/75
0/6
0/6
0/15
0/6
0/6
0/15
0/6
• 0/6
8/15
4/6
4/6
12/15
Pulmonary
Metastasis
0/75
0/6
0/6
0/15
0/6
0/6
0/15
0/6
0/6
2/15
0/6
1/6
14/15
QUALITY OF EVIDENCE
Strengths of study: conducted for most of the animals' llfespan; time-to-
tumor Information
Weakness of study: Isomerlc composition not reported
Overall adequacy: adequate
*Source: N1gam et al., 1984a
0824p
9-36
06/10/86
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TABLE 9-23
Incidence of Liver Neoplasms In Male Swiss Mice Fed T-HCH In the
Diet from 8-10 Weeks of Age up to 22 Months of Agea
Age at Examination
(months)
8-11
12-14
15-17
18-22
Dose
(ppm)
125
250
500
0
125
250
500
0
125
250
500
0
125
250
500
0
Tumor Incidence15
0/10
4/17
28/37
0/22
0/10
9/12
10/10
0/16
8/20
12/12
not examined
2/22c
9/15
not examined
not examined
2/22c
Strengths of study:
Weaknesses of study:
Overall adequacy:
QUALITY OF EVIDENCE
sufficient duration of exposure; several doses tested;
time-to-tumor Information
composition of compound not reported; no matched
controls0
Adequate
aSource: Hunlr et al., 1983
^Combined Incidence of benign hepatic nodules and hepatocellular carcinomas.
Control Incidences are taken from a similar experiment 1n male Swiss mice
conducted 1n the same laboratory and reported In the same paper.
Clnc1dence In controls killed at 15-20 months of age (see footnote b)
0824p
9-37
06/10/86
-------
TABLE 9-24
Incidence of Liver Tumors In Mice Fed T-HCH 1n the Diet
from 8-10 Weeks of Exposure up to 20 Months of Exposure3
Strain Sex
Swiss M
M
M
F
F
F
BALB/c M
N
F
F
Dose and Duration
of Exposure
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
500 ppm 2 months
500 ppm 2 months
500 ppm 2 months
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
500 ppm 3 months
500 ppm 3 months
500 ppm 3 months
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
Age at
Examination
(months)
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
Tumor
Incidence**
0/22
0/16
2/22
28/37
10/10
12/12
0/15
0/10
0/10
0/20
0/16
1/20
3/16
6/16
14/14
0/10
0/8
11/12
0/8
0/8
1/15
9/10
10/10
NR
0/8
0/9
2/20
7/10
10/10
NR
0824p
9-38
06/10/86
-------
TABLE 9-24 (cent.)
QUALITY OF EVIDENCE
sufficient duration of exposure; time-to-tumor Informa-
tion; two strains and both sexes examined
composition of compound not reported
adequate
Strengths of study:
Weakness of study:
Overall adequacy:
aSource: Munlr et al., 1983
^Combined Incidence of benign hepatic nodules and hepatocellular carcinomas
NR a Not reported
0824p
9-39
06/10/86
-------
TABLE 9-25
Derivation of Potency Factor (F) for T-HCH
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposure (ppm)
Transformed doses (mg/kg/day)*:
Tumor Incidence:
Unadjusted 1/ED^p:
1/ED10 (F Factor):
Munlr et al., 1983
oral
mouse
Swiss
male
diet
0.03 kg
from 8-10 weeks of age until 15-17
months of age (-15 months)
same as above
24 months
liver
benign hepatic nodules and hepato-
cellular carcinomas
0
0
2/22
125
16.25
8/20
250
32.5
12/12
0.148735599
8.1
*Assumes a food factor of 0.13
0824p
9-40
06/10/86
-------
A potency factor of 8.1 and a CAG Group rating of B2 place T-HCH' \n the
MEDIUM category of the CERCLA ranking scheme. A summary of all HCH cancer
data Is presented In Section 9.3.
9.3. SUMMARY OF ALL HCH CANCER DATA
The summary of the animal cardnogenldty data for a-, B-, Y-»
6- and e-HCH Is presented 1n Table 9-26. Such summary considerations
Indicate that at dietary doses In excess of 100-200 ppm, cancer of the liver
often results mainly In the mouse and sometimes 1n the rat. Tumor occur-
rence can take place as early as 24-36 weeks following commencement of the
HCH dosing regimen. The resulting estimates of cancer potency from a number
of studies place the q * parameter In the 1.3-6.3 (mg/kg/day)'1 range
(corrected for body weight differences and Iess-than-l1fet1me dosing
schedules). The technical mixture, which Is a mixture of the Isomers, most
closely relates to a-HCH In category 82 and q * comparisons. a-HCH Is
the largest component at 65%; therefore, 1t suggests a general additive
contribution of the components with the largest (a) Imposing the cancer
characteristics of T-HCH mixture.
0824p 9-41 10/27/86
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10. REFERENCES
Abel, P.O. 1980. Toxldty of Y-hexachlorocyclohexane (llndane) to
Gammarus pulex: Mortality 1n relation to concentration and duration of
exposure. Freshwater B1ol. 10(3): 251-259.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985-1986. Threshold limit values for chemical substances In the work
environment adopted by ACGIH with Intended changes for 1985-1986. Cincin-
nati, OH. p. 1-114.
Ahdaya, S.M., R.J. Monroe and F.E. Guthrle. 1981. Absorption and distribu-
tion of Intubated Insecticides 1n fasted mice. Pestle. Blochem. Physlol.
16(1): 38-46.
Ahmed, F.E., R.W. Hart and N.3. Lewis. 1977. Pesticide Induced DNA damage
and Its repair 1n cultured human cells. Mutat. Res. 42: 161-174.
Allsup, T. and D. Walsh. 1982. Gas chromatographlc analysis of chloro-
phenylmercaptuHc add Undane metabolites. J. Chromatogr. 236(2):
421-428. (CHed In U.S. EPA. 1985a)
Altmann, H.J., C. Boehme and H. Uehleke. 1983. Studies on the kinetics of
B-HCH 1n rats and mlnlplgs. In; Hexachlorcyclohexan Schadst. Lebensm.,
Mater. Zwe1 Kollog., Meeting date 1979-1980. p. 101-106. (Ger.) [CA
99(23):189331s]
0825p 10-1 06/10/86
-------
Anderson, 0. and J.A. Styles. 1978. An evaluation of 6 short-term tests
for detecting organic chemical carcinogens. Appendix 2. The bacterial
mutation test. Br. J. Cancer. 37: 924-930.
Angerer, J., R. Helnrlch and H. Laudehr. 1981. Occupational exposure to
hexachlorocyclohexane. Int. Arch. Occup. Environ. Health. 48(4): 319-324.
Angerer, J., R. Haass and R. Helnrlch. 1983. Occupational exposure to
hexachlorocyclohexane. VI. Metabolism of y-hexachlorocyclohexane In man.
Int. Arch. Occup. Environ. Health. 51(1): 59-67.
Angerer, J., R. Helnrlch and H. Laudehr. 1985. Occupational exposure to
hexachlorocyclohexane. Int. Arch. Occup. Environ. Health. 48(4): 319-324.
(Cited In U.S. EPA, 1985a)
Arthur, R.D., J.D. Cain and B.F. Barrentlne. 1976. Atmospheric levels of
pesticides In the Mississippi delta. Bull. Environ. Contain. Toxlcol. 15:
129-134.
Babu, K.A., S.K. Nlgara, B.C. Lakkad, et al. 1981. Effect of hexachloro-
cyclohexane on somatic and melotlc divisions In male Swiss mice. Bull.
Environ. Contam. Toxlcol. 26(4): 508-512.
Baker, M.T., R.M. Nelson and R.A. Van Dyke. 1985. The formation of chloro-
benzene and benzene by the reductive metabolism of llndane In rat liver
mlcrosomes. Arch. Blochem. Blophys. 236(2): 506-514. [CA 102(13):107833a]
0825p 10-2 06/10/86
-------
Bakthavathsalam, R. and Y.S. Reddy. 1981. Survival growth of the fish
Anabas testudlneus (Bloch) exposed to Undane. Indian J. Environ. Health.
23(4): 270-274.
Baquar, S.R. and N.R. Kahn. 1971. Effect of y-HCH on the mltotlc cells
of P1sum satlvum L. Rev. B1ol. (Lisbon). 7: 195-202.
Barros, S.B. and A.M. Sallba. 1978. Tox1c1ty of the hexachlorocyclohexane
In rats. Toxicology. 10(3): 271-279.
Barros, S.B.H., K. S1m1zu and V.B.C. Junquelra. 1982. Renal and hepatic
add and alkaline phosphatases activity during experimental technical
hexachlorocyclohexane poisoning. An. Farm. Qu1m. Sao Paulo. 22: 11-17.
(Por.) (Taken from IAP/84/07444)
Basha, S.M., K.S.P. Rao, K.R.S.S. Rao and K.V.R. Rao. 1983. Differential
toxldty of malathlon, BHC and carbaryl to the freshwater fish, Tllapla
mossamblca (Peters). Bull. Environ. Contam. Toxlcol. 31(5): 543-546.
Basha. S.M., K.S.P. Rao, K.R.S.S. Rao and K.V.R. Rao. 1984. Respiratory
potentials of the fish (Tllapla mossamblca) under malathlon, carbaryl and
Undane Intoxication. Bull. Environ. Contam. Toxlcol. 32(5): 570-574.
Baumann, K., J. Angerer, R. Helnrlch and G. Lehnert. 1980. Occupational
exposure to hexachlorocyclohexane. I. Body burden of HCH-lsomers. Int.
Arch. Occup. Environ. Health. 47: 119-127. (CHed 1n U.S. EPA, 1985a)
0825p 10-3 06/10/86
-------
Benes, V. and R. Sram. 1969. Mutagenlc activity of some pesticides 1n
DrosophUa melanoqaster. Ind. Med. 38: 50-52.
Bevenue, A., J.W. Hylln, Y. Kawano and T.W. Kelley. 1972. Organochlorlne
pesticide residues 1n water, sediment, algae and fish, Hawaii--1970-1971.
Pest. MonH. J. 6: 56-64.
Bhatt, O.K., S.K. N1gam, B.C. Lakkad, et al. 1981. Sequential hlstocheml-
cal changes 1n the distribution of alkaline phosphatase 1n BHC-lnduced liver
tumors In pure Inbred Swiss mice. Cell Mol. Blol. 27(2-3): 231-238.
Bluzat, R. and J. Seuge. 1979. Effects of three Insecticides (llndane,
fenthlon, and carbaryl) on the acute toxldty to four aquatic Invertebrate
species and the chronic toxldty to the pulmonate mollusc Lymnea. Environ.
Pollut. 18(1): 51-70.
Borghl, H., S. Pu1seux-0ao, S. Bonotto and D. Hourslangou-Neubrun. 1973.
