HEPTACHLOR
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERIA DOCUMENT
HEPTACHLOR
CRITERIA
Aquatic Life
For heptachlor the criterion to protect freshwater
aquatic life as derived using the Guidelines is 0.0015 /ig/1
as a 24-hour average and the concentration should not exceed
0.45 ^ig/1 at any time.
For heptachlor the criterion to protect saltwater
aquatic life as derived using the Guidelines is 0.0036 ^g/1
as a 24-hour average and the concentration should not exceed
0.05 ^g/1 at any time.
Human Health
For the maximum protection of human health from the
potential carcinogenic effects of exposure to heptachlor
through ingestion of water and contaminated aquatic organ-
isms, the ambient water concentration is zero. Concentra-
tions of heptachlor estimated to result in additional life-
time cancer risks ranging from no additional risk to an addi-
tional risk of 1 in 100 thousand are presented in the Criter-
ion Formulation section of this document. The Agency is con-
sidering setting criteria at an interim target risk level in
the range of 10"^, 10"^, or 10"^ with corresponding criteria
of 0.23 ng/1, 0.023 ng/1, and 0.0023 ng/1, respectively.
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HEPTACHLOR
Introduction
Heptachlor is a broad spectrum insecticide of the group
of polycyclic chlorinated hydrocarbons called cyclodiene in-
secticides. It was introduced in 1948 as a contact insecti-
cide under the trade names E 3314 and Velsicol 104. During
the period 1971 to 1975 the most important use of heptachlor
was to control soil insects for corn cultivation and other
crop production. Since 1975 both the applications and pro-
duction volume of heptachlor have undergone dramatic changes
as a result of the sole producer's voluntary restriction of
demestic use and the subsequent issuance by the Environmental
Protection Agency of a registration suspension notice for all
food crops and home use of heptachlor, effective August 2,
1976. However, significant commercial use of heptachlor for
termite control or non-food plants continues and numerous
formulation plants and packaging facilities have remained in
operation.
Pure heptachlor is a white crystalline solid with a
camphor-like odor having the molecular formula CigHsCly, a
molecular weight of 373.35, and a vapor pressure of 3 x 10"^
mm Hg at 25 degrees C (Metcalf, 1955; Windholz, 1976). It
has a solubility in water of 0.056 mg/1 at 25 to 29 degrees C
and is readily soluble in relatively non-polar solvents
(Metcalf, 1955). The chemical name for heptachlor is 1, 4,
5, 6, 7, 8, 8-heptachloro-3a, 4, 7, 7a-tetrahydro-4, 7-metha-
noindene. It is produced by means of a Diels-Alder addition
reaction which joins cyclopentadiene to hexachlorocyclopenta-
diene (Windholz, 1976).
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Technical grade heptachlor has the typical composition
of approximately 73 percent heptachlor, 21 percent trans-
(gamma) chlordane, 5 percent heptachlor, and 1 percent chlor-
dene isomers (Anonymous, 1974). Technical heptachlor is a
tan, soft, waxy solid with a melting point range of 46 to 74
degrees C. It has a vapor pressure of 4 x 10~4 mm Hg at 25
degrees C and a density of 1.65 to 1.67 g/ml at 25 degrees C.
In general, heptachlor is quite stable to chemical reac-
tions such as dehydrochlorination, autooxidation, and thermal
decomposition. However, in the environment, heptachlor under-
goes numerous microbial, biochemical, and photochemical reac-
tions .
Conversion of heptachlor to heptachlor epoxide has been
reported in microorganisms (Miles, et al. 1969), in plants
(Gannon and Decker, 1958), in soils (Lichtenstein, 1960;
Lichtenstein, et al. 1970, 1971; Nash and Harris, 1972) and
in mammals (Davidow and Radomski, 1953a; Radomski and
Davidow, 1953) and represents the principal metabolite of
heptachlor. Although it has been reported that heptachlor
epoxide is less toxic in several invertebrate species than
heptachlor (von Halacka and Polster, 1971), numerous other
studies have demonstrated that the epoxide form is of equal
toxicity (Schimmel, et al. 1976a) or greater toxicity
(Georgacakis and Khan, 1971) than the parent compound in
invertebrates, and two to ten times more toxic in mammals
(Radomski and Davidow, 1953; Buck, et al. 1959).
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The photodecomposition of heptachlor to photoheptachlor
has been demonstrated in various solvent solutions using
ultraviolet lamps, and as thin films using natural sunlight
(Benson, et al. 1971). Although numerous photoisomers are
produced, photoheptachlor (III) appears to predominate.
Numerous investigations have demonstrated that photohepta-
chlor is two to five times more toxic than the parent com-
pound to insects (Khan, et al. 1969) and aquatic vertebrates
(Georgacakis and Khan, 1971; Khan, et al. 1973). Heptachlor
epoxide has also been shown to undergo photodecomposition to
photoheptachlor epoxide (IIIB) when exposed to UV light or
sunlight (Graham, et al. 1973) and has been reported to ex-
hibit greater toxicity than the epoxice (Ivie, et al. 1972).
Heptachlor can also be biologically converted to chlor-
dene, 3-chlorochlordene, 1-hydroxychlordene, chlordene epox-
ide, l-hydroxy-2, 3-epoxychlordene, and 2-chlorochlordene.
However, these metabolites have been shown to be considerably
less toxic to rats than heptachlor (Mastri, et al. 1969a,b) .
Heptachlor was tentatively identified at levels greater
than 0.002 jug/1 in 15 of 96 river water samples tested by
Weaver, et al. (1965). Heptachlor and/or heptachlor epoxide
have been reported present in plankton-algae and aquatic
insects (Hannon, et al. 1970), crayfish, crabs, shellfish and
fish (Albright, et al. 1975; Casper, et al. 1969; Smith and
Cole, 1970; Hannon, et al. 1970).
Heptachlor and heptachlor epoxide will bioconcentrate in
numerous species and will accumulate in the food chain.
Heptachlor/heptachlor epoxide bioconcentration factors as
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high as 17,600 in the oyster, Crassostrea virginica (Stickel,
1968; Schimmel, et al. 1967a), have been reported.
Heptachlor epoxide is readily stored in the adipose tis-
sue of rats and dogs but may also be found in liver, brain,
and other tissues. It has been found in human milk samples
and has also been detected in fetal blood and placenta.
The persistence of heptachlor and heptachlor epoxide in
the environment is well known. Heptachlor also has been
shown to be converted to the more toxic metabolite, hepta-
chlor epoxide, in various soils (Gannon and Bigger, 1958;
Lichtenstein, 1960; Lichtenstein, et al. 1971; Nash and
Harris, 1972) and plants (Gannon and Decker, 1958).
Heptachlor has been demonstrated to be highly toxic to
aquatic life, to persist for prolonged periods in the envi-
ronment, to bioconcentrate in organisms at various trophic
levels, and to exhibit carcinogenic activity in mice.
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REFERENCES
Albright, L.J., et al. 1975. Chlorinated hydrocarbon resi-
dues in fish, crabs, and shellfish of the Lower Fraser River,
its estuary and selected locations in Georgia Strait, British
Columbia. 1972-1973. Pestic. Monitor. Jour. 9: 134.
Anonymous. 1974. Chlorinated insecticides. CRC Press,
Cleveland, Ohio.
Benson, W.R., et al. 1971. Photolysis of solid and dis-
solved dieldrin. Jour. Agric. Food Chem. 19: 66.
Buck, W.B., et al. 1959. Oral toxicity studies with hepta-
chlor and heptachlor epoxide in young calves. Jour. Econ.
Entomol. 52: 1127.
Casper, V.L., et al. 1969. Study of chlorinated pesticides
in oysters and estuarine environment of the Mobile Bay area.
Gulf Coast Mar. Health Sci. Lab., Ala. Water Improvement
Coming. Ala. State Dep. Publ. Health and Ala. Dep. Conserv.
Unpubl. rep.
Curley, A., and R. Kimbrough. 1969. Chlorinated hydrocarbon
insecticides in plasma and milk of pregnant and lactating
women. Arch. Environ. Health 18: 156.
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Davidow, B., and J.L. Radomski. 1953a. Isolation of an
epoxide metabolite from fat tissues of dogs fed heptachlor.
Jour. Pharmacol. Exp. Ther. 107: 259.
Davidow, B., and J.L. Radomski. 1953b. The metabolite of
heptachlor, its estimation, storage, and toxicity. Jour.
Pharmacol. Exp. Ther. 107: 266.
Gannon, N., and J.H. Bigger. 1958. The conversion of aldrin
and heptachlor to their epoxides in soil. Jour. Econ. Ento-
mol. 51: 1.
Gannon, N., and G.C. Decker. 1958. The conversion of aldrin
to dieldrin on plants. Jour. Econ. Entomol. 51: 8.
Georgackakis, E., and M.A.Q. Khan. 1971. Toxicity of the
photoisomers of cyclodiene insecticides to freshwater ani-
mals. Nature 233: 120.
Graham, R.E., et al. 1973. Photochemical decomposition of
heptachlor epoxide. Jour. Agric. Food Chem. 21: 284.
Hannon, M.R., et al. 1970. Ecological distribution of
pesticides in Lake Poinsett. S. Dak. Trans. Am. Fish Soc.
99: 496.
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Ivie, G.W., et al. 1972. Novel photoproducts of heptachlor
epoxide, trans-chlordane, and trans-nonachlor. Bull. Envi-
ron. Contam. Toxicol. 7: 376.
Khan, M.H., et al. 1969. Insect metabolism of photoaldrin
and photodieldrin. Science 164: 318.
Khan, M.A.Q., et al. 1973. Toxicity-metabolism relationship
of the photoisomers of certain chlorinated cyclodien insecti-
cide chemicals. Arch. Environ. Contam. Toxicol. 1: 159.
Kutz, F.W., et al. 1977. Survey of pesticide residues and
their metabolites in humans. Iri pesticide management and
insecticide resistance. Academic Press, New York.
Lichtenstein, E.P. 1960. Insecticidal residues in various
crops grown in soils treated with abnormal rates of aldrin
and heptachlor. Agric. Food Chem. 8: 448.
Lichtenstein, E.P., et al. 1970. Degradation of aldrin and
heptachlor in field soils. Agric. Food Chem. 18: 100.
Lichtenstein, E.P., et al. 1971. Effects of a cover crop
versus soil cultivation on the fate of vertical distribution
of insecticide residues in soil 7 to 11 years after soil
treatment. Pestic. Monitor. Jour. 5: 218.
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Mastri, C., et al. 1969a. Acute oral toxicity study on four
chlordanes in albino rats. Industrial Bio-Test Lab. Sub-
mitted by Velsicol Chem. Corp. IBT No. A7367, June 23.
Unpubl. rep.
Mastri, C., et al. 1969b. Acute oral toxicity study on two
chlordanes in female albino rats. Industrial Bio-Test Lab.
Submitted by Velsicol Chem. Corp. IBT No. A7518, August 21.
Unpubl. rep.
Metcalf, R.L. 1955. Organic insecticides. Interscience
Publishers, John Wiley and Sons, Inc., New York.
Miles, J.R.W., et al. 1969. Metabolism of heptachlor and
its degradation products by soil microorganisms. Jour. Econ.
Entomol. 62: 1334.
Mash, R.G., and W.G. Harris. 1972. Chlorinated hydrocarbon
insecticide residues in crops and soil. Jour. Environ. Oual.
Radomski, J.L., and B. Davidow. 1953. The metabolism of
heptachlor, its estimation, storage, and toxicity. Jour.
Pharmacol. Exp. Ther. 107: 266.
Schimmel, S.C., et al. 1976a. Heptachlor: toxicity to and
uptake by several estuarine organisms. Jour. Toxicol. Envi-
ron. Health 1: 955.
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Smith, R.M., and C.F. Cole. 1970. Chlorinated hydrocarbon
insecticide residues in winter flounder Pseudopliuronetes
amerecances, from Weveantic River Estuary. Mass. Jour. Fish
Res. Board Can. 27: 2374.
Stickel, L.F. 1968. Organochlorine pesticides in the envi-
ronment: Bur. Sports Wildl. Spec. Sci Rep. Wilddl. No. 19.
U.S. Dep. Inter., Washington, D.C.
von Halacka, K., and M. Polster. 1971. Alimentary toxicity
of heptachlor. Port. Vitae 16: 17.