Effects of llndane on AcetabulaMa medlterranea. Protoplasma. 78(1-2):
99-112.
Boulekbache, H. and C. Spless. 1974. Effect of llndane on trout fry (Salmo
1r1deus G1bb). Changes 1n glycolytlc enzymes. Bull. Soc. Zool. Fr. 99(1):
79-85. (Taken from PESTAB/76/1492)
Brooksbank, P. 1983. The Canadian Network for Sampling Organic Compounds
In Precipitation. Environment Canada, Inland Waters Directorate, Water
Quality Branch Tech. Bull. No. 129.
0825p 10-4 06/10/86
-------
Buselmaler, W., G. Rohrborn and P. Propping. 1972. MutagenlcHy Investi-
gating with pesticides In the host-mediated assay and the dominant-lethal
test 1n mice. B1ol. Zbl. 91: 311-325. (Cited In IARC, 1979)
Butler, P.A. 1963. Commercial fisheries Investigations, pesticide-wildlife
studies: A review of F1sh and Wildlife Service Investigations during
1961-1962. USDI Fish W1ldl. C1rc. 167: 11. (CHed 1n U.S. EPA, 1980b)
Butler, P.A. 1967. Pesticide residues 1n estuaMne mollusks. In.: Proc. of
the Natl. Symp. EstuaMne Pollution., Stanford Univ., Oept. of C1v1l
Engineering, Stanford, CA. (CUed In U.S. EPA, 1971)
Calabrese, A. 1971. Effects of some pollutants on embryos and larvae of
the American oyster and hard shell clam. Am. Chem. Soc. 01v. Water, Air
Haste Chem., Gen. Pap. 11(2): 64-75. [CA 79(7):39068j]
Canton, J.H. and H. Slooff. 1977. The usefulness of Lymnaea stagnalls L.
as a biological Indicator 1n lexicological bio-assays (model substance
a-HCH). Hater Res. 11(1): 117-121.
Canton, J.H., P.A. Greve, H. Slooff and G.J. Van Esch. 1975. Tox1c1ty,
accumulation, and elimination studies of o-hexachlorocyclohexane (a-HCH
with freshwater organisms of different trophic levels. Hater Res. 9(12):
1163-1169.
0825p 10-5 06/27/86
-------
Canton, J.H., G.J. Van Esch, P.A. Greve and A.B.A.M. Van Hellemond. 1977.
Accumulation and " elImlnatlon of y-hexachlorocyclohexane (y-HCH) by the
marine algae Chlamvdomonas and Dunallella. Water Res. 11(1): 111-115.
Canton, J.H., R.C.C. Wegman, T.J.A. Vulto, C.H. Verhoef and G.J. Van Esch.
1978. Toxlclty, accumulation and elimination studies of a-hexachloro-
cyclohexane with saltwater organisms of different trophic levels. Water
Res. 12(9): 687-690.
Castro, T.F. and T. Yoshlda. 1974. Effect of organic matter on the
blodegradatlon of some organochlorlne Insecticides In submerged soils. Soil
Sd. Plant Nutr. 20: 363-370.
Cesch1n1, P. and R. Chauchalx. 1980. Transfer of organochlorlne pesticide
residues Into cigarette smoke as a function of tobacco blends and filter
types. Beltr. Tabakforsch. 19(2): 134-138. (Taken from PESTAB/81/0381)
Chadwlck, R.W. and J.J. Freal. 1972. Identification of five unreported
llndane metabolites recovered from rat urine. Bull. Environ. Contain.
Toxlcol. 7(2-3): 137-146.
Chadwlck, R.W., L.T. Chuang and K. Williams. 1975. Dehydrogenatlon, a
previously unreported pathway of Undane metabolism In mammals. Pestle.
Blochem. Physio!. 5(6): 575-586.
Chadwlck, R.W., M.F. Copeland and C.J. Chadwlck. 1978a. Enhanced pesticide
metabolism, a previously unreported effect of dietary fibre 1n mammals.
Food Cosmet. Toxlcol. 16(3): 217-225.
0825p 10-6 06/10/86
-------
Chadwlck, R.W., C.C. Bryden, M.F. Copeland, J.J. Freal and S.W. Sovocool.
1978b. The Identification of three previously unreported Undane metabo-
lites from mammals. Chemosphere. 7(8): 633-640.
Chadwlck, R.W., E.J. Faeder. L.C. King, M.F. Copeland, K. Williams and L.T.
Chuang. 1978c. Effect of acute and chronic Cd exposure on Undane metabo-
lism. Ecotoxlcol. Environ. Saf. 2: 301-316. (Cited In U.S. EPA, 1985a)
Chand, B. and M. Ramachandran. 1980. Effect of dietary hexachlorocyclo-
hexane on certain biochemical changes 1n rats. Ind. J. Exp. B1ol. 18:
735-736. (Cited 1n U.S. EPA, 1985a)
Chernoff, N. and R.J. Kavlock. 1983. A teratology test system which
utilizes postnatal growth and viability In the mouse. Environ. Sd. Res.
27: 417-427.
Chin, E. and O.M. Allen. 1957. Toxlclty of an Insecticide to two species
of shrimp, Penaeus aztecus and Penaeus setlferls. Texas J. Scl. 9: 270.
(Cited In U.S. EPA, 19805)
Chin, Y.N. and K.I. Sudderuddln. 1979. Effect of methamldophos on the
growth rate and esterase activity of the common carp CypMnus carplo L.
Environ. Pollut. 18(3): 213-220.
Chlou, C.T., V.H. Freed. L.J. Peters and R.L. Khonert. 1980. Evaporation
of solutes from water. Environ. Int. 3(3): 231-236.
0825p 10-7 06/10/86
-------
Chovelon, A., L. Geoger, C. Gulayets, et al. 1984. Pesticide and PCB
levels In fish from Alberta (Canada). Chemosphere. 13(1): 19-32.
Cole, R.H., R.E. Frederick, R.P. Healy and R.G. Rolan. 1984. Preliminary
findings of the priority pollutant monitoring project of the Nationwide
Urban Runoff Program. J. Water Pollut. Control Fed. 56: 898-908.
Colson, J.G. 1979. Benzene hexachloMde. In: K1rk-0thmer Encyclopedia of
Chemical Technology, Vol. 5, 3rd ed., H. Grayson and D. Eckroth, Ed. John
Wiley and Sons, Inc., New York. p. 808-818.
Cope, O.B. 1965. Sport fishery Investigation. Ijn: Effects of Pest1c1d« 1n
Ftsh and Wildlife, 1964 Research Findings of the Fish and Wildlife Service.
U.S. Fish W1ldl. Serv., Clrc. 226. p. 51-63. (Cited 1n U.S. EPA, 1971)
Cope, O.B. 1966. Contamination of the freshwater ecosystem by pesticide.
J. Appl. Ecol. 3: 33-44. (Cited 1n Plmentel, 1971; U.S. EPA, 1971)
Culley, O.O., Jr. and O.E. Ferguson. 1969. Patterns of Insecticide resis-
tance In the mosquHoflsh, Gambusla afflnls. J. F1sh. Res. Board Can. 26:
2395-2401.
Czegledl-Janko. G. and P. Avar. 1970. Occupational exposure to Undane:
Clinical and laboratory findings. Br. J. Ind. Med. 27(3): 283-286.
Das, B. and P.K. Singh. 1977. Detox1cat1on of the pesticide benzene-
hexachlorlde by blue-green algae. H1crob1ol. Lett. 4(14): 99-102.
0825p 10-8 06/10/86
-------
Davis, H.C. and H. H1du. 1969. Effects of pesticides on embryonic develop-
ment of clams and oysters and on survival and growth of the larvae. F1sh.
Bull. 67(2): 383-404. (Cited In U.S. EPA, 1972)
OeBrabander, M., R. Van deVelre, F. Aerts, S. Geuens and J. Hoebeke. 1976.
A new culture model facilitating rapid quantitative testing of mltotlc
spindle Inhibition In mammalian cells. J. Natl. Cancer Inst. 56: 357-363.
(Cited 1n U.S. EPA, 1985a)
Deo, P.G., S.B. Hasan and S.K. Majumder. 1980. IsomeMzatlon of beta-HCH
In aqueous solution. J. Environ. Sd. Health B. 15(2): 147-164.
Des1, I. 1974. Neurotox1colog1cal effect of small quantities of llndane.
Int. Arch. ArbeHsmed. 33: 153-162. (CUed 1n U.S. EPA, 1985a)
Des1, I., L. Varga and I. Farkas. 1978. Studies on the Immunosuppresslve
effect of organochlorlne and organophosphorlc pesticides In subacute experi-
ments. J. Hyg. Epldemlol. Mlcroblol. Immunol. (Praha). 22(1): 115-122.
(CUed In U.S. EPA, 1985a)
Dewan, A., S.K. Gupta, J.P. Jan1 and S.K. Kashyap. 1980. Effects of
llndane on antibody response to typhoid vaccine In weanling rats. J.
Environ. Sc1. Health. [B]. 15(4): 395-402. (CHed 1n U.S. EPA, 1985a)
DlkshHh, T.S.S. and K.K. Oatta. 1977. Comparative response of male rat to
parathlon and llndane Individually and In a mixture, in: Proc. Int. Symp.
Ind. Toxlcol. Environ. Pollut. Human Health, p. 631-737.
0825p 10-9 06/10/86
-------
DlkshHh, T.S.S., S.K. Tandon, K.K. Oatta, P.K. Gupta and J.R. BehaM.
1978. Comparative response of male rats to parathlon and llndane: H1sto-
pathologlcal and biochemical studies. Environ. Res. 17(1): 1-9.
01 Toro, D.M. and P.R. Paquln. 1984. Time variable model of the fate of
DOE and Undane In a quarry. Environ. Toxlcol. Chem. 3(2): 335-353.
D1ve, 0., H. Leclerc and G. Personne. 1980. Pesticide toxldty on the
dilate protozoan Colpldlum campylum; Possible consequences of the effect of
pesticides In the aquatic environment. Ecotoxlcol. Environ. Saf. 4(2):
129-133.
Ooelman, P., I. Haanstra, E. De RuHer and J. Slange. 1985. Rate of
mlcroblal degradation of high concentrations of alpha-PHC In soil under
aerobic and anaerobic conditions. Chemosphere. 14(5): 565-570.
Ouggan, R.E., P.E. Cornellussen, M.B. Ouggan, B.M. McMahon and R.J. Martin.
1983. Pesticide Residue Levels In Foods In U.S. from July 1, 1969 to June
30, 1976. Food and Drug Administration and Association of Official Analyti-
cal Chemists Publication.
Dulnker, J.C. and M.T.J. HUlebrand. 1979. Behavior of PCB, pentachloro-
benzene, hexachlorobenzene, alpha-HCH, gamma-HCH, beta-HCH, dleldMn, endMn
and P.P'-DDD In the Rhlne-Meuse estuary and the adjacent coastal area.
Neth. J. Sea Res. 13: 256-281.
0825p 10-10 06/10/86
-------
Dzlerzawski, A. 1977. Embryotoxlcl ty studies of llndane \n the golden
hamster, rat and r-abblt. Bull. Vet. Inst. Pulawy. 21(3-4): 85-93. (Cited
In U.S. EPA, 1985a)
Earl, F.L., E.J. Van Loon, B.E. Melveger. et al. 1970. Llndane toxldty.
A comparative study In dogs and miniature swine with and without phenobarbl-
tal. Toxlcol. Appl. Pharmacol. 17: 287. (CHed In U.S. EPA, 1985a)
Elchler, D., W. Heupt and W. Paul. 1983. Comparative study on the distri-
bution of a-BHC and f-BHC 1n the rat with particular reference to the
problem of Isomerlzatlon. Xenob1ot1ca. 13(11): 639-648.
Elsenrelch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic
contaminants 1n the Great Lakes ecosystem. Environ. Scl. Technol. 15(1):
30-38.
Elsler, R. 1969. Acute toxldtles of Insecticides to marine decapod crus-
taceans. Crustaceana. 16(3): 302-310. (CHed 1n U.S. EPA, 1972, 1980b;
Plmentel, 1971)
Elsler, R. 1970a. Acute toxldtles of organochlorlne and organophosphorus
Insecticides to estuarlne fishes. Bureau of Sport Fish. W1ldl., Tech. Paper
46. Government Printing Office, Washington, DC. 12 p.
Elsler, R. 1970b. Factors affecting pesticide-Induced toxldty In an
estuarlne fish. Bureau of Sport F1sh. Wlldl., Tech. Paper 45. Government
Printing Office, Washington, DC. 20 p.
0825p 10-11 10/28/86
-------
El Belt, I.O.D., J.V. Wheelock and D.E. Cotton. 1981. Pestlclde-mlcroblal
Interaction 1n the soil. Int. J. Environ. Studies. 16: 189-196.
Elezovlc, I. and V. MHrovlc-Tutundzlc. 1981. Acute toxldty of DOT,
Undane, and heptachlor In water on carp (CypMnus carp_lp L.) fry.
Vodoprlvreda. 13(73): 367-370. (Ser.) [CA 96(3):15837j]
Engst, R., R.M. Macholz, M. Kujawa, H.J. Lewerenz and R. Plass. 1976. The
metabolism of Undane and Its metabolites y-2,3,4,5,6-pentachlorocyclo-
hexene, pentachlorobenzene, and pentachlorophenol In rats and the pathways
of Undane metabolism. J. Environ. Sc1. Health, Part B. Bll{2): 95-117.
Engst, R., R.M. Macholz and M. Kujawa. 1979. Recent state of Undane
metabolism. Part II. Residue Rev. 72: 71-95.
Ernst, W. 1975. Absorption, secretion and metabolism of Undane-14C by
Mytllus edulls. Chemosphere. 4(6): 375-380.
Ernst, H. 1977. Determination of the bloconcentratlon potential of marine
organisms -- A steady state approach. I. Bloconcentratlon data for seven
chlorinated pesticides 1n mussles (Mytllus edulls) and their relation to
solubility data. Chemosphere. 6(11): 731-740.
Escoubet, P. 1978. Effects of Undane on cultures of marine phytoplank-
tonlc algae and cockles. Preliminary results. Rev. Int. Oceanogr. Med.
49:21-27. (Fre.) [CA 88(25):184243c]
0825p 10-12 06/10/86
-------
Falandysz, J. 1982. Chlorinated hydrocarbons In salmon netted In Gdansk
Bay, Baltic Sea (Poland). Meeresforschung. 29(4): 219-224. (Taken from
HEEP/83/12814)
Falandysz, J. 1984. Organochlorlne pesticides and polychlorlnated
blphenyls In livers of cod (Gadus morhua) from the southern Baltic, 1981.
2. Lebensm-Unters -Forsch. 179(4): 311-314. (Taken from HEEP/85/05140)
Federal Register. 1983. Intent to cancel pesticide products containing
llndane; denial of applications for registration of pesticide products
containing Undane; determination concluding the Rebuttable Presumption
Against Registration; availability of position document. 48 FR 48512.
Fitzgerald, G.P., G.C. Gerloff and F. Skoog. 1952. Stream pollution:
Studies on chemicals with selective toxldty to blue-green algae. Sewage
Ind. Wastes. 24(7): 888-896.
FHzhugh, O.G., A.A. Nelson and J.P. Frawley. 1950. The chronic tox1dt1es
of technical benzene hexachloMde and Us alpha, beta and gamma Isomers. J.
Pharmacol. Exp. Therap. 100: 59-66.
FHzloff, J.F. and J.C. Pan. 1984. Epox1dat1on of the Undane metabolite,
B-PCCH, by human- and rat-liver mlcrosomes. Xenob1ot1ca. 14(7): 599-604.
Fltzloff, J.F., J. Portlg and K. Stein. 1982. Llndane metabolism by human
and rat liver mlcrosomes. Xenob1ot1ca. 12(3): 197-202.
0825p 10-13 06/10/86
-------
Foulquler, L., A. Reynler, A. Grauby and P. Bovard. 1971. ToxIcHy of
Undane to eels (Anqullla Angullla L.) Compt. Rend. Acad. Agr. France.
57(12): 1060-1068. (Fre.) (Taken from HAPAB/72/02196)
Frawley, J P. and O.G. FHzhugh. 1949. Rate of disappearance of Isomers of
benzene hexachloMde from fat deposits In rats. Fed. Proc. 8: 292-293.
Freal, J.J. and W.R. Chadwlck. 1973. Metabolism of hexachlorocyclohexane
to chlorophenols and effect of Isomer pretreatment on Undane metabolism In
rat. J. Agrk. Food Chem. 21(3): 424-427.
Frelmane, T. and M. Grundule. 1976. Quantitative shifts of I1p1d fractions
1n carp under the effect of Undane and DDT. Eksp. Vodn. Tokslkol. 6:
248-254. [CA 88(19):131674n]
Frlsque, G.E., M. Galous and A. Bernes. 1983. Accumulation of two trace
pollutants (polychloroblphenyls and y-HCH) 1n aquatic bryophytes of the
Meuse River. Meded. Fac. Landbouwwet., Rljksunlv. Gent. 48(4): 971-983.
[CA 100(5):30637p]
Gaeta, S.A., N. Kadekaru, N. Perelra and L.R. Tommasl. 1983. Preliminary
observations on the toxlclty of y-UCH and mercury(II) chloride to ArtemVa
sallna. Bol. Inst. Oceanogr. (Univ. Sao Paulo). 32(1): 21-31. (Por.) [CA
102(ll):91089z]
0825p 10-14 06/27/86
-------
Geyer, H., P. Sheehan, 0. Kotzlas, D. Freltag and F. Korte. 1982. Predic-
tion of ecotoxlcol-oglcal behavior of chemicals: Relationship between physl-
cochemlcal properties and bloaccumulatlon of organic chemicals In the mussel
Mytllus edulls. Chemosphere. 11(11): 1121-1134.
Glotfelty, O.E., A.M. Taylor, B.C. Turner and W.H. Zoller. 1984. Volatili-
zation of surface-applied pesticides from fallow soil. J. Agrlc. Food Chem.
32: 638-644.
Gopalaswamy, U.V. and A.S. Alyar. 1984. Blotransformatlon of llndane 1n
the rat. Bull. Environ. Contam. Toxlcol. 32(2): 148-156.
Goto, H., M. Hattorl, T. Mlyagawa and M. Enomoto. 1972. Ecological Chem-
istry. II. Hepatoma formation In mice after administration of high doses of
hexachlorocyclohexane Isomers. Chemosphere. 1(6): 279-282. (Ger.)
Gray, L.E., Jr. and R.J. Kavlock. 1984. An extended evaluation of an U^
vivo teratology screen utilizing postnatal growth and viability 1n the
mouse. Teratog. Cardnog. Mutagen. 4(5): 403-426.
Grey, U.E., O.E. Marthre and S.J. Rogers. 1983. Potential exposure of
commercial seed-treating applicators to the pesticides carboxln-thlram and
llndane. Bull. Environ. Contam. Toxlcol. 31(2): 244-250.
Grover, P.L. and P. Sims. 1965. The metabolism of 2,3,4,5.6-pentachloro-
cyclohex-1-ene and hexachlorocyclohexane 1n rats. Blochero. J. 96: 521.
(Cited In U.S. EPA. 1980a)
0825p 10-15 10/28/86
-------
Gupta, P.K., V.S. Mujumdar and P.S. Rao. 1984. Studies on the toxldty of
some Insecticides -to a freshwater teleost Leblstes retlculatus (Peters).
Acta Hydrochlm. Hydroblol. 12(6): 629-636.
Haider, K. 1979. Degradation and metabo!1zat1on of llndane and other
hexachlorocyclohexane Isomers by anaerobic and aerobic soil microorganisms.
Z. Naturforsch. Tell C. 34(11): 1066-1069.
Halnes, T.A. 1983. OrganochloMne residues In brook trout (Salvellnus
fontlnalls) from remote lakes In the northeastern USA. Water A1r Soil
Pollut. 20(1): 47-54.
Hamellnk, J.L. and R.C. Waybrant. 1976. DDE and Undane In a large-scale
model lentlc ecosystem. Trans. Am. F1sh. Soc. 105: 124-134.
Hanada, M., C. Yutanl and T. M1yaj1. 1973. Induction of hepatoma In mice
by benzene hexachlorlde. Gann. 64: 511-513.
Hansen, P.O. 1979. Experiments on the accumulation of Undane (y-BHC) by
the primary producers Chlorella spec, and Chlorella pyrenoldosa. Arch.
Environ. Contam. Toxlcol. 8(6): 721-731.
Hansen, P.O. 1980. Uptake and transfer of the chlorinated hydrocarbon
llndane (r-BHC) In a laboratory freshwater food chain. Environ. Pollut.
(Series A). 21(2): 97-108.
0825p 10-16 10/28/86
-------
Hartley, D.M. and J.B. Johnston. 1983. Use of the freshwater clam
Corblcula manllensls as a monitor for organochlorlne pesticides. Bull.
Environ. Contam. Toxlcol. 31: 33-40.
Hashimoto, Y. and Y. Nlshluchl. 1981. Establishment of bloassay methods
for the evaluation of acute toxldty of pesticides to aquatic organisms. J.
Pest. Sc1. 6(2): 257-264.
Hawley, G.G., Ed. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 526.