Weaver, L., et al. 1965. Chlorinated hydrocarbon pesticides
in major U.S. river basins. Publ. Health Rep. 80: 481.
Weber, J.B. 1972. Interaction of organic pesticides with
particulate matter in aquatic and soil system. Adv. Chem.
Ser. Ill: 55.
Windholz, M., ed. 1976. The Merck Index. Merck and Co.,
Inc., Rahway, N.J.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Heptachlor has been widely used for such purposes as fire ant
and qeneral insect control in much of the United States. Numerous
studies on the acute toxicity of heptachlor to freshwater fish and
invertebrate species have been conducted (Tables 1, 2, and 5).
Most of these studies were carried out under static conditions
with exposure levels based on unmeasured rather than measured con-
centrations. In most instances tests used technical-grade hepta-
chlor as the toxicant. Technical-grade heptachlor usually con-
sists of 72 percent heptachlor and 28 percent impurities. These
impurities are primarily gamma chlordane and nonachlor. There are
insufficient data to evaluate the relative toxicities of the
various grades of heptachlor and the impact of the impurities on
the toxicity determinations. Because of the unknown contribution
of the impurities, all data included in this document are reported
in concentrations of the actual material used for testing. Some
authors used technical material in testing and then calculated
*The reader is referred to the Guidelines for Deriving Water Qual-
ity Criteria for the Protection of Aquatic Life [43 FR 21506 (May
18, 1978) and 43 FR 29028 (July 5, 1978)] and the Methodology
Document in order to better understand the following discussion
and recommendation. The following tables contain the appropriate
data that were found in the literature, and at the bottom of each
table are the calculations for deriving various measures of toxi-
city as described in the Guidelines.
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calculated concentrations as 100 percent heptachlor for data
reporting. These data were converted back to concentrations of
technical-grade heptachlor in this document.
Some studies have been reported on the impact of water
hardness and temperature to acute toxicity (Henderson et al.
1959, 1960; Bridges, 1965; Macek,et al. 1969; Naqvi, 1973). In
general, water hardness and temperature may have had some effect
(see Acute Toxicity).
Heptachlor epoxide is the most commonly found degradation
product of heptachlor. Both heptachlor and its epoxide have been
reported in fish residues (Andrews^et al.. 1966; Macek^et al.
1976). There are few data on the relative toxicity to freshwater
organisms of these two materials. What is available suggests that
the epoxide is not more toxic than heptachlor itself (Frear and
Boyd, 1967) . Because of the common occurrence of both materials
and the inadequacy of the relative toxicity information, criteria
should be based on the total concentration of heptachlor and its
epoxide.
Acute Toxicity
In all but one case (Macek^et al. 1976) (Table 5), data on
acute toxicity were obtained in static tests. In every case
exposure concentrations were unmeasured. Values for standard
tests with fish and invertebrate species are reported in Tables 1
and 2. Some additional acute mortality data are found in Table 5.
Eight fish and ten invertebrate species have been tested.
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In general, fish were less sensitive to heptachlor than were
invertebrate species. Adjusted LC50 values for fish ranged from
3.8 yg/1 for a 96-hour exposure with the rainbow trout to 175 yg/1
for a 96-hour exposure with the qoldfish (Table 1). Adjusted LC50
values for invertebrate species ranqed from 0.8 va/1 for a 96-hour
exposure with the stonefly, Pteronarcella badia, to 68 yg/1 for a
48-hour exposure with the cladoceran, Sinocephalus serrulatis
(Table 2). Larvae of the Fowler's toad were tested by Sanders
(1970) (Table 5); the 96-hour LC50 was 440 ug/1.
Many authors, cited in Tables 1 and 2, reported values for
numerous other pesticides in addition to heptachlor. No clear
relationship regarding the toxicity of heptaclor compared to other
pesticides was found. For example, Sanders (1972) found that with
the scud, Gammarus fasciatus, heptachlor was substantially less
toxic than DDT and endrin. For the freshwater glass shrimp,
however/ there was little difference on toxicity of the three
pesticides. For the stonefly, Pteronarcys californica, heptachlor
was less toxic than endrin and more toxic than DDT (Sanders and
Cope, 1968). Katz (1961) found with Chinook salmon, Oncorhynchus
tshawvtscha, and coho salmon, Oncorhynchus kisutch, DDT and endrin
were more toxic than heptachlor while with rainbow trout hepta-
chlor was more toxic than DDT. It is difficult to determine how
much of the variations in results are due to differences in
species sensitivity and how much to test variability. However, it
seems probable that species sensitivity varies considerably with
different pesticides. It is also apparent from Tables 1 and 2
that heptachlor is generally highly toxic in an acute exposure.
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Macekjet al. (1976) reported an incipient LC50 of 7.0 ug/1
for the fathead minnow. This incipient LC50 was derived with
flow-throuqh testing procedures by determining when no additional
significant mortality (less than 10 percent) was observed at any
concentration during a 48-hour period. A linear regression
equation was calculated by converting test concentrations and
corresponding mortalities into logarithms and probits, respec-
tively. This equation was then used to determine the incipient
LC50. Due to analytical difficulties, however, actual concentra-
tion determinations were not made, but rather were based on
nominal values.
Water hardness was found to have a possible slight effect on
the toxicity of heptachlor (Henderson, et al.. 1959). The adjusted
96-hour LC50 values for fathead minnows exposed to technical-grade
heptachlor in soft and hard water were 71 ug/1 and 43 ug/1,
respectively.
Bridges (1965) found that toxicity to redear sunfish
increased at higher temperatures (Table 1). Unadjusted 24-hour
EC50 values decreased (toxicity increased) from 92 ug/1 at 45° F
to 22 ug/1 at 85° F. Macek,et al. (1969) found an increase in
toxicity to rainbow trout when tested at .7.2 and 12.7° C as
compared to the toxicity at 1.6° C (Table 1). Naqvi (1973) found
100 percent mortality of tubificid worms, Branchiura sowerbyi, at
2,500 ug/1 when tested at 4.4 and 32.2° C (Table 5). At 21.0° C
no mortality occurred. Sanders and Cope (1966) found that with
the cladoceran, Simoceohalus serrulatus, the unadjusted 48-hour
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EC50 values for heptachlor were 47 yg/1 at 60° F and 80 ug/1 at
70° F (Table 2) .
Only one acceptable study was found that compared the
relative toxicity of heptachlor to its common degradation product
heptachlor epoxide. Frear and Boyd (1967), using an unspecified
grade material, determined the 26-hour LC50 for Daphnia magna to
be 50 ug/1 for heptachlor and 120 ug/1 for heptachlor epoxide
(Table 5). There are insufficient data, therefore, to support the
hypothesis that the epoxide degradation product is more toxic to
aauatic life than the parent compound.
Many authors reported LC50 values for fish after 24, 48, and
96 hours of exposure to heptachlor. In general, toxicity
increased slightly with time. However, considerable species
variation existed. The ratios of 96-hour/24-hour and
96-hour/48-hour LC50 values ranged from 0.45 to 0.97 and 0.57 to
1.00, respectively. The geometric means of the ratios grouped by
species were 0.62 for 96-hour/24-hour LC50 values and 0.78 for
96-hour/48-hour LC50 values. Considering the limited number of
data points, these values are very close to the recommended
Guideline values for adjustment of.data to equivalent 96-hour
values (0.66 and 0.81 for adjustment of 24- and 48-hour LC50
values, respectively). Guideline values were used where
necessary.
The relationship of exposure time to LC50 values was more
dramatic and variable for invertebrate species. The range of
values for the ratio of 96-hour/24-hour LC50 values was 0.06 to
0.56. Exposure time, therefore, can significantly affect LC50
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values for invertebrate species exposed to heptachlor. The
geometric mean of the ratios was 0.20. Considering the wide
variation in values, coupled with the limited data points, the
Guideline value of 0.26 was used in the one instance where an
adjustment factor for exposure period was necessary.
The absence of flow-through tests with measured exposure
concentrations is primarily a function of the state-of-the-art of
aquatic toxicology at the time when the majority of testing
occurred. Improved test procedures would probably give a better
picture of the acute toxicity of heptachlor.
The Final Fish and Invertebrate Acute Values were derived
using values listed in Tables 1 and 2. Results from the litera-
ture were adjusted using Guideline procedures to be equivalent to
96-hour, flow-through toxicant-measured LC50 values. The final
acute values were calculated according to Guideline procedures and
were found to be 7.5 ug/1 for fish and 0.45 ug/1 for inverte-
brate species. Therefore, the Final Acute Value is 0.45 ug/1.
Chronic Toxicity
The only available chronic study was that of Macek,et al.
(1976) with heptachlor and the fathead minnow (Table 3). This
life-cycle test lasted 40 weeks during which growth, survival, and
reproduction were monitored. Concentrations tested were 1.84,
0.86, 0.43, 0.20, 0.11, and 0.0 ug/1. All fish exposed to 1.84
ug/1 were dead after 60 days. No adverse effects on parental fish
or their offspring were noted at concentrations of 0.86 ug/1 or
lower. The maximum acceptable heptachlor concentration for
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fathead minnows was estimated to be between 0.86 and 1.84 ug/1.
No valid chronic test data were available for any inverte-
brate species. However, in general, invertebrate acute values
were considerably lower than fish acute values. In fact, some
invertebrate LC50 values were lower than the fathead minnow
chronic value. It is reasonable to expect, therefore, that some
invertebrate chronic values would be lower than the available fish
chronic value.
Data on the acute toxicity of heptachlor to fathead minnows
indicate that this species is somewhat less sensitive than other
fish species in general. Chronic tests with more sensitive
species might have resulted in lower chronic effect levels.
However, because there are no fathead minnow acute tests with
measured exposure concentrations, no application factors can be
calculated, and a quantitative relationship between acute and
chronic values cannot be determined. It is difficult, therefore,
to speculate on how the chronic value might be adjusted to take
into account that more sensitive species other than by the
recommended Guideline sensitivity factors. The Final Fish Chronic
Value for heptachlor is 0.19 ug/1.
Plant Values
No studies using aquatic plants are available.
Residues
As part of the fathead minnow chronic study of Macek,et al.
(1976), fish residue levels were determined. Residues in the
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eviscerated carcasses of fish after 276 days of exposure were
measured at each exposure concentration. Residues of heptachlor
and heptachlor epoxide were combined. Heptachlor epoxide residues
were reported as generally constituting 10 to 24 percent of the
total residue. The amount of total residue accumulated was found
to be approximately 20,000 times the concentration in the water.
The residue was proportional to the level of exposure and
reasonably linear over the range of concentrations tested.
It should be noted that no adverse effects were found with
the fish which were used to determine accumulation in the above
study. Fish at the high concentration (1.84 ua/1) were all dead
after 60 days of exposure, and residue levels were not determined
in these fish. Residues in fish at the next highest concentration
(0.86 ug/1) were approximately 18 mg/kg with no measured
detriment.
Current U.S. Food and Drug Administration guidelines limit
the concentration of heptachlor in food for human consumption to
0.3 mg/kg and for domestic animals, 0.0 3 mg/kg. Only one measure
of the equilibrium bioconcentration of heptachlor has been
reported (Macek/et al. 1976) . Based on the data from this one
study, in order to prevent fish from exceeding FDA guidelines, a
heptachlor concentration of 0.0015 ug/1 should not be exceeded.
The Residue Limited Toxicant Concentration (RLTC) is, therefore,
0.0015 ug/1 (Table 4). The RLTC is the lowest value found for
heptachlor exposures to aquatic life. The Final Chronic Value is,
therefore, 0.0015 ug/1.
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Miscellaneous
Andrews; et al. (1966) studied the impact of a single applica-
tion of technical-grade heptachlor in several earthen ponds (Table
5). Initial concentrations as technical-grade heptachlor (rather
than percent active ingredient as was done by the authors) in the
test ponds ranged from 17.4 to 69.4 pg/1. Residue levels measured
in stocked bluegills were not proportional to dosage. Time to
peak residue levels depended on concentration with the lower
concentrations peaking within 24 hours. Residue concentrations at
all test levels decreased to below detectable limits by the end of
8 4 days. Although the data were not usable for calculating
bioconcentration values in this document, maximum bioconcentration
factors, based on peak residue levels for total heptachlor,
heptachlor epoxide, and related compounds compared to initial dose
concentrations in pg/1 technical-grade heptachlor, ranged from 638
to 1,326. The highest level was at one of the intermediate level
ponds.