Henderson, C., Q.H. Pickering and C.M. Tarzwell. 1959. Relative toxl-cHy
of ten chlorinated hydrocarbon Insecticides to four species of fish. Trans.
Am. F1sh. Soc. 88: 23-32.
Herbst, M. and G. Bodensteln. 1972. Toxicology of llndane. Iri: Llndane,
E. Ulmann, Ed. Verlag K. Shllllnger Publ. Freiburg 1m Brelsgaw. p. 23-82.
(Cited In U.S. EPA, 1980a, 1985a)
Herbst, M., I. Uelsse and H. Koellmer. 1975. Possible hepatocarclnogenlc
effects of llndane. Toxicology. 4(1): 91-96.
Herzberg, A., A. Gelman and A.S. Perry. 1980. The location of llndane
(y-hexachlorocyclohexane) In fish after deliberate poisoning. Bamldgeh
(Bull. Fish Cult. Israel). 32(1): 16-19. (Taken from PESTAB/81/0750)
0825p 10-17 10/28/86
-------
Hill, O.W. and P.L. McCarty. 1976. Anaerobic degradation of selected
chlorinated hydrocarbon pesticides. J. Water Pollut. Control Fed. 39:
1259-1277.
HHachl, M., K. Yamada and S. Takayama. 1975. Cytologlc changes Induced In
rat liver cells by short-term exposure to chemical substances. J. Natl.
Cancer Inst. 54: 1245-1247. (CUed In IARC, 1979)
IARC (International Agency for Research on Cancer). 1979. IARC Monograph
on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Hexachloro-
cyclohexane (technical HCH and Undane). IARC, WHO, Lyon, France. Vol. 20,
p. 195-239.
Inman, C.B.E. and A.P.M. Lockwood. 1977. Some effects of methylmercury and
Undane on sodium regulation 1n the amphlpod Gammarus duebenl during changes
1n the salinity of Its medium. Comp. Blochem. Physlol. 58C: 67-75.
Ishldate, M., Jr. and S. Odashlma. 1977. Chromosome tests with 134 com-
pounds on Chinese hamster cell Vn vUro — A screening for chemical carcino-
gens. Hutat. Res. 48: 337-354.
Ito, N., H. Hagasakl, M. Aral, S. Suglhara and S. Haklura. 1973a. H1sto-
loglc and ultrastructural studies on the hepatocardnogenlclty of benzene
hexachloMde In mice. J. Natl. Cancer Inst. 51(3): 817-826.
0825p 10-18 10/28/86
-------
Ito, N., H. Nagasaki, M. Aria, et al. 1973b. Hlstopathologlc studies on
liver tumorlgenes Is Induced In mice by technical polychloMnated blphenyls
and Its promoting effect on liver tumors Induced by benzene hexachlorlde.
J. Natl. Cancer Inst. 51(5): 1637-1646.
Ito, N., H. Nagasaki, H. Aoe, et al. 1975. Brief communication: Development
of hepatocellular carcinomas 1n rats treated with benzene hexachlorlde. J.
Natl. Cancer Inst. 54: 801-805.
Ito, N., M. Hananouchl, S. Suglhara, et al. 1976. Reversibility and
IrreverslbllIty of liver tumors In mice Induced by the o-1somer of
1,2,3,4,5,6-hexachlorocyclohexane. Cancer Res. 36(7, Pt. 1): 2227-2234..
Jeanne, N. 1979. Effects of llndane on the division, cell cycle and
biosynthesis of two unicellular algae. Can. J. Bot. 57(13): 1464-1472.
Jenssen, 0. and C. Ramel. 1980. The mlcronucleus test as part of a short-
term mutagenldty test program for the prediction of cardnogenlclty evalu-
ated by 143 agents tested. Mutat. Res. 75: 191-202.
Johnson, U.W. and M.J. Flnley. 1980. Handbook of acute toxlclty of chemi-
cals to fish and aquatic Invertebrates. U.S. Dept. of Interior, F1sh and
U1ldl. Serv., Washington, DC. Res. Publ. 173.
Joshl, A.G. and M.S. Rege. 1980. Acute toxlclty of some pesticides and a
few Inorganic salts to the mosquito fish Gambusla afflnls (Balrd and
Glrard). Indian J. Exp. B1ol. 18(4): 435-437.
0825p 10-19 10/28/86
-------
Juarez, A. and J.A. Guzman. 1984. Chronic effect of five organochlorine
Insecticides on larvae of Bufo arenarum (H). Commun. Blol. 2(4): 411-415.
(CA 101:224365q)
Kaiser, K.L.E. 1982. Early determination of organochloMne contamination
from residue ratios 1n the sea lamprey (Petromyzon marlnus) and Us lake
whlteflsh (Coreqonum clupeaformls) host. Can. J. F1sh. Aquat. Sc1. 39:
571-579.
Kanazawa, J. 1981. Measurement of the bloconcentratlon factors of pesti-
cides by freshwater fish and their correlation with phys1cochem1cal proper-
ties or acute toxldtles. Pestle. Sc1. 12(4): 417-424.
Kanazawa, J. 1982. Relationship between the molecular weights of pesti-
cides and their bloconcentratlon factors by fish. ExpeMentla. 38(9):
1045-1046.
Kanazawa, J. 1983. A method of predicting the bloconcentratlon potential
of pesticides by using fish. JARQ. 17: 173-179.
Kar, S. and P.K. Singh. 1979. Effect of nutrients on the toxldty of
pesticides carbofuran and hexachlorocyclohexane to blue-green alga Nostoc
muscorum. Z. Allg. Mlkroblol. 19(7): 467-472.
Kashyap. S.K., S.K. N1gam, R.C. Gupta, A.B. Karnlk and S.K. Chatterjee.
1979. Carclnogenlclty of hexachlorocyclohexane (BHC) In purebred Swiss
mice. J. Environ. Sc1. Health, Part B. 814(3): 305-318.
0825p 10-20 10/28/86
-------
Katz, M. 1961. Acute toxldty of some organic Insecticides to three
species of salmonlds and to the three-spine stickleback. Trans. Am. Fish.
Soc. 90(3): 264-268.
Kaur, K. and S. Kirk. 1983. Effect of BHC and sumlthlon on ovarian
recrudescence In common carp, Cyprlnus carplo. Indian J. Ecol. 19(2):
182-187.
Keith, L.H., W.A. Garrison, F.R. Allen, et al. 1976. Identification of
organic compounds In drinking water from thirteen U.S. cities. In: Identi-
fication and Analysis of Organic Pollutants In Water, L.H. Keith, Ed. Ann
Arbor Science, Ann Arbor, MI. p. 329-373.
Kenaga, E.E. 1980. Predicted bloconcentratlon factors and soil sorptlon
coefficients of pesticides and other chemicals. Ecotoxlcol. Environ. Saf.
4: 26-38.
Khamldov, M.K. 1984. Experimental study of the effect of Industrial grade
hexachloran on pregnancy and physical development of the progeny 1n 3
generations. Med. Zh. Uzb. 5: 57-60. (Russ.) [CA 101(21):185619d]
Khera. K.S., C. Uhalen, G. TMvett and G. Angers. 1979. Teratogenlclty
studies on pestlcldal formulations of dlmethoate, dluron and llndane In
rats. Bull. Environ. Contain. Toxlcol. 224(4-5): 522-529.
0825p 10-21 10/28/86
-------
Kiraly, J., I. Szentesl, M. Ruzlcaka and A. Czelre. 1979. Chromosome
studies In workers' producing organophosphate Insecticides. Arch. Environ.
Contam. Toxlcol. 8: 309-319. (Cited 1n U.S. EPA, 1985a)
Kltamura, S., D. Sumlno and K. Hayakawa. 1970. No title provided. Japan
J. Publ. Health. 17: 108-112. (Cited In U.S. EPA, 1980a, 1985a)
Kohnen, R., K. Haider and G. Jagnow. 1975. Investigations on the mlcroblal
degradation of Undane In submerged and aerated moist soil. Environ. Qual.
Saf. Suppl. 3: 223-236.
Konasewlch. D., W. Traversy and H. Zar. 1978. Great Lakes Water Quality.
Status Report on Organic and Heavy Metal Contaminants 1n the Lakes Erie,
Michigan, Huron and Superior Basins. Implementation Committee of the Great
Lakes Water Quality Board, Windsor, Ontario. July.
Kopecek, K., F. Fueller, W. Ratzmann and W. Slmonls. 1975. Light dependent
Insecticide effect on unicellular algae. Ber. Btsch. Bot. Ges. 88(2):
269-281. (Ger.) [CA 84(19):131132b]
Korn, S. and R. Earnest. 1974. Acute toxlclty of twenty Insecticides to
striped bass, Morone saxat111s. Calif. F1sh Game. 60: 128-131.
Krayblll, H.F. 1977. Global distribution of carcinogenic pollutants In
water. Ann. N.Y. Acad. Scl. 298: 80-89.
0825p 10-22 10/28/86
-------
KMshnakumaM, M.K. 1977. Sensitivity of the alga Scenedesmus acutus to
some pesticides. L-1fe Sc1. 20: 1525-1532.
Kujwa, M., R. Engst and R. Macholz. 1977. On the metabolism of llndane.
in: Proc. In. Symp. Environ. Pollut. Human Health, p. 661-672. (Cited 1n
U.S. EPA, 1980a, 1985a)
Kuntz, K.W. and N.O. Harry. 1983. Chlorinated organic contaminants 1n
water and suspended sediments of the lower Niagara river. J. Great Lakes
Res. 9: 281-286.
Kurlhara, N., K. Tanaka and M. NakaJIma. 1979. Mercapturlc add formation
from llndane 1n rats. Pestle. Blochem. Physlol. 10: 137-150. (Cited In
U.S. EPA, 1980a, 1985a)
Kutz, F.H., A.R. Yobs and H.S.C. Yang. 1976. National Pesticide Monitoring
Programs. l£: Air Pollution from Pesticides and Agricultural Processes,
R.E. Lee, Jr., Ed. CRC Press. Cleveland, OH. p. 95-137.
Lakkad, B.C.. S.K. Nlgam, A.B. Karnlk, et al. 1982. Dominant-lethal study
of technical-grade hexachlorocyclohexane In Swiss mice. Mutat. Res.
101(4): 314-320.
Lakshmanan, F.L., A Pommer and 0. Patterson. 1979. Chlorinated hydrocarbon
Insecticide residues 1n tissues of rats before and after reduction of body
fat by dietary restriction. J. Agrlc. Food Chem. 27(4): 720-725. (Cited
In U.S. EPA, 19803. 1985a)
0825p 10-23 10/28/86
-------
Laug, E.P. 1948. Tissue distribution of a toxicant following oral Inges-
tlon of the y-lsomer of benzene hexachlorlde by rats. J. Pharmacol. Exp.
Ther. 93: 277-281.
Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic
activity of nine chlorinated phenols, seven chlorinated benzenes and three
chlorinated hexanes. Environ. Mutagen. 1: 143. (Cited In U.S. EPA, 1985a)
Leatherland, J.F. and R.A. Sonstegard. 1982. Bloaccumulatlon of organo-
chloMnes by yearling coho salmon (Oncorhynchus klsutch Walbaum) fed diets
containing Great Lakes coho salmon, and the pathophyslologlcal responses of
the recipients. Comp. Blochem. Physlol. C. 72C(1): 91-99.
Lehman, A.J. 1952a. Chemicals In foods: A report to the Association of
Food and Drug Officials on current development. Part II. Pesticides.
Section IV. Biochemistry. U.S. Assoc. Food Drug Office Quart. Bull. 16:
85-91. (Cited In U.S. EPA, 1980a, 1985a)
Lehman, A.J. 1952b. Chemicals In foods: A report to the Association of
Food and Drug Officials on current developments. Part II. Pesticides.
Section V. Pathology. U.S. Assoc. Food Drug Office Quart. Bull. 16:
126-132. (CHed 1n U.S. EPA, 1980a, 1985a)
Lehman, A.J. 1965. Summaries of pesticide toxldty. Part I. Chlorinated
organic compounds. Assoc. of Food and Drug Officials of the United States,
Topeka, KS. p. 27-29. (CHed In U.S. EPA, 1985a)
0825p 10-24 10/28/86
-------
Lewis, R.G. and R.E. Lee, Jr. 1976. A1r pollution from pesticides sources,
occurrence and dls'perslon. In: Air Pollution from Pesticides and Agricul-
tural Processes. CRC Press, p. 5-51.
L1chtenste1n, E.P., T.W. Fuhremann and K.R. Schulz. 1971. Persistence and
vertical distribution of DOT, Undane and aldrln residues, ten and fifteen
years after a single soil application. J. AgMc. Food Chem. 19: 713-721.
L1u, P.T.Y. 1982. The role of genetic factors and route of administration
on the metabolic disposition of Undane In mice. Dissert. Abstr. 438:
1049. (Cited In U.S. EPA, 1985a)
Lyman, H.J.. W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 2-14, 4-9,
15-11, 15-24.
Macek, K.J. and W.A. McAllister. 1970. Insecticide susceptibility of some
common fish family representatives. Trans. Am. F1sh. Soc. 99(1): 20-27
Macek, K.J., C. Hutchlnson and O.B. Cope. 1969. The effects of temperature
on the susceptibility of bluegllls and rainbow trout to selected pesticides.
Bull. Environ. Contam. Toxlcol. 4: 174-183.
Macek, K.J., et al. 1976. Chronic toxUHy of Undane to selected aquatic
Invertebrates and fishes. U.S. EPA. Ouluth. MN. EPA-600/3-76-046. (CUed
In U.S. EPA, 1980b)
0825p 10-25 10/28/86
-------
Macholz, R.M., R. Knoll, H.J, Lewerenz, M. Petrzika and R. Engst. 1982a.
Metabolism of a-hexachlorocyclohexane. Free metabolites \n urine and
organs of rats. Xenoblotlca. 12(4): 227-231.
Macholz, R.M., R. Knoll, H.J. Lewerenz and R. Plass. 1982b. B1odegradat1on
of beta-hexachlorocyclohexane. Free metabolites In rat urine and organs.
Arch. Toxlcol. 50: 85-88.
Mackay, D. and P.J. Lelnonen. 1975. Rate of evaporation of low-solubility
contaminants from water bodies to atmosphere. Environ. Sc1. Technol. 9:
1178-1180.
MacRae, I.C., Y. Yamaya and T. Yoshlda. 1984. Persistence of hexachloro-
cyclohexane Homers 1n soil suspensions. Soil B1ol. Blochem. 16: 285-286.
Madhu, C., K.J. Rao and K.V.R. Rao. 1984. Hematologlcal changes In
Sarotherodon mossamblcus exposed to llndane. J. Food Sc1. Technol. 21(1):
53-55. [CA 101(ll):85266t]
Malty, A.K. and J. Saxena. 1979. Effects of BHC on a freshwater species of
Daphnla (Daphnla carlnata King). Natl. Acad. Scl. Lett. (India). 2(3):
113-114. [CA 91(ll):84650b]
Halalyandl, M., S.M. Shah and P. Lee. 1982. Fate of alpha-BHC and gamma-
BHC Isomers under simulated environmental conditions. J. Environ. Scl.
Health Part A Environ. Sc1. Eng. 17(3): 283-298.
0825p 10-26 10/28/86
-------
Marcelle, C. and J.P. Thome. 1983. Acute toxlclty and bloaccumulation of
"Mndane in gudgeon, Goblo qoblo (L). Bull. Environ. Contam. Toxicol.
31(4): 453-458.
Marcelle, C. and J.P. Thome. 1984. Relative Importance of dietary and
environmental sources of llndane in fish. Bull. Environ. Contam. Toxicol.
33(4): 423-429.
Marchal-Segault, D. 1982. Effects of llndane, an organochlorlde Insecti-
cide, on the thyroid of Xenopus laevls Daudln larvas In premetamorphlc
stages. C.R. Seances Soc. B1ol. Ses F11. 176(6): 839-848. (Fre.) [CA
98(21):174399a]
Marchal-Segualt, D. and F. Ramade. 1981. The effects of llndane, an
Insecticide, on hatching and postembryonlc development of Xenopus laevls
(Daudln) anuran amphibian. Environ. Res. 24(2): 250-258.
Martin, O.B. and W.A. Hartman. 1985. Organochlorlne pesticides and
polychlorlnated blphenyls In sediment and fish from wetlands In the north
central United States. J. Assoc. Off. Anal. Chem. 68(4): 712-717.
Mathur, S.P. and J.B. Saha. 1975. Mlcroblal degradation of llndane 14C
In a flooded sandy loam soil. Soil Sc1. 120: 301-317.
Matsumura, F. and H.J. Benezet. 1973. Studies on the bloaccumulatlon and
mlcroblal degradation of 2,3,7,8-tetrachlorod1benzo-p-d1ox1n. Environ.
Health Perspect. 253-258.
0825p 10-27 10/28/86
-------
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed. The
Resource Agency of"CalIfornla, State Water Qual. Cont. Board. Publ. 3-A.
HcLeay, O.J. 1976. Rapid method for measuring acute toxldty of pulpmlll
effluents and other toxicants to salmonld fish at ambient room temperature.
J. Fish. Res. Board Can. 33: 1303-1311.
Metcalf, R.L., I.P. Kapoor, P.Y. Lu, C.K. Schuth and P. Sherman. 1973.
Model of ecosystem studies of the environmental fate of six organochlorlne
pesticides. Environ. Health Perspect. 4: 35-44.
Meyer, P.P. 1965. The effect of formulation differences on toxldty. of
benzene hexachloMde to golden shiners. Jjr. Proc. 17th Ann. Conf. Southeast
Assoc. Game Fish Comm. p. 186-190. (Cited 1n U.S. EPA, 1971)
Morgan, D.P., E.M. Stockdaly, R.J. Roberts and A.M. Walter. 1980. Anemia
associated with exposure to llndane. Arch. Environ. Health. 35(5): 307-310.
Morlya, M., T. Ohta, K. Watanabe, T. Mlyazawa, K. Kato and Y. Shlrasu.
1983. Further mutagenlcUy studies on pesticides In bacterial reversion
assay systems. Mutat. Res. 116 (3-4): 185-216.
Morrison, R.T. and R.N. Boyd. 1973. Organic Chemistry, 3rd ed. Allyn and
Bacon, Inc., Boston, MA. p. 457-458.
0825p 10-28 10/28/86
-------
Muller, 0., H. Klepel, R.M. Macholz, H.J. Lewerenz and R. Engst. 1981.
ElectroneurophysloToglcal studies on neurotoxlc effects of hexachlorocyclo-
hexane Isomers and y-pentachlorocyclohexane. Bull. Environ. Contam.
Toxlcol. 27(5): 704-706.
Munlr, K.M. and S.V. Bhlde. 1984. Deviations In ornlthlne-related metabo-
lism during hexachlorocyclohexane-lnduced hepatocarclnogenesls In mice:
Evidence for conversion of glutamate to ornlthlne. Environ. Res. 35(1):
180-187.
Munlr, K.M., C.S. Soman and V. Sumatl. 1983. Hexachlorocyclohexane-lnduced
tumorlgenldty In mice under different experimental conditions. TumoM.
69(5): 383-386.
Muralldhara, M., K. Krlshnakumar1 and S.K. Majumder. 1979. Effects of
carriers on the oral toxlclty of llndane (pesticide) (y-BHC) to albino
rats. J. Food Sc1. Technol. 16: 105-107. (CHed 1n U.S. EPA, 1985a)
Nagasaki, H. 1973. Chronic toxlclty of benzene hexachloMde (BHC). Nara
Igaku Zasshl. 24(1-2): 1-26. (Jap.). [CA 79(5):28178u]
Nagasaki, H., S. Tomll, T. Mega, M Marugaml and N. Ho. 1971. Development
of hepatomas In mice treated with benzene hexachlorlde. Gann. 62: 431.
(CHed 1n IARC, 1979; U.S. EPA, 1980a)
0825p 10-29 10/28/86
-------
Nagasaki, H., S. Tom11, T. Mega, M. Marugaml and N. Uo. 1972a. Hepatocar-
clnogenlc effect of a-, B-, Y-. and 6-lsomers of benzene hexachlorlde
In mice. Gann. 63(3): 393.
Nagasaki, H., S. Tomll, T. Mega, M. Marugaml and N. Ito. 1972b. Cardno-
genlclty of benzene hexachlorlde (BHC). ln_: Topics In Chemical Carclnogene-
sls, W. Nakahara, S. Takayama, T. Suglmura and S. Odashlma, Ed. Univ. of
Tokyo Press, Tokyo, p. 343-353.
Nagasaki, H., H. Kawabata, Y. Mlyata, et. al. 1975. Effect of various
factors on Induction of liver tumors In animals by the a-1somer of benzene
hexachlorlde. Gann. 66: 185-191.
Nalr, G.A. 1981. Toxic effects of certain bloddes on a fresh water mite,
Hydrachna trllobata vlets (Arachn1da:Hydrachno1dea:Hydrachn1dae). J.
Environ. Blol. 2(2): 91-96. [CA 97(1):1904n]
Nash, R.G. 1983. Comparative volatilization and dissipation rates of
several pesticides from soil. J. Agrlc. Food Chem. 31(2): 210-217.
NCI (National Cancer Institute). 1977. Bloassay of llndane for possible
carc1nogen1c1ty. CAS No. 58-89-9. NTIS PB-273480.