In an additional study by Andrews^et al. (1966), bluegills in
plastic pools were fed food containing heptachlor at either 25.0,
10.0, 5.0, or 0.0 mg/kg/day (Table 5). Tests were run in dupli-
cate. Variable residue values were obtained that were not
strictly dose-related. Although dosing through the diet was
continuous, uptake rates peaked at the different exposure levels
at various times, and in some cases secondary peak levels
occurred. There was only one pool at 10 mg/kg/day in which
residues were detected after 84 days. Apparently the fish reached
a stage where removal rates exceeded uptake rates.
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In vitro measurements of the effect of heptachlor on bio-
chemical activity have also been reported by several authors
(Table 5). The value of these data for criteria derivation is
limited, however, since no environmental dose relationships were
tested or derived.
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CRITERION FORMULATION
Freshwater - Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = 7.5 pg/1
Final Invertebrate Acute Value = 0.45 pg/1
Final Acute Value = 0.45 pg/1
Final Fish Chronic Value = 0.19 pg/1
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = 0.0015 pq/1
Final Chronic Value = 0.0015 pg/1
0.44 x Final Acute Value = 0.20 pg/1
The maximum concentration of heptachlor is the Final Acute
Value of 0.45 }ig/l, which is based on the more acutely sensitive
invertebrate organisms. Since 0.44 times the Final Acute Value
(0.44 x 0.45 pg/1 = 0.20 pg/1) is not lower than the Final Chronic
Value (0.0015 pg/1), the latter is the recommended 24-hour average
concentration.
CRITERION: For heptachlor the criterion to protect fresh-
water aquatic life as derived using the Guidelines is 0.0015 ^ig/1
as a 24-hour average and the concentration should not exceed 0.45
pg/1 at any time.
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Table 1. Freshwater fish acute values for heptachlor
or adl!12!S
Biiiibeay
Test Chemical
Cone/* Dcacniition
Time
llirs.t
DO
I
K)
Coho salmon, S
Oncorhynchus klautch
Chinook salmon, S
Oncorhynchus tshawytscha
Rainbow crout, S
Salroo salrdnerl
Rainbow crouc, S
Salmo galrdnerl
Rainbow trout, S
Salmo Ralrdnerl
Rainbow crout, S
Sal mo galrdnerl
Goldfish, S
Carasslus auracus
Fathead minnow, S
Plmephales promelas
Fathead minnow, S
Plmepha]es promelas
Guppy, S
Pnecllla reticulata
Bluegl11, S
Lepomls macrochlrus
Redear, S
Lepoinis mlcrolophus
Redear, S
Lepomls mlcrolophus
Redear, S
l.epomls mlcrolophus
Redear, S
l.eponil s mlcrolophus
U
U
U
U
U
U
U
U
Technical
Technical
Technical
Technical
Technical
Technical
Technical
Technical
Technical
Technical
Technlca1
Technical
Technical
Technical
Technical
grade**'* 96
grade*** 96
grade*** 96
grade 96
grade 96
grade 96
grade 96
grade 96
grade 96
grade 96
grade 96
grade 96
grade 24
grade 24
grade 24
LCbu
81.9
24.0
26.9
7.7
7.0
7.3
320
130
78
148
26
17
92
64
47
Adjusted
Lc'bU
dm/II hctfci. erice
44.8 KaCz, 1961
13.1 Katz, 1961
14.7 Katz. 1961
4.2 Macek, et al.
1969
3.8 Macek, et al.
1969
4.0 Macek, et al.
1969
175 Henderson,
ec al. 1959
71 Henderson,
et al. 1959
4 3 Henderson,
et al. 1959
81 Henderson,
et al. 1959
14 Henderson,
et al. 1959
9 Bridges, 1965
33 Bridges, 1965
23 Bridges, 1965
17 Bridges, 1965
-------
Table 1. (Continued)
ttioaaany Tost Clieoiicai Time
Or gam am Het.ltod* Cone .** Deticri it ion i nr a. 1
Redear, S II Technical grade 24
Lepomi s mlcrolophua
* S " static
** U <= unmeasured
***AuLhor converted from technical grade (72%) to 100% active Ingredient. For the purpose of this
criteria document. LC50 was converted back to technical grade.
29 4
Geometric mean of adjusted values - 29,4 pg/1 —ttt = 7-^ Mg/l
Adjusted
LOu LCt»l>
lu-i/1) juq/i> Keierfence
22 6 bridges, 1965
-------
Table 2. Freshwater invertebrate acute values
Oryjij^sm
Cladoccran,
Daphnla magna
Cladoccran,
Daphnla pulex
Cladoceran,
Simocephalus se
Bicusaay
Metnod*
S
S
S
atus
Cladoccran, S
Simocephalus serrulatus
Scud, S
Canunarus faclatua
Scud, S
Canunarus faclacua
Scud, S
_ Canunarus lacustrla
03
H> Crayfish, S
.u Orconectes nals
Freshwater glass shrimp, S
Palaeinonetes kadlakensia
Freshwater glass shrimp, S
Palaeinonetes kadlakensia
Stonefly, S
Claasscnla sabuloaa
Stonefly, S
Pteronarcella badla
Stonefly, S
Pteronarcys callfornlca
Test Chemical Time
Coiicx** Oescuption Ihrs
U 99% heptachlor 48
U Unspecified grade 48
U Unspecified grade 48
U Unspecified grade 48
U Technical grade 96
U Technical grade 96
U Technical grade 96
U Technical grade 96
U Technical grade 96
U Technical grade 24
U Technical grade 96
U Technical grade 96
U Technical grade 96
* S = static
** U = unmeasured
Geometric mean of adjusted values = 9.4 iig/1
^ = 0.45 Mg/1.
heptachlor
Adjusted
LCiu LC'jU
(iim/1 l
-------
Table 3. Freshwater fish chronic values for hepLachlor (Macek, eL al. 1976)
enconic
Limits Value
Ornani 010 Test* IU'i/1 > lug/1)
Fathead minnow, LC 0.86-1,84 1.26
Plmephales promelas
* LC " life cycle or partial life cycle
1 26
Ceometric mean of chronic values •» 1.26 ug/1 " 0-1' wg/1
Lowest chronic value «= 1.26 ng/1
CD
I
M
<_n
-------
Or uuniam
Table 4, Freshwater residues for heptuchlor
Bioconcentration Factoi
Time
(days)
k>: t e i cricfe
Fathead minnow,
Plmepliales promelas
20.000
276
Macek, et al. 1976
Maximum Permissible Tissue Concentration
Organ ism
Human
Domestic animals
Action Level or Effect
fish
animal feed
Concentration
(nK/kfl)
0.3
0,03
Reference
U.S. FDA Admin. Guideline
7420.08, 1973
U.S. FDA Adiuiu. Guideline
7426.OA. 1977
Residue Limited Toxicant Concentration «¦ yO^OOOT " 0.0000015 ing/kg or 0,0015 tig/1
-------
Table 5. Oilier freshwater data for heptachlor
03
I
Otgaiii sm
Rainbow trout,
Salino gal rdnerl
Rainbow crouc,
Salino galrdnerl
Aclandc salmon
(Juvenile),
SaImo aalar
Fathead minnow,
Pimcphales promelas
Mosqulcoflsh,
Gambusla afflnls
Test
Duration Et tect
Mosqulcoflsh,
Gambusla afflnls
B1uegi11,
Lepomls macrochlrus
BlueglI1,
Lepomls macrochlrus
Blueglll,
Lepomls macrochlrus
lilueglll,
l.epomls macrochlrus
Bluegll1,
l.epomis macrochlrus
15 mln
15 mln
24 hrs
10 days
48 hrs
36 hrs
677. inhibition
of NaK-ATPase
317. inhibition
of Mg-ATPase
Change In
temperature
selection
Incipient LC50
647. mortality
In cages
submerged In
ponds dosed
with
emulslflable
concentrate
LC50
171 days** Increased
nior tali ty
171 days** Dose-related
growth
decrease
Keeuit
Jlia^LL
37,350
3.735
No effect up to
25
0.5 lbs/acre
171 days* >907. mortality
171 days* Growth and
reproduction
171 days* Tissue
accumulation
No effect where
fish survived
Maximum accumu-
lation of 1326
x Initial dose
concentrat ion;
returned to
normal after
84 days
10 mg/kg/day
pet uifence
Davis, et al. 1972
Davls, et al. 1972
Peterson. 1976
7.0 Macek, et al. 1976
Mulla. 1963
70 Boyd & Ferguson, 1964
69.4 Andrews, et al. 1966
Andrews, cl al. 1966
Andrews, et al. 1966
Andrews, et al. 1966
5 to 25 mg/kg/day Andrews, ei al. 1966
-------
Table 5. (Continued)
orgdiu am
Blueglll,
Lepomla macrochtrus
Hluegill,
l.epomis macrochlrus
Blueglll,
Lepotnl a macrochlrus
Test
Duration
Et f. ect
171 days** Tissue
accumulation
25 rain
25 min
65-69°/.
inhibition of
NaK- and
Mg-ATPase
45-47X
Inhibition of
NaK- and
Mg-ATPase
Hesuit
Pet el KliCL-
Accumulaclon peaked Andrews, et a 1.
and subsequently
declined Co undetect-
able levels by day
112
1966
15,600
16,200
Cutkomp, et al. 1971
Blueglll, 96 hrs
Lepoials macrochlrua
Blueglll, 96 hrs
Lepomi s macrochlrus
blueglll. Unspecified
Lepomia macrochlrua
Blueglll, Unspecified
I.epoml s macroclii rus
Blueglll. Unspecified
I.epoml s ma croc hi rus
Blueglll, Unspecified
I.epoml s niacrochlrus
LC50 of
heptachlor as
emulsifiable
concentrate in
soft water
LC50 of
heptachlor as
emulslftable
concentrate in
hard water
87% inhibition of
Oj utilization by
initocliondr J a
29Z inhibition of
POi, utilization by
mitochondria
50% inhibition
of mitochondrial
Mg-ATPase
50% inhibition
of brain
NaK-ATPase
22 Henderson, et al. 1960
18 (lenderson, et al. 1960
370,000 Hlltibran, 1974
370,000 lliltibran, 1974
6,790 Yap, et al. 1975
16,434 Yap, et al. 1975
-------
Table 5. (Continued)
Test
Orqaru sm Duration
Bluegill, Unspecified
Lepomi9 macrochlrus
Fowler's toad 96 hrs
(larva),
Bufo woodhousll
fowlerl
Bullfrog (larva), 48 hrs
Rana catesbelana
Tublflcld worm, 72 hrs
Branchlura 6owerbyi
Tublflcld worm, 72 hrs
Branchlura sowerbyl
Tublflcld worm, 72 hrs
Branchiura sov;erby 1
Crayfish, Variable
Procambarus clarkll
Crayfish, Unspecified
Procambarus clarkll
t't t ect
507. Inhibition
of brain
NaK-ATPase
by heptachlor
epoxide
LC50
807. mortality
in cages
submerged in
ponds dosed
with
emulsiflable
concentrate
100% mortality
at 4.4°C
07. mortality
at 21.0''C
1007. mortality
at 32.2°C
Time to death
after consuming
contaminated
tublflcld worms;
worms placed In
clean water after
exposure were not
lethal
107. Inhibition
of brain
acetylcholinesterase
Aesuit
dm/1) Re(:ep:iicfc
8,179 Yap, et al. 1975
440 Sanders, 1970
5 lbs/acrc Mulla, 1963
2,500 Naqvi, 1973
2,500 Naqvi, 1973
2,500 Naqvi, 1973
2 hr Naqvi, 1973
933
Gullbault, et al. 1972
-------
Table 5, (Continued)
Organism
Numerous
miscellaneous
invertebrates
Cladoceran,
Daphnia magna
Cladoceron,
Daphnia mapna
Teet
G«™U.Sfl Effect
L71 days* 100% mortality
in 24 hra,
returned co
normal population
levels by day 14
26 hrs LC50 (heptachlor)
Result
JlliliU
R e t ti r ai ic fa
52.1 Andrews, et al. 1966
52
26 hrs LCSO (hcptachlor epoxide) 120
Frear £< Boyd, 1967
Frear & Boyd, 1967
* Tested in ponds, dosed on day 1 only. Authors dosed with technical-grade lieptachlor
and reported as vg/l active Ingredient. For the purposes of this document, values are
^ reported aa yg/l technical-grade lieptachlor.
o
** Tested In small pools. Technical-grade heptacfcilor was incorporated into fish food only
and fed for duration of test.