Nlethammer, K.R., O.H. White, T.S. Baskett and M.H. Sayre. 1984. Presence
and blomagnlfIcatlon of organochlorlne chemical residues 1n Oxbow Lakes of
northeastern Louisiana. Arch. Environ. Contain. Toxlcol. 13(1): 63-74.
Q825p 10-30 10/28/86
-------
Nlgam, S.K.. B.C. Lakkad, A.B. Karnlk, et al. 1979. Effect of hexachloro-
cyclohexane feeding on testlcular tissue of pure Inbred Swiss mice. Bull.
Environ. Contam. Toxlcol. 23(4-5): 431-437.
Nlgam, S.K., A.B. Karnlk, B.C. Lakkad and H. Venkatakrlshna-Bhatt. 1982.
Distribution of Isomers of BHC and related hlstopathology of Hver 1n hexa-
chlorocyclohexane (technical grade BCH) fed mice. Arch. Environ. Health.
37(3): 156-158.
Nlgam, S.K., K.N. Thakore, A.B. Karnlk and B.C. Lakkad. 1984a. Hepatic
glycogen. Iron distribution and hlstopathologlcal alterations In mice
exposed to hexachlorocyclohexane. Indian J. Med. Res. 79: 571-579.
Nlgam. S.K., B.C. Lakkad. A.B. Karnlk and K.M. Thakore. 1984b. Ultrastruc-
tural changes 1n Hver of mice exposed to hexachlorocyclohexane. Indian J.
Exp. Blol. 22(4): 199-204.
Nybom, N. and B. Knutsson. 1947. Investigations on C-mHosIs 1n AlHum
cepa. I. The cytologlcal effect of hexachlorocyclohexane. HeredHas. 33:
220-234. (Cited In IARC, 1979)
Oesch, P.. T. Frledberg, M. Herbst, H. Paul, N. Hnhelm and P. Bentley.
1982. Effects of Undane treatment on drug-metabolizing enzymes and liver
weight of DV1 mice In which 1t evoked hepatomas and nonsusceptlble rodents.
Chem.-B1ol. Interact. 40(1): 1-14.
0825p 10-31 10/28/86
-------
Ohlsa, N. and M. Yamaguchl. 1978. Degradation of gatmia-BHC In flooded
soils enriched with peptone. Agrlc. B1ol. Chem. 42: 1983-1987.
Oliver, 8.G. and M.N. Charlton. 1984. Chlorinated organic contaminants on
settling participates In the Niagara river vicinity of Lake Ontario.
Environ. Set. Technol. 18: 903-908.
OSHA (Occupational Safety and Health Administration). 1985. Code of
Federal Regulations. 29 CFR 1900.1000
Page, G.W. 1981. Comparison of groundwater and surface water for patterns
and levels of contamination by toxic substances. Environ. Scl. Technol.
15: 1475-1481.
Palmer, C.M. and I.E. Maloney. 1955. Preliminary screening for potential
alglcldes. Ohio J. Sc1. 55(1): 1-8.
Palmer, A.K., 0.0. Cozens, E.J.F. Splcer and A.N. Worden. 1978a. Effects
of llndane upon reproductive function In a 3-generat1on study In rats.
Toxicology. 10(1): 45-54.
Palmer, A.K., A.M. Bottomley, A.N. Worden, H. Frohberg and A. Bauer. 1978b.
Effect of Undane on pregnancy In the rabbit and rat. Toxicology. 9(3):
239-247.
0825p 10-32 10/28/86
-------
Pankow, J.F., L.M. Isabella and W.E. Asher. 1984. Trace organic compounds
In rain: 1. Sampler design and analysis by adsorption-terminal desorptlon.
Environ. Sc1. Technol. 18(5): 310-318.
Parejko, R. and C.L.J. Hu. 1977. Chlorohydrocarbons In Marquette F1sh
Hatchery lake trout (Salvellnus namaycush). Bull. Environ. Contam. Toxlcol.
17(1): 90-97.
Parejko, R., R. Johnston and R. Keller. 1975. Chlorohydrocarbons In Lake
Superior lake trout (Salvellnus namaycush). Bull. Environ. Contam. Toxlcol.
14(4): 480-488.
Parker, J.G. 1984. The effects of selected chemicals and water qualHy on
the marine polychaete Ophryotrocha dladema. Hater Res. 18(7): 865-868.
Pawar, K.R. and M. Katdare. 1983. ToxIcUy of Sumlthlon, BHC and Furadan
to the tadpoles of the frog Hlcrohyla ornata. Indian J. Environ. Health.
25(3): 214-217. [CA 100(9):63178t]
Petescu, S., V. Dobre, M. Lelbovld, Z. Petrescu and S.A. Ghelberg. 1974.
The effects of long-term administration of organochlorlne pesticides
(llndane, DOT) on the white rat. Rev. Med. ChU. 78(4): 831-842. (Rom.)
(Taken from PESTAB/75/2506)
Petrasek, A.C., I.J. Kugelman, B.H. Austern, T.A. Pressley, L.A. Ulnslow and
R.H. Wise. 1983. Fate of toxic organic compounds 1n wastewater treatment
plants. J. Hater Pollut. Control Fed. 55(10): 1286-1296.
0825p 10-33 10/28/86
-------
Pickering, Q.H. 1983. Chronic toxlcity to fathead minnow Pimephales
promelas of wastewater from a conventional wastewater treatment system
receiving oganlc priority pollutants. Environ. Pollut. Ser. A. 31(2):
105-117.
Plmental, 0. 1971. Ecological effects of pesticides on non-target species.
U.S. EPA, Washington, DC. NTIS PB-269-605.
Podrebarac, O.S. 1984. Pesticide, metal and other chemical residues In
adult total diet samples (XIV). October 1977-September 1978. J. Assoc.
Off. Anal. Chem. 67: 176-185.
Poradovsky, K., L. Roslval and A. Mesazarosova. 1977. Transpacental perme-
ation of pesticides during normal pregnancy. Cesk. Gynekol. 42: 405-410.
{Cited In U.S. EPA, 1980a, 1985a)
Portlg, J.P., et al. 1973. B1odegradat1on of a-hexachlorocyclohexane.
I. Glutathlone-dependent conversion to a hydrophlUc metabolite by rat liver
cytosol. Naunyn-Schmled's Arch. Pharmacol. 279: 185. (Cited In U.S. EPA,
1980a)
Probst, G.S., R.E. McMahon, L.E. Hill, C.Z. Thompson, J.K. Epp and S.B.
Neal. 1981. Chemically-Induced unscheduled DMA synthesis In primary rat
hepatocyte cultures: A comparison with bacterial mutagenlcUy using 218
compounds. Environ. Mutagen. 3(1): 11-32.
0825p 10-34 10/28/86
-------
Purchase, I.F.H., E. Longstaff, J. Ashby, et al. 1978. An evaluation of
sex short-term tests for detecting organic chemical carclnogenesls. Br. J.
Cancer. 37: 873-903.
Ramamoorthy, S. 1985. Competition of fate processes In the bloconcentra-
tlon of llndane. Bull. Environ. Contam. Toxlcol. 34: 349-358.
Randall, W.F., W.H. Dennis and M.C. Warner. 1979. Acute toxldty of
dechlorInated DOT, chlordane and Undane to blueglll (Lepomls macrochlrus)
and Daphnla maqna. Bull. Environ. Contam. Toxlcol. 21(6): 849-854.
Rao, P.S.C. and J.M. Davidson. 1982. Retention and transformation, of
selected pesticides and phosphorus In soil-water systems: A critical review.
ORD, U.S. EPA, Athen, GA. EPA-600/3-82-060.
Rao, P.S.B. and V.K. Venugopalan. 1984.. Llndane Induced respiratory
changes In juveniles of estuarlne fish Hugll cephalus (L1nn). Indian J.
Mar. Sc1. 13(4): 196-198. (CA 102:144468g)
Rao-Kovval1, S.S., S. Ghosh and A.V. Jayanthl. 1980. Chlorinated pesticide
residues on flue-cured tobaccos grown In Andra Pradesh. Tobacco Res. 6:
49-56.
Research and Consulting Co., Ltd. 1983. Llndane: Subchronlc oral dosing
(rat) study. EPA Pesticide Accession No. 250340. (Cited In U.S. EPA, 1985a)
Reuber, M.D. 1979. CardnogenlcHy of Undane. Environ. Res. 19: 460-481.
0825p 10-35 10/28/86
-------
Rlckard, O.G. and O.E.R. Dulley. 1983. The levels of some heavy metals and
chlorinated hydrocarbons In fish from the tidal Thames. Environ. Pollut.
(Ser. B). 5: 101-119.
Rlvett, K.F., H. Chesterman, D.N. Kellett, A.J. Newman and A.N. Horden.
1978. Effects of feeding llndane to dogs for periods of up to 2 years.
Toxicology. 9(3): 273-289.
Rocchl, P., P. Perocco, H. Alberghlnl, A. Flnl and G. Prodi. 1980. Effect
of pesticides on scheduled and unscheduled DNA synthesis of rat lymphocytes
and human lymphocytes. Arch. Toxlcol. 45(2): 101-108.
Rodgers, J.H.. Jr., K.I. Olckson and M.J. Oetoer. 1983. Bloconcentratlon
of llndane and naphthalene In bluegllls (Lepomls macrochlrus). Jji: 6th
Symp. Aquatic Toxicology and Hazard Assessment, Am. Soc. Test. Mater.,
Philadelphia, PA. p. 300-311. ASTM STP 802.
Rohrborn, G. 1977. Statement on the potential mutagenlclty of llndane.
Hooker Rebuttal submission. OPTS, U.S. EPA, Washington, DC. (Cited 1n U.S.
EPA. 1985a)
Sackmauerova, H., 0. Palusova and A. Szokolay. 1977. Contribution to the
study of drinking water, Danube water and blocenose contamination with
chlorinated Insecticides. Hater Res. 11(7): 551-556.
0825p 10-36 10/28/86
-------
Saleh, F.Y., K.L. Olckson and J.H. Rodgers, Jr. 1982. Fate of llndane In
the aquatic environment: Rate constants of physical and chemical processes.
Environ. Toxlcol. Chem. 1: 289-297.
Sanders, H.O. 1969. Toxlclty of pesticides to the crustacean Gammarus
lacustrls. Bureau of Sport Fish. H1ldl. Tech. Paper No. 25. Government
Printing Office, Washington, DC. (Cited In U.S. EPA, 1972, 1980b; Plmental,
1971)
Sanders, H.O. 1970. Pesticide toxlcltles to tadpoles of the western chorus
from, PseudacrIs tr1ser1ata. and Fowler's toad, Bufo woodhousll fowlerl.
Copela. 2: 246-251.
Sanders, H.O. 1972. Toxlclty of some Insecticides to four species of
malacostracan crustaceans. Bur. Sport F1sh. H1ldl. Tech. Paper 66. (Cited
In U.S. EPA, 1972, 1980D)
Sanders, H.O. and O.B. Cope. 1966. Toxlcltles of several pesticides to two
species of Cladocerans. Trans. Am. Fish. Soc. 95(2): 165-169.
Sanders, H.O. and O.B. Cope. 1968. The relative toxlclty of several pesti-
cides to three species of stoneflles. Llmnol. Oceanogr. 13: 112-117.
Sandhu, S.S., W.J. Warren and P. Nelson. 1978. Pestlddal residue 1n rural
potable water. J. Am. Water Works Assoc. 70: 41-45.
0825p 10-37 10/28/86
-------
SantolucHo, J.A. 1975. The use of quantitative EEG for detecting low-
level prolonged exposure to pesticides, in: Proc. Int. Symp. Recent Adv.
Assess. Health Eff. Environ. Pollut. 4: 2387-2394.
Sax, K. and H.J. Sax. 1968. Possible mutagenlc hazards of some food addi-
tives, beverages and Insecticides. Japan J. Genet. 43: 89-94.
Saxena, M.C., M.A. S1dd1qu1, A.K. Bhargava, T.D. Seth, C.R. KMshnamurtl and
0. Kutty. 1980. Role of chlorinated hydrocarbon pesticide 1n abortions and
premature labour. Toxicology. 17: 323-331. (Cited In U.S. EPA, 1985a)
Saxena, M.C.. M.K.J. S1dd1qu1. A.K. Bhargava, C.R. Krishna Hurtl and D.
Kutty. 1981. Placenta! transfer of pesticides In humans. Arch. Toxlcol.
48: 127-134. (Cited 1n U.S. EPA, 1985a)
Schlmmel, S.C., J.M. Patrick, Jr. and J. Forester. 1977. Toxldty and
bloconcentratlon of BHC and Undane In selected estuarlne animals. Arch.
Environ. Contain. Toxlcol. 6(2-3): 355-363.
Schmltt, C.J., J.L. ZaJIcek and M.A. Rlblck. 1985. National pesticide
monitoring program: Residues of organochlorlne chemicals 1n freshwater fish,
1980-1981. Arch. Environ. Contam. Toxlcol. 14: 225-268.
Schulte-Hermann, R. and U. Parzefall. 1981. Failure to discriminate
Initiation from promotion of liver tumors In a long-term study with the
phenobarbltal-type Induced a-BHC and the role of sustained stimulation of
hepatic growth and monooxygenases. Cancer Res. 41(1): 4140-4146.
0825p 10-38 10/28/86
-------
Schwarzenbach, R.P. and J. Westall. 1981. Transport of nonpolar organic
compounds from surface water to groundwater, laboratory studies. Environ.
Scl. Technol. 15: 1360-1367.
Sethunathan, N. and T. Yoshlda. 1973. Degradation of chlorinated hydro-
carbons by ClostrIdlum sp. Isolated from llndane-amended, flooded soil.
Plant Soil. 38: 663-666.
Seuge, J. and R. Bluzat. 1979. Chronic toxldty of carbaryl and llndane to
the freshwater mollusc Lymnea stagnalls L. Water Res. 13(3): 285-293.
(Fre.)
Seuge. J. and R. Bluzat. 1983. Chronic toxldty of three Insecticides
(carbaryl, fenthlon and Undane) In the freshwater snail Lymnaea staqnalls.
Hydrob1olog1a. 106(1): 65-72.
Shahln, M.M. and R.C. Von Borstel. 1977. Mutagenlc and lethal effects of
a-benzene hexachlorlde, dlbutyl phthalate and tHchloroethylene In
Saccharomyces cerevlslae. Mutat. Res. 48(2): 173-180.
Sharma, A.K. and S. Gosh. 1969. A comparative study on the effects of
certain chemical agents on chromosomes. Acta B1ol. Acad. Sc1. Hung. 20:
11-21. (Cited 1n IARC, 1979)
Sharom. M.S., J.R.W. Miles, C.R. Harris and F.L. McEwen. 1980. Persistence
of 12 Insecticides In water. Water Res. 14(8): 1089-1093.
0825p 10-39 10/28/86
-------
Shell Oil Co. 1982. The effects of water hardness, temperature and size of
test organisms on" the susceptibility of freshwater shrimp Gaimiarus pulex
(L.) to toxicants. Office of Toxic Substances, U.S. EPA, Washington, DC.
TSCA 8d submission 878210074.
Shlmazu, H., N. Shlralshl, T. Akematsu, N. Ueda and T. Suglyama. 1976.
Carclnogenlclty screening tests on Induction of chromosomal aberrations In
rat bone marrow cells U> vivo. Mutat. Res. 38: 347.
Shlrasu, Y., M. Morlya, K. Kato, A. Furuhashl, and T. Kada. 1976. Mutagen-
Iclty screening of pesticides In the mlcroblal system. Mutat. Res. 40:
19-30. (CHed 1n U.S. EPA, 1985a)
Shlvanandappa, T. and M.K. Krlshnakumarl. 1981. H1stochem1cal and biochem-
ical changes In rats fed dietary benzene hexachlorlde. Indian J. Exp. Blol.
19(12): 1163-1168.
Shlvanandappa, T. and M.K. Krlshnakumarl. 1983. BHC-lnduced testlcular
dysfunction In rats. Acta Pharmacol. Toxlcol. 51(1): 12-17.
Shlvanandappa, T., M.K. Krlshnakumarl and S.K. Majumder. 1982. Inhibition
of steroldogenlc activity In the adrenal cortex of rats fed benzene hexa
chloride BHC. Experlentla (Basel). 38(10): 1251-1253.
Shtenberg, A.I. and C. Mametkullev. 1976. Effect of the y-lsomer of
hexachlorocyclohexane (HCCH) on the functional state of the sexual glands In
rats. Vopr. PHan. 4:62-67. (Rus.) [CA 85{17):117679z]
0825p 10-40 10/28/86
-------
Shukla, G.S. and Omkar. 1983. Acute toxlclty of Insecticides to a
freshwater prawn Hacrobrachlum lamarrel (M. Edwards). Indian J. Environ.
Health. 25(1): 61-63. [CA 100(3):18986u]
S1dd1qu1, M.K.J., M.C. Saxena and C.R. Krishna Murtl. 1981a. Storage of
DDT and BHC In adipose tissue of Indian males. Int. J. Environ. Anal. Chem.
10: 197-204. (Cited In U.S. EPA, 1985a)
Slddlqul, M.K.J., M.C. Saxena, A.K. Bhargava, C.R.K. Murtl and D. Kutty.
1981b. Chlorinated hydrocarbon pesticides 1n blood of newborn babies In
India. Pestle. Monlt. J. 15(2): 77-79.
Singh, D.N., R.K. Tyagl and R.S. Panwar. 1981. Toxldty of some organic
bloddes to a freshwater fish, CypMnus carplo communls. J. Environ. B1ol.
2(3): 41-46. [CA 97(9) :67466c] (Cited In Pickering, 1983)
Slooff, W. 1979. Detection limits of a biological monitoring system based
on fish respiration. Bull. Environ. Contain. Toxlcol. 23(4-5): 517-523.
Snow, J.R. 1958. A preliminary report on the comparative testing of some
of the newer herbicides. ln_: Proc. 11th Ann. Conf. Southeast Assoc. Game
Fish Comm. p. 125-132. (CUed 1n U.S. EPA, 1971, 1972)
Srlvastava, P.N. and A.S. Naraln. 1982. Leukocytlc and nemos tat1c reac-
tions of the Indian catfish, Heteropneustes fossllls. subjected to environ-
mental pollution by sewage, fertilizers and Insecticides. Acta Pharmacol.
Toxlcol. 50(1): 13-21.
0825p 10-41 10/28/86
-------
Stanley, C.W., J.E. Barney, II, M.R. Helton and A.R. Yobs. 1971. Measure-
ment of atmospheric levels of pesticides. Environ. Sd. Technol. 5:
430-435.
Steffey, K.L., J. Mack, C.W. MacMonegle and H.B. Petty. 1984. A ten-year
study of chlorinated hydrocarbon Insecticide residues 1n bovine milk In
Illinois, 1972-1981. J. Environ. Sd. Health B. 19: 49-65.
Stein, K., J. Portlg, H. Fuhrmann, M. Koransky and G. Noack. 1980. SteMc
factors In the pharmacoklnetlcs of llndane and a-BHC 1n rats. Xeno-
blotlca. 10(1): 67-78.
Stephenson, R.R. 1983. Effects of water hardness, water temperature and
size of the test organisms on the susceptibility of the freshwater shrimp,
Gammarus pulex (L.) to toxicants. Bull. Environ. Contain, toxlcol. 31:
459-466.
Stewart, D.K.R. and M.O. Chlsholm. 1971. Long-term persistence of BHC, DDT
and chlordane In a sandy loam soil. Can. J. Soil Sd. 61: 379-383.
Strachan, W.M.J. 1985. Organic substances 1n the rainfall of Lake
Superior: 1983. Environ. Toxlcol. Chem. 4: 677-683.
Strachan, H.M.J. and H. Huneault. 1979. Polychlorlnated blphenyls and
organochlorlne pesticides 1n Great Lakes precipitation. J. Great Lakes Res.
5: 61-68.
0825p 10-42 10/28/86
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Strand, J.A., III, B.E. Vaughan and J.T. Cummins. 1967. PesUcldal Control
of Contaminant Matro-Invertebrates Encountered In Laboratory Culture of
Marine Sea Weeds. NTIS AD-648854.
Strelt, B. 1979. Uptake, accumulation and release of organic pesticides by
benthlc Invertebrates. 3. Distribution of l4C-atraz1ne and 14C-Hndane
In an experimental 3-step food chain microcosm. Arch. Hydroblol. 55:
373-400.
Suglhara, S., K. H1rao, H. Hananouchl and N. Ito. 1975. Ultra-structural
studies on hepatomas Induced by benzene hexachlorlde (BCH). J. Electron
Mlcrosc. 24: 192.
Suglura, K., T. Washlno, M. Hattorl, E. Sato and M. Goto. 1979. Accumula-
tion of organochlorlne compounds In fishes. Differences of accumulation
factors by fishes. Chemosphere. 8(6): 359-364.
Sullivan, J.H. 1980. Pesticide residues In Imported species. A survey for
chlorinated hydrocarbons. J. AgMc. Food Chem. 28(5): 1031-1034.
Szyroczynskl, G.A. and S.H. Wal1szewsk1. 1981a. Comparison of the content
of chlorinated pesticide residues 1n human semen, testicles and fat tissues.