-------
SALTWATER ORGANISMS
Introduction
Heptachlor is a chlorinated hydrocarbon pesticide that has
had wide usage in the United States as a crop insecticide. It has
been shown to be toxic to aquatic life, to accumulate in plant and
animal tissues, and to persist in aquatic ecosystems.
Earlier studies reported toxicity of this material to fresh-
water organisms. More recently, pertinent studies have been
completed that demonstrate acute and chronic toxicity and bio-
accumulation potential to inhabitants of estuarine and marine
waters.
Acute Toxicity
Heptachlor has been shown to be acutely toxic to a number of
saltwater fish and invertebrate species. Many of the aquatic
toxicity tests with heptachlor have used technical-grade material,
containing approximately 72 percent heptachlor and a 22 to 28
percent mixture of trans-chlordane, cis-chlordane, nonachlor and
related compounds. Heptachlor epoxide is a common metabolite of
heptachlor. There are insufficient data to evaluate relative
toxicity of these components. However, the data available suggest
that toxicity of the technical material is attributable to the
heptachlor and heptachlor epoxide components and that toxicities
of heptachlor and heptachlor epoxide are similar (Schimmel^et al.
1976a).
The 96-hour LC50 values (Table 6) derived from flow-through
tests with four fish species range from 0.85 to 10.5 ug/1 (Hansen
B-21
-------
and Parrish, 1977; Korn and Earnest, 1974; Schimmel, et al.
1976a). Results of static exposures of eight fish species are
more variable and yield higher LC50 values than those from
flow-through tests, i.e., 0.8 to 194 ug/1 (Eisler, 1970a; Katz,
1961) . LC50 values derived from tests utilizing aeration or
static test procedures probably underestimate the toxicity of
heptachlor, due to its probable high volatility during toxicity
testing (Schimmel, et al. 1976a; Goodman^t al. 1978).
Saltwater invertebrate species seem to be more sensitive to
heptachlor and its metabolite, heptachlor epoxide, than are
fishes, and demonstrate a greater variability in sensitivity of
species (Table 7). Of the seven species tested, the commercially
valuable pink shrimp is especially sensitive with 96-hour LC50
values as low as 0.03 ug/1 (Schimmel/et al. 1976a). Other
species, such as the blue crab and American oyster are 2,100 to
950 times less sensitive, respectively, than the pink shrimp
(Butler, 1963). As with fishes, 96-hour LC50 values derived from
static exposures or exposures based on unmeasured concentrations
probably underestimate toxicity of heptachlor and heptachlor
epoxide to invertebrate species. For example, the 96-hour LC50 of
heptachlor to the grass shrimp based on a static exposure using
unmeasured concentrations is 440 ug/1 (Eisler, 1969), whereas the
results from a flow-through test with measured concentrations is
1.06 ug/1 (Schinunel, et al. 1976a). The same relationship is true
for the American oyster. Static test results (Butler, 1963) were
27 and 30 yq/1 and, using flow-through procedures and measured
concentrations, Schimmel#et al. (1976a) determined a 96-hour LC50
B-22
-------
of 1.5 yg/1. These results demonstrate the need for adjustment
factors for testing procedures. The range of unadjusted LC50
values for saltwater invertebrate species is from 0.03 to 440 yg/1
and is similar to the comparable range of 0.9 to 80 ug/1 for
freshwater invertebrate species.
During toxicity testing with heptachlor, there is apparently
an appreciable loss of heptachlor by volatilization due to
aeration or mixing (Schimmel,et al. 1976a; Goodman,et al. 1978).
This loss appears to be the principal cause of the variability in
the data for the grass shrimp and American oyster due to different
testing techniques as discussed above. It is felt that this loss
is not adequately accounted for by the Guideline's adjustment
factors for static vs. flow-through procedures and measured vs.
unmeasured test concentrations. This may explain why the Final
Fish Acute Value (0.85 yg/1) and Final Invertebrate Acute Value
(0.05 yg/1) are based on the lowest test result with flow-through
procedures and measured concentrations rather than the geometric
mean LC50 values divided by the sensitivity factors.
Unfortunately, there are too few data for heptachlor to derive
adjustment factors specific to heptachlor.
Chronic Toxicity
The chronic toxicity of heptachlor to the sheepshead minnow
(Tables 8 and 11) (Hansen and Parrish, 1977) was measured in an
18-week partial life-cycle exposure, begun with juveniles.
Survival was affected at concentrations of 2.8 ug/1 and greater.
Egg production was significantly decreased at the lowest
B-23
-------
concentration tested, 0.71 g/1, but not at the next highest
concentration, 0.97 yg/1. However, significant impairment of egg
production also occurred at test concentrations of 1.9 to 5.7
pg/1. Because of this anomaly in the data, test results were
placed in Table 11 rather than Table 8. Significant effects on
reproduction occurred at a concentration of 0.06 of the 96-hour
LC50 obtained in this test (96-hour LC50 = 10.5 ug/1; Hansen and
Parrish, 1977).
In a 28-day exposure starting with sheepshead minnow embryos,
hatching was unaffected, but survival of fry was significantly
reduced from that of controls at measured concentrations of 2.24
to 4.3 jig/1 (Goodman, et al. 1978). Growth of fry was
significantly reduced at concentrations of 2.04 ug/1 and above. -
No detrimental effects were observed at 1.22 ug/1.
Comparison of data from the embrvo-larval portion of the
partial chronic exposure (Hansen and Parrish, 1977) with results
of the 28-dav embryo-larval test (Goodman,et al. 1978) shows
survival of fry was reduced at a similar concentration in both
exposures (2.8 pg/1 and 2.24 jjg/1, respectively). Therefore, for
heptachlor, results from the embryo-fry exposure could be used to
predict the results of a life-cycle toxicity test rather
accurately.
The species sensitivity factor appears to be justified, since
the sheepshead minnow has been shown to be generally less sensi-
tive in acute studies with heptachlor than are other fishes (Table
6). No other fish can now be tested in life-cycle tests for
comparison of chronic sensitivity. Therefore, 0.12 yg/1 is the
Final Fish Chronic Value.
B-24
-------
No data are available on the chronic toxicity of saltwater
crustaceans or other saltwater invertebrate species.
Plant Effects
Information on the sensitivity of aquatic plants, including
algae and rooted vascular plants, is limited to one test using a
4-hour exposure of a natural phytoplankton community (Table 9). A
concentration of 1,000 ug/l caused a 94.4 percent decrease in
productivity (Butler, 1963) and is the Final Plant Value.
Residues
Heptachlor and heptachlor epoxide bioconcentrate from water
into the tissues of marine organisms (Tables 10 and 11). The only
bioconcentration factors (BCF) available at steady-state for
heptachlor and heptachlor epoxide are those for fish (Table 10).
Adult sheepshead minnows exposed to technical-grade material for
126 days accumulated heptachlor and heptachlor epoxide an average
of 37,000 times that in the exposure water (Hansen and Parrish,
1977) . Juvenile sheepshead minnows exposed in two separate
experiments for 28 days to technical-grade material bioconcen-
trated 5,700 and 7,518 times the concentration in the water
(Hansen and Parrish, 1977; Goodman,et al. 1976).
Spot exposed for 24 days to technical-grade material reached
a maximum concentration of heptachlor in the tissues (whole body)
after three days (BCF = 6,000; Schimmel/et al. 1976b). In the
same exposure, maximum levels of heptachlor epoxide were reached
in whole fish after 17 days. After a 28-dav period of depuration.
B-25
-------
less than 10 percent of the maximum amount of heptachlor remained
in tissues; it was either lost or metabolized to the epoxide
( Schimnel, et al. 1976b).
Data derived from Table 10 on saltwater residues for hepta-
chlor and FDA maximum tissue concentrations of heptachlor
allowable in animal feed (0.03 mg/kg), produce a Residue Limited
Toxicant Concentration (RLTC) or 0.0036 yg/1. Of the four
components used to establish the Final Chronic Value, as
prescribed by the Guidelines, the RLTC is lowest and the Final
Chronic Value is 0.0036 yg/1.
Miscellaneous
Other bioconcentration information (Table 11) available for
heptachlor and heptachlor epoxide are based on short-term
exposures and are probably not steady-state values (Schimmel/et
al. 1976a). Two species of shrimp (Penaeus duorarum and
Palaemonetes vulgaris) showed less bioconcentration in 96-hour
exposures to technical heptachlor than did another invertebrate
species, the American oyster, in a similar exposure (average BCF
of 425 for shrimp and 6,200 for oysters). Three fish species
exposed for 96-hours to technical heptachlor showed an average BCF
of 9,333 (range 2,800 to 21,300) whereas three invertebrate
species in a similar exposure had an average BCF of 2,350 (range
200 to 8,500). In contrast, the equilibrium fish bioconcentration
factor averaged 12,000 (range 3,435 to 37,000; Table 10).
B-26
-------
Schimmel, et al. (1976a) reported a 15 percent mortality of
the pink shrimp at an unmeasured concentration of 0.0046 pq/1
(Table 11), an amount of heptachlor that is not detectable in salt
water using present technology. Therefore, it seems reasonable to
be concerned about the adequacy of the RLTC to protect penaeid
shrimp, or other very sensitive species, in a chronic or long-term
exposure.
Table 11 contains no effect data at lower concentrations than
those in previous tables, except the work of Hansen and Parrish
(1977), which was discussed earlier.
B-27
-------
CRITERION FORMULATION
Saltwater - Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = 0.85 pg/1
Final Invertebrate Value = 0.05 pg/1
Final Acute Value = 0.05 pg/1
Final Fish Chronic Value = 0.12 pg/1
Final Invertebrate Chronic Value = not available
Final Plant Value = 1,000 ^ig/1
Residue Limited Toxicant Concentration = 0.0036 pg/1
Final Chronic Value = 0.0036 pg/1
0.44 x Final Acute Value = 0.22 pg/1
Criterion Formulation
To derive the criterion, the maximum concentration is the
Final Acute Value of 0.05 pg/1 and the 24-hour average concentra-
tion is the Final Chronic Value of 0.0036 pg/1. No important
adverse effects on marine aquatic orqanisms have been reported to
be caused by concentrations lower than the 24-hour average concen-
tration. But some data for the pink shrimp indicate concern for
this and related species.
CRITERION: For heptachlor the criterion to protect saltwater
aquatic life as derived using the Guidelines is 0.0036 pg/1 as a
24-hour average and the concentration should not exceed 0.05 pg/1
at any time.
B-28
-------
Table 6. Marine: fish acute values for heptachLor
Ad) usLud
Bioaceay Test Chemical Time I.Cbu uj'ju
Ojraarjigin Mfctnod* Deacn i-ition
-------
Table 6. (Continued)
Priapism
bioassay Test Chemical Time LCbi,
Me thou* Cone ,** Description (lira)
Adjusted
l.CbO
tug/i| heterence
White mullet, KT
MukII curema
Striped mullet, S
MurII cephalus
Northern puffer, S
Sphaeroldes maculatu3
U
U
**
48
96
96
3
194
IBS
1.87
106
103
Butler,
1963
Elaler,
1970a
Eisler,
1970a
* S = static, FT = flow-through
** U ° unmeasured, M = measured
**'* tnton'ol. Soc. Am. reference standard
**** Technical material; also contains 22% trans-chlordane, 2% cis-chlordane, and 2% nonachlor
***** Technical material; 72% heptachlor and 28% related compounds
Geometric mean of adjusted values » 7,06 ng/1 3*7^ " ® i'g/1
Lowest value from a flow-through test with measured concentrations = 0.85 ng/1
-------
Table 7. Marine invertebraLe ucuio
Biouaeay TCBt Chemical
Oi. nun ism Methoti* Cope .** Deacription
American oyster, FT U
Crassostrea vlrglnlca
American oyster, FT U
Crassostrea vlrglnlca
American oyster, FT M ****
Crassostrea vlrglnica
03
I
00
Blue crab, FT
Ca 11 lnectea sapltlua
Sand shrimp, S
Crangon septemsplnosa
Hermit crab, S
Pafturus lonRlcarpua
Korean shrimp, S
Palaemon macrodactylua
Grass shrimp, S
Palaeinonetes vulgaris
Crass shrimp, FT
Palaemonetes vulgaris
U
U
U
99%
*****
Pink shrimp,
Penaeus duorarum
FT
Pink shrimp,
Penaeus duorarum
FT
99.87.
Pink shrimp, FT U
Penaeus duorarum
PJnk shrimp, FT M ******
Penaeus duorarum
lues for heptachlor
Adjusted
Tloie l.C^U LCiU
{fu u ) (ii |/1) Iti'i/ 1) Weteience
96 2 7*'** 20.8 Butler, 1963
96 30*** 23.1 Butler. 1963
96 1.5 1.5 Schlmmel,
et al.
1976a
48 63*** 20.8 Butler, 1963
96 8 6.8 Elsler, 1969
96 55 46.6 Elsler, 1969
96 14.5 12.3 Schoettger,
1970
96 440 373 Elsler. 1969
96 1.06 1.06 Schlmmel,
et al.
1976a
96 0.11 0.11 Schlmmel,
et al.
1976a
96 0.03 0.03 Schlmmel,
et al.
1976a
48 0.3*** 0 10 Butler. 1963
96 0.04 0.04 Schlmmel,
et al .
1976a
-------
Table 7. (Continued)
Adjusted
Bioaeeay Test Cuemicai Time LC5u I.CbO
Or Hun 10 in Metftod* Cone .** Description | lira) I lug/1 > Ketei ence
* S ° static, FT » flow-through
** U = unmeasured, M •» measured
**"* EC50: decreased growth of oyster or loss of equilibrium In pink shrimp or blue crabs
**** Technical material; also contains 22% trans-chlordane; 2% cis-chlordane, and 2% nonachlor
***** Entomol. Soc. Am. reference standard
****** lleptachlor epoxide, 99% pure
7 ?
Geometric mean of adjusted values - 7.2 pg/1 jr-gi = 0.15 pg/1
Lowest species geometric mean fvoin flow-through tests with measured concentrations = 0.05 pg/1
-------
Table 8. Marine fish chronic values for hcptachlor (Goodman, ec al. 1978)
Chronic
Limita Value
Organi am Test* |i hi/ 11 (im/I)
Sheepsliead minnow, E-I. 1.22-2. OA""* 0.79
CyprlnoJon varlegatus
* E-L = embryo-larval
** Technical material; also contains 27% trans-chlordane, 2% cls-chlordane, and 2"L nonachlor
Geometric mean of chronic values =0.79 Mg/1 677" ° pg/1
Lowest chronic value •• 0,79 pg/1
-------
Table 9. Marine plane effects for heptachlor (Sutler, 1963)
Concentration
Organism Et tect fug/JI
Natural phytoplankton 94.4% decrease 1,000
conmiunltles in productlvityi
Lowest plant value 1,000 Mg/1
CD
I
OJ
-------
Table 10. Marine residues for heptachlor
Organism
Sheepshead minnow (Juvenile),
Cyprinodon varlegatus
Sheepshead minnow (adult),
Cyprinodon varlegatus
Sheepshead minnow (Juvenile),
Cyprinodon variegatus
Spot,
I.eiostoinus xantlmrus
Bioconceiitration factor
5,700*
37,000*
7,518*
6.000**
T i ire
(days)
28
126
28
2/.
netetence
Hansen & Parrish, 1977
Hansen & Parrish, 1977
Goodman, et al. 1978
Schinunel, et al. 1976b
00
u>
U1
OrpanIsm
Domestic animals
Maximum Permissible Tissue Concentration
Action Level or Effect
animal feed
Concentrat ion
(mR/kf>)
0.03
Reference
U.S. FDA Admin.
Guideline -
7426.04, 1977
* Concentration of heptachlor, heptachlor epoxide, trans-chlordane, and cis-chlordane in whole
fish divided by concentration of heptachlor and trans-chlordane measured in water.
** Concentration of heptachlor and heptachlor epoxide in whole fish divided by concentration of
heptachlor in water.
Geometric mean bloconcentration factor for all species = 8,365
Lowest residue concentration = 0.03 mg/kg = 0.0000036 mg/Ug or 0.0036 pg/1
-------
Table 11, Other mail no da La for heptachlor
00
1
U)
-------
Table 11. (Continued)
W
I
u>
Test
Organlam Puratjpn
Sheepahead minnow, 96 hrs
Cyprtnodon varlegatus
Sheepshead minnow, 126 days
Cvprlnodon var1egatus
Muminichog, 96 hrs
Fundulus heteroclltus
Muminichog, 96 hrs
Fundulus heteroclltus
Mummichog, 96 hrs
Fundulus heteroclltus
Mummichog, 96 hrs
Fundulus heteroclltus
Mummichog, 96 hrs
Fundulus heteroclltus
Mummichog, 96 hrs
Fundulus heteroclltus
Mummichog, 96 hrs
Fundulus heteroclltus
Mummichog, 96 hrs
Fundulus heterocl1tus
Mummichog, 96 hrs
Fundulus heteroclitus
Mummichog, 96 hrs
Fundulus heteroclltus
Mummichog, 240 hrs
Fundulus heteroclltus
Plnfish, 96 hrs
l.UKodon rhomboides
Spot, 96 hrs
I.eiostomus xanthurus
£Lt£ci
Bloconcentration*
faclor = 7,400 to 21,300
decreased egg
production
0-25% mortality
12 o/oo salinity
0-257. mortality
18 o/oo salinity
50-757. mortality
24 o/oo salinity
25-50% mortality
30 o/oo salinity
25-507. mortality
36 o/oo salinity
07. mortality
10°C
0% mortality
15°C
0-25% mortality
20°C
50-757. mortality
25°C
0-25% mortality
30°C
LC50
Bioconcentratlon*
factor = 2,BOO to 7,700
Uloconcentration*
factor = 3,000 to 13,800
Reeult
Jug/il
Schiinmel, et al. 1976a
0.71 Hansen & Parrish, 1977
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
50 Eisler, 1970b
11 Eisler, 1970b
Schiminel , et al . 1976a
Scliimnicl, et al. 1976a
-------
Table 11, (Continued)
Organlam
Test
Bumlfin Effect
Result
<>ig/U Reference
Schlironel, eL al. 1976a
Spot,
l.elostomus xanthurus
96 hra Bioconcentratlon**
factor = 3,600 to 10,000
* Concentration of heptachlor In whole body divided by concentration of heptachlor In water.
Organism exposed to technical heptachlor (657. heptachlor, 22% trans-chlordane, 2% cis-
chlordane, and 2% nonachlor) .
** Concentration of heptachlor in whole body divided by concentration of heptachlor in water.
Organism exposed to analytical-grade heptachlor (99.8% heptachlor).
*** Concentration of heptachlor epoxide in whole body divided by concentration of heptachlor
epoxide in water. Organism exposed to heptachlor epoxide (99%).
03
OJ
00
-------
REFERENCES
Andrews, A.K., et al. 1966. Some effects of heptachlor on
bluegills (Lepomis macrochirus). Trans. Am. Fish. Soc. 95:
297.
Boyd, C.E., and D.e. Ferguson. 1964. Susceptibility and
resistance of mosquito fish to several insecticides. Jour.
Econ. Entomol. 57: 430.
Bridges, W.R. 1965. Effects of time and temperature on the
toxicity of heptachlor and kepone to redear sunfish. Pages
247-249 In C.M. Tarzwell, ed. Biological problems in water
pollution, 3rd Seminar 1962. U.S. Publ. Health Serv. 999-
WP-25.
Butler, P.A. 1963. Commercial Fisheries Investigations,
Pesticide-Wildlife Studies, a Review of Fish and Wildlife
Service Investigations During 1961-1962. U.S. Dep. Inter.
Fish and Wildl. Circ. 167: 11.
Cutkomp, L.K., et al. 1971. ATPase activity in fish tissue
homogenates and inhibitory effects of DDT and related com-
pounds. Chem. Biol. Interactions 3: 439.
Davis, P.W., et al. 1972. Organochlorine insecticide, herb-
icide and polychlorinated biphenyl (PCB) inhibition of NaK-
ATPase in rainbow trout. Bull. Environ. Contam. Toxicol.
8: 69.
B-39
-------
Eisler, R. 1969. Acute toxicities of insecticides to marine
decapod crustaceans. Crustaceana 16: 302.
Eisler, R. 1970a. Acute toxicities of organochlorine and
organophosphorus insecticides to estuarine fishes. Bur.
Sport Fish. Wildl. Tech. Paper No. 46. U.S. Dep. Inter.
Eisler, R. 1970b. Factors affecting pesticide-induced toxi-
city in an estuarine fish. Bur. Sport Fish. Wildl. Tech.
Paper 45. U.S. Dep. Inter. 20 p.
Frear, D.E.H., and J.E. Boyd. 1967. Use of Daphnia magna
for the microbioassay of pesticides. I. Development of stan-
dardized techniques for rearing Daphnia and preparation of
dosage-mortality curves for pesticides. Jour. Econ. Entomol.
60: 1228.
Goodman, L.R., et al. 1978. Effects of heptachlor and toxa-
phene on Laboratory-reared embryos and fry of the sheepshead
minnow. Proc. 30th Annu. Conf. S.E. Assoc. Game Fish Comm.
p. 192.
Guilbault, G.G., et al. 1972. Effect of pesticides on
cholinesterase from aquatic species: crayfish, trout and
fiddler crab. Environ. Lett. 3: 235.
B-40
-------
Hansen, D.J., and P.R. Parrish. 1977. Suitability of sheeps-
head minnows (Cyprinodon variegatus) for life-cycle toxicity
tests. Pages 117-126 in F.L. Mayer and J.L. Hamelink, eds.
Toxicology and hazard evaluation. ASTM STP 634, Am. Soc.
Test. Mater.
Henderson, C., et al. 1959. Relative toxicity of ten chlori-
nated hydrocarbon insecticides to four species of fish. Trans.
Am. Fish. Soc. 88: 23.
Henderson, C., et al. 1960. The toxicity of organic phos-
phorus and chlorinated hydrocarbon insecticides to fish.
Pages 76-88 I_n C.M. Tarzwell, ed. Biological problems in
water pollution, 2nd Seminar 1959. U.S. Publ. Health Serv.,
R.A. Taft Sanitary Eng. Center Tech. Rep. WGO-3.
Hiltibran, R.C. 1974. Oxygen and phosphate metabolism of
bluegill liver mitochondria in the presence of some insecti-
cides. Trans. 111. State Acad. Sci. 67: 228.
Katz, M. 1961. Acute toxicity of some organic insecticides
to three species of salmonids and to the threespine stickle-
back. Trans. Am. Fish. Soc. 90: 264.
Korn, S., and R. Earnest. 1974. Acute toxicity of twenty
insecticides to striped bass, Morone saxtilis. Calif. Fish
Game. 60: 128.
B-41
-------
Macek, K.J., et al. 1969. The effects of temperature on the
susceptibility of bluegills and rainbow trout to selected
pesticides. Bull. Environ. Contain. Toxicol. 4: 174.
Macek, K.J., et al. 1976. Toxicity of four pesticides to
water fleas and fathead minnows. U.S. Environ. Prot. Agency,
EPA 600/3-76-099.
Mulla, M.S. 1963. Toxicity of organochlorine insecticides
to the mosquito fish Gambusia affinis and the bullfrog Rana
catesbeiana. Mosq. News 23: 299.
Naqvi, S.M.Z. 1973. Toxicity of twenty-three insecticides
to a tubificid worm Branchiura sowerbyi from the Mississippi
• delta. Jour. Econ. Entomol. 66: 70.
Naqvi, S.M.Z., and D.E. Ferguson. 1970. Levels of insecti-
cide resistance in freshwater shrimp, Palaemonetes kadiakensis.
Trans. Am. Fish. Soc. 99: 696.
Peterson, R.H. 1976. Temperature selection of juvenile
atlantic salmon (Salmo salar) as influence by various toxic
substances. Jour. Fish. Res. Board Can. 33: 1722.
Sanders, H.O. 1969. Toxicity of pesticides to the crusta-
cean Gammarus lacustris. U.S. Bur. Sport. Fish. Wildl.
Tech. Pap. 25: 3.
B-42
-------
Sanders, H.O. 1970. Pesticide toxicities to tadpoles of the
western chorus frog Pseudacris triseriata and Fowler's toad
Bufo woodhousii fowleri. Copeia 2: 246.