Andrologla. 13(3): 250-252. (Cited In U.S. EPA. 1985a)
Szymczynskl, G.A. and S.H. Uallszewskl. 1981b. Content of chlorinated
pesticides In human semen of a random population. Int. J. Andrology. 4(6):
674-699. (Cited In U.S. EPA, 1985a)
0825p 10-43 10/28/86
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Takeda, T. 1978. Effects of DOT, BHC and PCB on the growth of fish.
Kyushu Daigaku Nogakubu Gakugel Zasshi. 32(4): 141-145. (Jap.) [CA
91(5):33793t]
Tanabe, S., T. Mori and R. Tatsukawa. 1983. Global pollution of marine
mammals by PCBs, ODTs and HCHs (BHCs). Chemosphere. 12: 1269-1275.
Tanabe, S., H. Tanaka and R. Tatsukawa. 1984. Polychloroblphenyls, z DDT
and hexachlorocyclohexane Isomers In the western North Pacific ecosystem.
Arch. Environ. Contam. Toxlcol. 13(6): 731-738.
Tanaka, K., N. Kurlhara and H. NakaJIma. 1979. Oxldatlve metabolism of
llndane and Its Isomers with mlcrosomes from rat liver and house fly
abdomen. Pestle. Blochem. Physlol. 10(1): 96-103. (Cited In U.S. EPA,
1980a, 1985a).
Tarzwell, C.M. 1959. The toxldty of some organic Insecticides to fishes.
in: Proc. 12th Ann. Conf. Southeast Assoc. Game Fish Comrn. p. 233-239.
(Cited 1n U.S. EPA, 1971)
Thorpe, E. and A.I.T. Walker. 1973. Toxicology of dleldrln (HEOO). II.
Comparative long-term oral toxlclty studies In mice with dleldrln, DDT,
phenobarbHone, 8-HCH and Y-BHC. Food Cosmet. Toxlcol. 11(3): 433-442.
Tooby, T.E. and F.J. Durbln. 1975. Llndane residue accumulation and elimi-
nation In rainbow trout (Salmo galrdnerll) and roach (Rutllus rutHus).
Environ. Pollut. 8(2): 79-89.
0825p 10-44 10/28/86
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Tooby, I.E., P.A. Hursey and J.S. Alabaster. 1975. Acute toxIcHy of 102
pesticides and miscellaneous substances to fish. Chem. Ind. (London). 12:
523-526.
Tsui, P.T.P. and P.J. McCart. 1981. Chlorinated hydrocarbon residues and
heavy metals In several fish species from the Cold Lake area In Alberta,
Canada. Int. J. Environ. Anal. Chem. 10: 277.
Tu, C.M. 1976. Utilization and degradation of llndane by soil microorgan-
isms. Arch. Mlcroblol. 108: 259-263.
Turner, J.C. and V. Shanks. 1980. Absorption of some organochlorlne
compounds by the rat small Intestine -- jji vivo. Bull. Environ. Contam.
Toxlcol. 24(5): 652-655.
Tzoneva-Maneva, M.T., F. Kalolanova and V. Georgleva. 1971. Influence of
dlazlnon and llndane on the mltotlc activity and the caryotype of human
lymphocytes, cultivated In vitro. I_n: Proc. XII Internal. Cong. Soc. Blood
Transfusions. Moscow, 1969, Blbl. Haemat. No. 38, part 1. Basel Karger.
p. 344-347. (Cited 1n IARC, 1979)
U.S. EPA. 1972. Hater Quality Criteria 1972. A report of the committee In
water quality criteria. Washington. DC. NTIS PB-236-199.
U.S. EPA. 1973. Unpublished report. BHC-Hndane. Criteria and Evaluation
Division, Office of Pesticide Programs, Washington, DC. 280 p. (Cited In
U.S. EPA, 1985a)
0825p 10-45 10/28/86
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U.S. EPA. 1976. Quality Criteria for Water. Washington, DC. EPA
440/9-76-023. NTIS PB-263-943.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. Office of Pesticides and Toxic Substances, CIO, Wash-
ington, DC.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Hexachloro-
cyclohexane. Criteria and Standards Division, Washington DC. NTIS
PB 297-924/3.
U.S. EPA. 1980b. Ambient Water Quality Criteria Document for Hexachlpro-
cyclohexane. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Water Regulations and Standards, Washington, DC. EPA 440/5-80-054. NTIS
PB 81-117657.
U.S. EPA. 1981. TreatabllHy Manual Vol. 1. TreatabllHy data. Office of
Research and Development, Washington, DC.
U.S. EPA. 1982a. Health Effects Assessment for B-Hexachlorocyclohexane.
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. TR-82-524.
0825p 10-46 03/18/88
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U.S. EPA. 1982b. Health and Environmental Effects Profile for Llndane.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid
Waste, Washington, DC. TR-82-664.
U.S. EPA. 1984a. Health Effects Assessment for Llndane. 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. NTIS PB86-134673/AS.
U.S. EPA. 1984b. Summary Table of Hazard Ranking for Reportable Quantities
under CERCLA. OHEA-C-073.
U.S. EPA. 1985a. Drinking Water Criteria Document for Llndane. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. (Final draft)
U.S. EPA. 1985b. 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. Integrated Risk Information System (IRIS). Reference
Dose (RfD) for Oral Exposure for Llndane. Online (Verification date
01/22/86). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
0825p 10-47 03/18/88
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U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
Velth, G.D., D.L. OeFoe and B.V. Bergstedt. 1979. Measuring and estimating
the bloconcentratlon factor of chemicals In fish. J. Fish. Res. Board Can.
36(9): 1040-1048.
Velson, F.P.J. and O.F. Alderdlce. 1967. ToxkHles of two Insecticides to
young coho salmon. J. Fish. Res. Board Can. 24: 1173-1175.
Vonk, J.W. and J.K. Qulrljns. 1979. Anaerobic formation of alpha-hexa-
chlorocyclohexane from gamma-hexachlorocyclohexane In soil and by Esche-
rlchla coll. Pestle. Blochem. Physlol. 12(1): 68-74.
Wassermann, M., M. Rorv, B. Bercov1c1, 0. Wassermann, S. Cucos and A. Pines.
1982. Premature delivery and organochlorlne compounds: Polychlorlnated
blphenyls and some organochlorlne Insecticides. Environ. Res. 28(1):
106-112.
Welsse, I. and M. Herbst. 1977. CarclnogenlcHy study of llndane In the
mouse. Toxicology. 7: 233-238.
Welch, R.M. and J.W.A. Ftndlay. 1981. Excretion of drugs In human breast
milk. Drug Metab. Rev. 12(2): 261-278.
Wellborn, T.L.J. 1971. ToxkUy of some compounds to striped bass flnger-
Ungs. Prog. FIsh-CultuMst. 33(1): 32-36.
0825p 10-48 03/18/88
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WhHten, O.K. and C.J. Goodnight. 1966. ToxIcHy of some common Insecti-
cides to tublflcldS. J. Water Pollut. Control Fed. 38: 227-235.
WHO (World Heath Organization). 1967. 1966 Evaluations of some pesticide
residues 1n food. WHO/Food Add.767/32. p. 126-147. (Cited In IARC, 1979)
WHO (World Heath Organization). 1969. 1968 Evaluations of some pesticide
residues In food. WHO/Food Add./69.35. p. 17-31. (Cited In IARC, 1979)
Williams, D.T., E.R. Nestmann, G.L. Lebe, F.M. Bevolt and R. Olson. 1982.
Determination of mutagenlc potential and organic contaminants of Great Lakes
drinking water. Chemosphere. 11: 263-276.
Wilson, A.J. 1965. Chemical assays. lt±: Ann. Rep. Bureau of Comm. F1sh.
Blolog. Lab., Gulfbreeze, FL. U.S. Bur. Comm. Fish. C1rc-. 247. (CHed In
Plmental, 1971)
Wlndholz, M., Ed. 1983. Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 789.
Yamamoto, T., T. Egashlra, Y. Yamanaka, T. Yoshlda and Y. Kurolwa. 1983.
Initial metabolism of gamma-hexachlorocyclohexane (f-HCH) by rat Hver
mlcrosomes. J. Pharmacoblo-Dyn. 6(10): 721-728.
Yamato, Y., M. Koyanaga and T. Watanabe. 1983. Comparative bloaccumulatlon
and elimination of BHC Isomers In short-necked clam Venerupls japonlca and
guppy Poedlla retlculata. Bull. Environ. Contain. Toxlcol. 31(3): 352-359.
0825p 10-49 03/18/88
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Zarooglan, G.E., J.F. Heltsch and M. Johnson. 1985. Estimation of blocon-
centratlon In marine species using structure-activity models. Environ.
Toxlcol. Chem. 4(1): 3-12.
Zesch, A., K. NHzsche and M. Lange. 1982. Demonstration of the percutane-
ous resorptlon of a UpophlUc pesticide and Us possible storage In the
human body. Arch. Dermatol. Res. 273: 43-49. (Cited 1n U.S. EPA, 1985a)
Zoeteman, B.C.J., K. Harmsen, J.8.H.J. Unders, C.F.H. Morra and W. Sloof.
1980. Persistent organic pollutants In river water and groundwater on the
Netherlands. Chemosphere. 9: 231-249.
0825p 10-50 03/18/88
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APPENDIX
LITERATURE SEARCHED
This profile 1s based on data Identified by computerized literature
searches of the following:
CASR online (U.S. EPA Chemical Activities Status Report)
CAS online STN International
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In October, 1985. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 6 and 7), and the
following secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1980. Documentation of the Threshold Limit Values, 4th ed. . (In-
cludes Supplemental Documentation, 1981, 1982, 1983). Cincinnati,
OH. 486 p.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985. TLVs: Threshold Limit Values for Chemical Substances and
Physical Agents In the Workroom Environment with Intended Changes
for 1985-1986. 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.
0826p A-l 06/10/86
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Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 13817-5112.
Grayson, M. and D. Eckroth, Ed. 1978-1983. K1rk-0thmer 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. WHO, IARC, Lyons. France.
ITII (International Technical Information Institute). 1982. Toxic
and Hazardous Industrial Chemicals Safety Manual for Handling and
Disposal with Toxldty and Hazard Data. ITII, Tokyo, Japan. 700 p.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, P.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co.. NY.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials, 5th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1984. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1985. Status Report on Rebuttable Presumption Against
Registration (RPAR) or Special Review Process. Registration Stan-
dards and the Data Call In Programs. Office of Pesticide Programs,
Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington. DC.
USITC (U.S. International Trade Commission). 1983. Synthetic
Organic Chemicals. U.S. Production and Sales. 1982. USITC Publ.
1422, 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.
0826p A-2 06/10/86
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In addition, approximately 30 compendia of aquatic toxlclty 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 M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, 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.
0826p A-3 06/10/86
U.S. Environmental Protection
Region 5. library (PL- 1?J)
7 / West Jackson Boulevard, \2U\ Flow
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