Sanders, H.O. 1972. Toxicity of some insecticides to four
species of malacostracan crustaceans. U.S. Bur. Sport Fish.
Wildl. Tech. Pap. 66: 3.
Sanders, H.O., and O.B. Cope. 1966. Toxicities of several
pesticides to two species of cladocerans. Trans. Am. Fish.
Soc. 95: 165.
Sanders, H.O., and O.B. Cope. 1968. The relative toxicities
of several pesticides to naiads of three species of stone-
flies. Limnol. Oceanogr. 13: 112.
Schimmel, S.C., et al. 1976a. Heptachlor: toxicity to and
uptake by several estuarine organisms. Jour. Toxicol. Envi-
ron. Health 1: 955.
Schimmel, S.C., et al. 1976b. heptachlor: uptake, depura-
tion, retention and metabolisdm by spot, Leiostomus xanthurus.
Jour. Toxicol. Environ. Health 2: 169.
Schoettger, R.A. 1970. Fish-Pesticide Research Laboratory,
Progress in Sport Fishery Research. Bur. Sport Fish. Wildl.
Resour. Publ. 106. U.S. Dep. Inter.
B-43
-------
U.S. Food and Drug Administration. 1973. Administrative
Guideline Manual. Guideline No. 7420.08, Attachment F.
U.S. Food and Drug Administration. 1973. Administrative
Guideline Manual. Guideline No. 7426.04, Attachment G.
Wilson, A.J. 1965. Chem. assays. Annu. Rep. Bur. Commer-
cial Fish. Eiol. Lab. Gulf Breeze, Fla. U.S. Bur. Comm.
Fish. Circ. 247: 6.
Yap, H.H., et al. 1975. Iji vitro inhibition of fish brain
ATPase activity by cyclodiene insecticides and related com-
pounds. Bull. Environ. Contam. Toxicol. 14: 163.
B-44
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Mammalian Toxicology and Human Health Effects
Exposure
Water. Heptachlor and/or heptachlor epoxide have been found in the
major river basins within the United States. Weaver, et al. (1965)
reported that from 96 river sampling points from around the U.S., IS
showed presumptive evidence of heptachlor residues. They also reported
that heptachlor epoxide was not detectable in any of the samples taken-.
They explained the failure to find heptachlor epoxide in their samples
by indicating that the analytical sensitivity for heptachlor was in the
range of 0.002 to 0.010 jig/1, while only 0.07S pg/1 for heptachlor
epoxide. Breidenbach, et al. (1967] did an extensive survey of the
water in the major river basins within the U.S. and in instances where
they were detectable found levels of heptachlor ranging from 0.001 to
0.035 jug/1 and heptachlor epoxide levels ranging from 0.001 to 0.020
/ig/l» with a mean concentration for both of 0.0063 j&g/I (U.S. EPA, 1976).
They went on to add that 24 percent of the water grab samples taken in
1965 showed positive to presumptive evidence of heptachlor residues, and
that heptachlor epoxide was present in 25 percent of their samples.
Their level of analytical sensitivity was 0.001 /ig/1 for both heptachlor
and heptachlor epoxide. Another survey conducted by the U.S. Geological
Survey of 11 western U.S. streams showed heptachlor levels ranging from
0.005 jig/1 to 0.015 jug/l when found and heptachlor epoxide levels ranging
from 0.005 to 0.010 jag/1 when found, with one sample showing 0.090 p.g/1
heptachlor epoxide (Brown and Nishioka, 1967].
C-l
-------
Food. Food can add significantly to man's exposure to heptachlor
and heptachlor epoxide. This occurs through biomagnification of hepta-
chlor/heptachlor epoxide through the food chain. For example, U.S. EPA,
(1976) reported data from Hannon/et al. (1970), which reported the
average heptachlor/heptachlor epoxide residues in the Lake Poinsett,
S. Oak. ecosystem as: 0.006 fig/1 "for water; 0.3 jugAg for bottom sediment;
1.0 Jig/kg for crayfish; 1.1 jigAg for plankton-algae; 8.0 fig/kg for
fish; and 312.0 fig/kg for aquatic insects. Additionally, there is an
approximate ten to fifteenfold increase in heptachlor residues found in
body fat, milk butterfat, and in the fat of eggs of poultry and livestock
as compared to residue levels found in their normal food rations (U.S.
EPA, 1976).
Since 1964 the Food and Drug Administration has reported pesticide
residues in their Total Diet Study, sometimes called the "Market Basket
Study" (Johnson and Manske, 1977). Their "market basket" of food repre-
sents the basic 2-week diet of 16 to 19-year-old males, statistically
the Nation's highest percapita consumers, which is collected in each of
several geographic areas. The foods analyzed in these studies are
prepared in the manner in which they would be normally served and eaten.
The latest published study covers food collected from August 1974 to
July 197S in 20 different cities (Johnson and Manshe, 1977). Their
results showed that only three of the 12 food classes in this study
contained detectable residues of heptachlor epoxide (Table 1) . In
these three instances, the heptachlor epoxide levels were found to range
from 0.0006 to 0.003 ppm.
C-2
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Nisbet (19773 calculated the average daily intake of heptachlor
epoxide from the FDA's Market Basket Studies' standardized diet and
estimated that the daily intake of heptachlor epoxide ranged from 1 to 3
jug/day between 1965 and 1970, and from 0.29 to 0.64 jig/day between 1971
and 1974. Nisbet questioned the calculated decrease in residue levels
observed between the two time periods since the decrease coincided with
FDA's change in analytical methodology. Nisbet (1977) stated that there
was apparently a dilution effect taking place when FDA switched method-
ologies and he regards the total Diet Survey for heptachlor epoxide as
only semi-quantitative. He states that the results suggest an overall
mean daily intake, in the standardized diet, of the order of 1 ug/day of
heptachlor epoxide.
The U.S. Department of Agriculture's Food Surveillance Program
found heptachlor epoxide residues greater than 0.03 ag/kg in 19 percent
of red meat, 17 percent of poultry, and 14 percent of dairy products in
the years 1964 to 1974 (Nisbet, 1977).
The FDA and USDA studies address only food sold in interstate
commerce. There is evidence that game fish may contribute to the daily
dietary exposure of heptachlor and heptachlor epoxide in addition to
that estimated for commercially bought fish. A national study by the
U.S. Department of the Interior during the spring and fall of 1967 and
the spring of 1968 reported that heptachlor and/or heptachlor epoxide
was found in 32 percent of the 590 fish samples examined (Henderson,
1969). Results were reported as ag/kg wet weight whole fish, and ranged
from 0.01 to 3.33 mg/kg when found. It must be noted that these results
represent the whole fish, not just the portions man eats, so it is
possible that much of the residues are accumulated in the uneaten portion
(Henderson, 1969).
C-3
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Tablei Heptachlor epoxide residues in food
(Johnson and Manske, 1977]
Positive Coiroosites
Food
Average
Concentration
class ppm
Total number
Number reported
as trace
Range uum
I
Dairy
Products
0.0004
11
5
0.0006-0.003
II
Meat, Fish
and Poultry
0.001-
13
4
0.001-0.003
VIII
Garden
Fruits
Trace
1
1
Trace
C-4
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A bioconcentration factor (BCF) relates the concentration of a chemical
in water to the concentration in aquatic organisms, but BCF's are not avail-
able for the edible portions of all four major groups of aquatic organisms
consumed in the United States. Since data indicate that the BCF for lipid-
soluble compounds is proportional to percent lipids, BCF's can be adjusted
to edible portions using data on percent lipids and the amounts of various
species consumed by Americans. A recent survey on fish and shellfish con-
sumption in the United States (Cordle, et al. 1978) found that the per
capita consumption is 18.7 g/day. From the data on the 19 major species
identified in the survey and data on the fat content of the edible portion
of these species (Sidwell, et al. 1974), the relative consumption of the
four major groups and the weighted average percent lipids for each group can
be calculated:
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each of these groups,
the weighted average percent lipids is 2.3 for consumed fish and shellfish.
C-5
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Measured steady-state bioconcentratiori factors were obtained for hepta-
chlor using three species of fish:
Organism
Sheepshead minnow
(juvenile),
Cyprinodon variegatus
Sheepshead minnow
(adult),
Cyprinodon variegatus
Sheepshead minnow
(juvenile),
Cyprinodon variegatus
Spot,
Leiostomus xanthuru
Fathead minnow,
Pimephales promelas
BCF
5,700
37,000
7,518
6,000
20,000
Percent
Lipids
Adjusted
BCF
2,662
17,020
3,458
4,600
5,750
Reference
Hansen &
Parrish,
1977
Hansen &
Parrish,
1977
Goodman,
et al.
1978
Schimmel,
et al.
1976b
Macek, et
al. 1976
Each of these measured BCF's was adjusted from the percent lipids of the
test species to the 2.3 percent lipids that is the weighted average for con-
sumed fish and shellfish. The geometric mean was obtained for each species
and then for all species. Thus the weighted average bioconcentration factor
for heptachlor and the edible portion of all aquatic organisms consumed by
Americans is calculated to be 5,200.
C-6
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Infants are exposed to heptachloT and heptachlor epoxide through
mother's milk (Savage, 1976), cow's milk (Ritcey, et al. 1972; Johnson
and Manske, 1977) and commercially prepared baby foods (Lipscomb, 1963).
A recent nationwide study, done during 1975-76, indicates that 63.1
percent of the 1936 mothers' milk samples possessed heptachlor epoxide
residues (Savage, 1976). The fat adjusted mean concentration for
heptachlor epoxide in the mothers' milk with levels above the 1 jug/1
sensitivity level, was 91.36 Jig/1 with a range of IS.24 to 2050 pg/1.
It therefore appears that many nursing infants have been exposed to
heptachlor epoxide and it is probable that a certain percentage have
been exposed to levels that exceeded the levels in dairy products
(Savage, 1976). Whole cow's milk and evaporated milk did not show a
trace of heptachlor epoxide in the U.S. FDA's 1974-75 Market Basket
Survey (Johnson and Manske, 1977), but a Canadian study which expressed
the residues on a fat basis, reported heptachlor epoxide residue levels
of 5.00 jug/1 in evaporated milk (Ritcey, et al. 1972). Commercially
prepared baby food was tested by the FDA during a period of July 1963 to
June 1967 and heptachlor epoxide residues were found in 0.9 percent of
684 samples with most of the positive samples showing residues in the
range of trace to 0.03 mg/kg (Lipscomb, 1968). Therefore it appears
that infants raised on mothers' milk run a greater risk of ingesting
heptachlor epoxide than if they were fed cow's milk, and/or commercially
prepared baby food.
C-7
-------
Ritce^ et al. (1972) investigated the effects of cooking and
heating poultry containing 28.1 mg of heptachlor epoxide per kg of
tissue on a dry weight basis (U.S. EPA, 1976). They found baking
reduced the residue level to 22.5 nig/kg; steaming to 22.1 mg/kg; and
frying resulted in no change. They also found that heating in a closed
container at 350°F for 60 to 90 minutes reduced the residue to 16.0 to
19.5 mg/kg.
Inhalation. Volatilization is a major route of loss of heptachlor
from treated surfaces, plants and soils (Nisbet, 1977). It has been
concluded, from various surveys, that heptachlor and to a lesser extent,
heptachlor epoxide are widespread in our ambient air with typical mean
concentrations of approximately 0.5 ng/m3 (Nisbet, 1977). Levels of
heptachlor and heptachlor epoxide in the air vary both geographically
and seasonally (Stanley, et al. 1971). Higher levels have been found
generally in rural agricultural areas where crop spraying was practiced
(Stanley, et al. 1971; Nisbet, 1977). However, certain suburban areas
have exhibited a substantial concentration of heptachlor in their
ambient air (Nisbet, 1977).
Nisbet (1977) has reported air surveys where agricultural fields
have been treated with technical heptachlor (2 lb/acre) and the air
above and downwind from the fields showed heptachlor concentrations as
high as 244 ng/m3 immediately after application. After 3 weeks the
concentrations remained as high as 15.4 ng/m3. One survey reported
heptachlor concentrations as high as 600 ng/m3 in air over a treated
field and this field showed high concentrations in the air throughout
the growing season, at least from May to OctobeT (Nisbet, 1977).
C-8
-------
Nisbet (1977) states that these "high concentrations found above and
downwind from treated fields are obviously significant sources of
exposure for persons living and working in or near the treated areas."
Arthur, et al. (1976) conducted a 3 year study in 1972-74 of Stone-
ville, Miss, which is reported as one of the highest pesticide usage
areas of the U.S. due to intensive cotton production. They found
heptachlor in 62 percent of their monthly samples with an average level
of 0.25 ng/m3 and a maxiimnn concentration of 0.3 ng/m3. Heptachlor
epoxide was found in 36 percent of the monthly samples at an average
level of 0.21 ng/m-3 and a maximum concentration of 9.3 ng/m3 (Arthur,
et al. 1976; Nisbet, 1977).
Stanley, et al. (1971) found heptachlor in only two out of nine
U.S. localities studied and did not detect heptachlor epoxide in any of
the localities. The localities showing residues were Iowa City, Iowa,
and Orlando, Fla., with maxim;an heptachlor levels of 19.2 ng/m3 and 2.3
ng/m3, respectively.
Nisbet (1977) calculated the typical human exposure to heptachlor
to be 0.01 yig/individual/day based on an ambient air mean concentration
of 0.3 ng/m3 and breathing 20 m3 of air per day. He states further that
even in Jackson, Miss., which has a mean air level as high as 6.3 ng/mJ,
the average individual would inhale only 0.13 jug/day of heptachlor. The
significance of these figures is dependent upon the efficiency of lung
absorption of heptachlor and heptachlor epoxide which does not appear to
be reported for humans (Nisbet, 1977). Based on the information presented
here, it appears that inhalation is not a major route for human exposure
C-9
-------
to heptachlor and its metabolites. However, an experiment by Arthur,
et al. (1975) using rabbits, although controversial (Nisbet, 1977),
suggests that inhalation may be a significant route of exposure even at
ambient levels as low as 1.36 ng/m^.
Dermal. Limited information is available regarding the dermal
route of exposure to heptachlor and/or heptachlor epoxide. However, it
may be assumed that persons handling this compound would be dermally
exposed. Kazen, et al. (1974) found that chlordane, a compound structur-
ally similar to heptachlor, could be found on a man's skin 2 years after
occupational exposure. Gaines (1960) found that rats dermally exposed
to technical grade heptachlor had LD^q values of 195 mg/kg for males and
250 mg/kg for females, while the LD5Q values for orally exposed rats
were 10.0 mg/kg for males and 162 mg/kg for females. Xylene was used as
the vehicle to dissolve and apply the heptachlor and the solution was
applied at a rate of 0.0016 ml/kg body weight.
It is significant to note that the U.S. EPA suspended most uses of
heptachlor effective August 1, 1976 including most agricultural, home,
and garden uses of technical grade heptachlor.
Pharmacokinetics
Absorption and distribution. Heptachlor and/or heptachlor epoxide
are both readily absorbed from the gastrointestinal tract (Radomski and
Oavidow, 1953; Mizyukova and Kurchatov, 1970; Matsumura and Nelson,
1971). Mizyukova and Kurchatov (1970) showed that pure heptachlor
reaches all organs and tissues of female rats within one-half to 1 hour
after a single dose (120 mg/kg) of heptachlor was delivered directly
into the stomach. After 4 hours the metabolite of heptachlor (heptachlor
C-10
-------
epoxide) was found in the blood, liver, and fatty tissue. After a few
days the concentration of heptachlor in all organs and tissues fell,
while at the same time there was a rapid increase in heptachlor epoxide
levels. By the end of 1 month only traces of heptachlor could be found
in the fatty tissue, chiefly in the form of its metabolic products and
no heptachlor or its metabolites could be found in the blood or kidneys.
However, a small amount of heptachlor epoxide was found in the liver.
After 3 to 6 months the level of heptachlor epoxide in fatty tissues
became stabilized.
Radomski and Davidow (1955) used both dogs and rats and found, for
rats, that after 2 months on a diet of 30-35 mg/kg of heptachlor, the
highest concentration of heptachlor's metabolite (heptachlor epoxide)
was found in the fat, with markedly lower amounts in the liver, kidney
and muscle, and none was detected in the brain. Female dogs dosed at 1
mgAg daily for a period of 12 to IS months showed the same heptachlor
epoxide distribution as did the rats except the dog livers appeared to
contain more heptachlor epoxide than the kidneys and muscles. The
lowest detectable concentration of heptachlor epoxide in this study was
0.6 mg/kg.
The degTee to which heptachlor or heptachlor epoxide is absorbed by
inhalation has not generally been reported (Nisbet, 1977). Arthur,
et al. (1975) conducted a controversial study (Nisbet, 1977) where they
exposed white rabbits to the ambient air of Stoneville, Miss., an area
of high pesticide use. Their controls weTe housed indoors at Mississippi
State University, an area of low pesticide usage. They found that
between July 1972 and October 1972 the heptachlor epoxide level in the
C-ll
-------
adipose tissue from Stoneville was 0,059 mg/kg while only 0.016 ng/kg
was found in the same tissue in rabbits from Mississippi State. The air
heptachlor epoxide level at Stoneville was reported to be 1.36 ng/m3,
while the Mississippi State University air heptachlor epoxide level was
so low that they did not take air samples. The level of heptachlor in
the air at both geographic locations was not given. They also stated
that no heptachlor epoxide residues were detected in the feed of either
group. They calculated the average daily respiratory intake for rabbits
in Stoneville, Miss, as 0.002 jug/day. These data, even though contro-
versial, indicate that heptachlor epoxide can be absorbed to a signifi-
cant degree after inhalation as determined by rabbit adipose tissue
residues.
Several studies released in the late 1960*s indicate' that the
human placenta, that separates a growing fetus from the mother, does not
provide adequate protection against chlorinated hydrocarbon pesticides
such as heptachlor epoxide (Selby, et al. 1969; Zavon, et al. 1969;
Curley, et al. 1969). Selby, et al. (1969) found that women who had
high levels of heptachlor or heptachlor epoxide in their blood also had
high levels of heptachlor and heptachlor epoxide in their placenta.
Hiey also reported a heptachlor epoxide distribution between the placenta
and maternal blood in a ratio of 5.8:1 (placenta ppb:matemal blood ppb)
based on the geometric means of 54 placental and S3 maternal blood
samples. Polishuk, et al. (.1977 b) has shown that heptachlor epoxide
was higher in the extracted lipids of fetal blood and placenta than in
the maternal blood and uterine muscle lipids. Zavon, et al. (1969)
reported that fetal or neonatal tissue taken from stillborn or soon dead
C-12
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children showed that heptachlor epoxide levels paralleled the concent-
rations found in adults. Curley, et al. (1969] conducted an extensive
study using stillborn and soon dead infants, along with the cord blood
of live neonates and found that the heptachlor epoxide levels in the
various tissues and cord blood sampled varied greatly, but were within
the range observed in adults. Therefore, any exposure of heptachlor or
heptachlor epoxide to the mother will also expose the fetus to heptachlor
epoxide.
Metabolism and excretion. Early studies carried out by Radomski
and Davidow [Radomski and Davidow, 1953; Davidow and Radomski, 1953)
show that both the rat and the dog rapidly metabolize ingested heptachlor
to heptachlor epoxide by epoxidation (figure l) and that heptachlor
epoxide accumulates primarily in fat tissue. They also reported a
positive relationship between the amount of heptachlor in the diet and
the amount of heptachlor epoxide stored in the fat tissue. The female
rats in this study accumulated approximately six times as much heptachlor
epoxide in their fat tissue than did the males.
Matsumura and Nelson (1971) fed four male albino rats 10 mgAg of
heptachlor epoxide (99 percent pure) for 30 days (approximately 5 mg
heptachlor epoxide/rat/30 days) and found that they excreted 950 ug of a
fecal metabolite (figure 2 ) and 66 ug of heptachlor epoxide in the
feces in the 30 day period. Mizyukova and Kurchatov (1971) found that
the excretion, of the non-stored, heptachlor and its metabolites occurs
within the first 5 days, chiefly through the gastrointestinal tract and
to a smaller extent in the urine.
C-13
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Figure - 1
FAECAL META30UTE
Figure - 2.
Int. Agency Res. Cancer, 1974
C-14
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One very important route of excretion of heptachlor and heptachlor
epoxide for females is through lactation (Jonsson, et al. 1977). This
'study indicates that milk is a primary excretory route for heptachlor
and its metabolites. It is also generally thought that the heptachlor
epoxide concentration in mothers' milk is a good indicator of the body
burden of heptachlor epoxide which is stored in the lactating mother's
body (Jonsson, et al. 1977; Strassman and Kutz, 1977). Polishuk, et al.
(1977 a) found that overweight women excreted lower quantities of
pesticides such as heptachlor epoxide in their milk than did women of
normal weight. They also found that women of the ages 20 to 29 excreted
higher pesticides levels in their milk than did women of the ages 50 to
39, even though the younger women had lower pesticides levels in their
plasma.
Kroger (1972) carried out a human milk study based on 53 samples
collected from two Pennsylvania regions during 1970 and found that all
of the samples contained heptachlor epoxide with an average concentration
of 0.16 mg/1. Savage, et al. (1975) carried out a similar survey in
Colorado in 1970-1971 with 40 human milk samples and found 25 percent of
the samples contained heptachlor epoxide at levels ranging from trace
amounts to 5 /ig/1. Strassman and Kutz (1977) conducted a study in Arkansas
and Mississippi in 1975-1974 containing 57 milk samples and found heptachlor
epoxide residues in 35.1 percent of the samples and at least a trace
amount of heptachlor epoxide in 64.9 percent of the samples. The levels
in this study ranged from trace to 0.03 mg/1 and the mean concentration
was 0.004 mg/1. They also found trace to quantifiable amounts of trans-
nonachlor, which indicates exposure to heptachlor or chlordane.
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Savage (1976) reported the results of an extensive study involving
1456 human milk samples from selected sites within the continental U.S.
conducted during 1975. He found that only 2 percent showed heptachlor
residues, but 63.1 percent of the mothers' milk samples showed heptachlor
epoxide residues that ranged from 15.24 to 2,050 jig/1 on a fat adjusted
basis, with a mean concentration of 91.56 /ig/1. Savage also found that
11 percent of the high residue group of women were either occupationally
exposed or lived in households where a household member was occupationally
exposed. Jonsson, et al. (1977) reported that 24 percent of 51 human
milk samples collected from St. Louis in 1977 contained an average
heptachlor epoxide level of 0.0027 mg/1. Other studies concerning
heptachlor epoxide in human milk in other countries include: Ritcsy,
et al. (1972); Polishuk, et al. (1977 a); and Bakkan and Seip (1976).
One major problem with the excretion of heptachlor epoxide in
mothers' milk is that it becomes a major vehicle for exposing the neonate
(Strassman and Kutz, 1977). This exposure to the neonate is an addition
to the body burden which already exists due to exposure in-utero (Polishuk,
et al. 1977 b; Zavon, et al. 1969; Selby, et al. 1969; Curley, et al. 1969).
Residues of heptachlor epoxide in adipose tissue and other tissues
and fluids are indicative of the body burden and the exposure to heptachlor
and heptachlor epoxide (Kutz, et al. 1977). Biopsied human adipose
tissue was used by Bums (1974) to study the heptachlor epoxide levels
in 302 hospital patients from 1969 to 1972 in the lower Rio Grande
Valley in Texas. He found that over the study period. 98 percent of the
adipose samples possessed heptachlor epoxide residues with a mean value
of 0.11 mg/kg. An extensive survey of human adipose tissue levels for
C-16
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heptachlor epoxide has been published by Kutz, et al. (I977)• ¦ Tissues
were collected during postmortem examinations and from surgical excisions
and rejected samples collected from patients known or suspected of
pesticide poisoning, cachectic patients, and patients institutionalized
for extended periods. The samples were obtained within the conterminous
48 states and the sampling sites were picked to be representative of the
U.S. populations. The five-year study showed that heptachlor epoxide
can be found in over 90 percent of the U.S. population at approximate
mean levels of 0.08 to 0.09 mg/kg (see TableZ).
In addition to the storage of heptachlor epoxide in human adipose
tissue, a minor component (trans-nonachlor) of both technical heptachlor
and technical chlordane has also been found (Sovocool and Lewis, 1975].
They sampled nine composite human fat samples from nine census divisions
of the U.S. and found eight of the nine samples possessed trans-nonachlor.
Also found in lesser amounts were cis-nonachlor and "early-eluting"
nonachlor. Five of the nine composite samples were also positive for
heptachlor epoxide and oxychlordane. These data suggest that nonachlors
may be more resistant to metabolism than heptachlor, and occurrence of
the nonachlors in human tissues appears to be strong evidence of exposure
to heptachlor or chlordane pesticides (.Sovocool and Lewis, 1975).
Several other researchers have reported heptachlor epoxide residues
in human adipose tissue in other countries including: Curley, et al.
(1973); Wassermann, et al. £1974); Abbott, et al. C1972)J and Wassennann,
et al. (1972).
C-17
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Table 2L Heptachlor epoxide residues
in human adipose tissue
(Kuts, et al. 1977)
Survey Sample Percent Geometric Maximum
year (fiscal! si2e positive mean QngAz) value mg/kg
1970
1412
94.76
0.09
10.62
1971
1615
96.22
0.09
1.53
1972
1913
90.28
0.08
1.21
1973
1095
97.72
0.09
0.84
1974
898
96.21
0.08
0.77
C-18
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Health Effects
Acute, subacute and chronic toxicity. The acute toxicities of
heptachlor and its metabolites have LO^q values ranging from 6 mg/kg to
S31 mg/kg (Table 3 ) depending upon the animal species, toxicant used,
and the mode of administration. Radomski and Davidow (1955) were the
first to report that heptachlor epoxide is two to four times more toxic
than heptachlor itself in mice when given intravenously. Buck, et al.
(1959) later observed heptachlor epoxide to be approximately 10 times
more toxic than heptachlor in dairy calves when given orally. The most
toxic metabolite is photo-heptachlor epoxide [ill B] (Ivie, et al. 1972)
which is formed by exposure of heptachlor epoxide to ultraviolet light
or sunlight with the presence of a photosensitizer on plants. Ivie, et
al. (1972) reported the LD^q values for male Swiss-Webster mice to be IS
mg/kg for heptachlor epoxide; 36 mg/kg for the intermediate photo
metabolite photo-heptachlor epoxide [il]; and 6 mg/kg for photo-heptachlor
epoxide [ill B]. Gaines (1960) conducted acute LDSQ studies using oral
doses of heptachlor in the Sherman Strain of rat and found LD_^ values
of 100 mg/kg in males and 162 mg/kg in females respectively, while the
acute dermal LD^q toxicity of heptachlor in males was 19S mg/kg and 250
mg/kg for females. Harbison (1975) used neonatal and adult Sprague-
Oawley rats (120 to 150 gm) to show that the newborn rat is more resistant
to heptachlor than the adult. The intraperitoneal LO^q for the adult
male rats was 71 mg/kg* while 531 mg/kg* was found for newborn rats.
(~Assumed to be mg/kg body weight). Gak (1976) reported heptachlor LD_Q
values for the mouse, rat, and hamster to be 70 mg/kg, 10S mg/kg, and
100 mg/kg of body weight respectively.
C-19
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Table 3 Heptachlor and heptachlor metabolites LD^
Route
Organism of LDSq
Sex 3 Strain Compound Administration fag/Teg) Reference
Mouse
CSwiss-Webster)
Heptachlor
epoxide
i.p.
13
Ivie, et al, 1972
Mouse
CSwiss-Webster)
Photo-heptachlor
epoxide II
i.p.
36
Ivie, et al, 1972
Mouse
(Swiss-Webster)
Photo-heptachlor
epoxide (III B)
i.p.
6
Ivie, et al, 1972
Rat (M- Sherman)
Heptachlor
oral
100
Gaines, 1960
Rat (F-Sherman)
Heptachlor
oral
162
Gaines, 1960
Rat (M-Sherman)
Heptachlor
dermal
195
Gaines, 1960
Rat (F-Sherman)
Heptachlor
dermal
250
Gaines, 1960
Rat (M-Sprague-
Dawley)
Heptachlor
i.p.
71*
Harbison, 1975
Rat (N-Sprague-
Dawley)
Heptachlor
i.p.
531*
Harbison, 1975
Mouse
Heptachlor
oral
70
Gak, et al, 1976
Rat
Heptachlor
oral
10S
Gak, et al, 1976
Hamster
Heptachlor
oral
100
Gak, et al. 1976
• a assumed to be mg/kg body- weight
i.p. 3 intraperitoneal!/
M a male
F = female
N a neonate
C-20
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Heptachlor is generally classified as a neurotoxin because it
produces abnormal stimulation of the central nervous system when animals
are exposed to high doses. In an attempt to elucidate the toxic action
of heptachlor, numerous studies have taken place to demonstrate the
biochemical changes induced by heptachlor toxicity. St. Omer (1971)
studied the convulsions produced by heptachlor in rats and found that
the intensity of the convulsions was directly correlated with the rise
in brain ammonia and the periods between seizures were associated with
decreased levels of brain ammonia. St. Omer and Ecobichon (1971) reported
that acute administration of heptachlor in rats significantly elevated
their brain acetylcholine content with some decrease in acetylcholine
concentration during the period of severest seizure activity. They
suggest that these changes seen in the brain level of ammonia and
acetylcholine during heptachlor exposure may be part of the mechanism of
convulsion induction. Hrdina, et al. (1974) administered heptachlor
chronically for 45 days to rats and found the acetylcholine level in the
cerebro-cortex to be decreased and the serotonin (5-HT) level significantly
increased in the brain-stem. They also found that an acute dose of
heptachlor (200 mg/kg) produced body hypothermia.
Changes in the energy-linked functions of the mitochondria have
been studied by Pardini, et al. (1971) and Settlemire, et al (1974).
Paxdini, et al. (1971) reported that heptachlor (lp mole/flask) depressed
the mitochondrial succinoxidase system to 5.8 percent of the level of
uninhibited controls and that heptachlor epoxide did not depress the
system at all. Heptachlor also depressed the mitochondrial activity of
NADH-oxidase to 8.6 percent of uninhibited controls, while heptachlor
C-21
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epoxide again had no effect. They speculated that since heptachlor did
not interact at any step in the electron transport chain after cytochrome
C that the site of heptachlor interaction may be either at complex III
or at complex I and II of the mitochondrial electron transport chain.
Settlemire, et al. (1974) found that heptachlor caused dramatic changes
in the membrane of mouse mitochondria at concentrations as low as 54 n
moles. They stated that the increase in respiration (oxidation 0f
succinate) observed when ADP.and heptachlor were added was probably
caused by increasing permeability of membranes to succinate or by producing
conformational changes of such a nature that the intrinsic activity of
the respiratory chain is increased.
Heptachlor and heptachlor epoxide induction of liver microsomal
enzymes has been reported by Kinoshita and Kempf (1970) and Den Tonkelaar
and Van Esch (1974). Kinoshita and Kempf (1970) found heptachlor and
heptachlor epoxide to be very persistent inducers in rats of phosphoro-
thioate detoxification, O-demethylase, and N-demethylase in a dose
related manner. They also found that male rats were more sensitive to
heptachlor while female rats were more sensitive to heptachlor epoxide.
Den Toukelaar and Van Esch (1974) found that dietary heptachlor signifi-
cantly induced aniline hydroxylase, aminopyrine demethylase, and hexo-
barbital oxidase in rats at levels of 2 to 50 mg/lcg, 2 to SO mg/lcg, and
5 to 50 mg/lcg, respectively. Both groups reported that approximately 1
mg/lcg of heptachlor showed no effect on the induction of microsomal
enzymes.
Krampl (1971) reported that heptachlor caused an increase in the
enzymes glutamic-pyruvic transaminase (G?T) and aldolase (ALD) in the
C-22
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serum of rats. Histologic examinations of the livers revealed that
maximum alteration in hepatic morphology coincided with the days on
which hepatic and serum GPT and ALD activities were different from
normal. They stated that the increased enzyme activity was probably
related to altered membrane permeability, which allowed intracellular
enzymes to pass out of cells that were damaged but not necrotic. Welch,
et al. (1971) found that heptachlor stimulated the metabolism of estrone
by liver microsomal enzymes and inhibited the increase in uterine wet
weight in treated female rats.
Several studies have been conducted concerning the effects of
heptachlor on glucose homeostasis in the rat (Kacew and Singhal, 1975;
Kacew and Singhal, 1974; Singhal and Kacew, 1976). It was reported that
heptachlor administered either in small daily amounts over a prolonged
period of time or in a single oral dose, caused significant increases in
the activities of renal and hepatic pyruvate carboxylase, phosphoenol-
pyruvate carboxykinase, fructose 1,6-diphosphatase, and glucose 6-
phosphatase, as well as an elevation of blood and urinary glucose and
serum urea levels, and a depression of liver glycogen. They also found
that heptachlor caused a rise in the level of endogenous cyclic AMP and
augmented the activity of hepatic and renal adenylate cyclase. They
stated that their data support the hypothesis that the heptachlor-
induced alterations in glucose homeostasis are related to an initial
stimulation of cyclic AMP-adenylate cyclase system in liver and kidney
cortex.
Dvorak and Halacka £1.975) studied the ultrastructure of the liver
cells of pigs after the administration of small doses (2 to 3 mg/kg of
C-23
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body weight) of heptachlor and found a marked depletion of glycogen,
morphological changes in the granular endoplasmic reticulum, and increases
in the amount of agranular endoplasmic reticulum. With higher doses and
a longer duration of administration of heptachlor a greater occurrence
of liver lysosomes was also observed.
Reuber (1977 a) found that C3H male and female mice fed 10 mg/kg of
heptachlor or heptachlor epoxide developed hepatic vein thrombosis.
Heptachlor caused 15 percent of the females and 10 percent of the males
to develop thrombi, while heptachlor epoxide caused 11 percent of the
females and 7 percent of the males to develop thrombi. He also stated
that seven mice of the 39 that exhibited hepatic vein thrombosis also
possessed recent thrombi in the atria of the heart, while no thrombi
were found in any organs of the control mice. Liver cirrhosis was also
occasionally present in addition to liver carcinomas.
Mutagenicity. Marshall, et al. (1976) reported that both heptachlor
and heptachlor epoxide were not mutagenic when tested with Salmonella
typhimurium in the Ames assay. Cerey, et al. (1973) found that heptachlor
in oral doses of 1 to S mg/kg caused dominant lethal changes in male
rats, demonstrated by a statistically significant increase in the number
of resorbed fetuses in intact pregnant rats. They confirmed this h.y
finding a significant increase in the incidence of abnormal mitoses,
abnormalities of chromatids, pulverization, and translocation in the
bone marrow cells of their experimental animals. They concluded from
the data that rat fetuses in early and late stages of embryonic development
could be adversely affected by the use of heptachlcT. Ahmed, et al.
(1977] used SV-40 transformed human cells (VA-4) in culture to show that
C-24
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both heptachlor and heptachlor epoxide induced unscheduled DNA synthesis
in this system when metabolically activated with homogenized rat liver
supernatant. Therefore heptachlor has been reported to be a mutagenic
compound in mammalian studies but not in bacterial cell systems.
Teratogenicity. Mestitzova (1967) found that heptachlor administered
to rats in food at 6 mgAs body weight caused a marked decrease in
litter size, both in several litters of one generation as well as in
successive generations. The author also stated that the lifespan of
suckling rats is significantly shortened with the death rate being
highest during the first 24 to 48 hours. In long-term feeding studies
with heptachlor the same author observed the development of cataracts of
the lens, both in the offspring and the parent rats. Prolonged feeding
of heptachlor increased the chances of cataracts occurring in the parents,
while the cataracts in the offspring were observed shortly after their
eyes opened. They stated that the sequence of occurrence of the cataracts
excludes the possibility of recessive genetic traits or a vitamin B
deficiency as the causative factor.
Synergism or Antagonism. It has been reported that the protein
content in the diet can affect the acute toxicity of heptachlor in male
weanling rats (Webb and Miranda, 1973; Miranda, et al. 1973; Miranda
and Webb, 1974). These workers found that with a 10 percent dietary
level of protein, heptachlor was less acutely toxic in rats fed an
unsupplemented gluten diet than in animals pair-fed diets containing
gluten plus supplemental amino acids or casein plus 0.2 percent DL-
methionine. When the dietary protein level was raised to 18 percent,
heptachlor was twice as toxic to rats pair-fed casein diets, as compared
C-25
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to rats fed unsupplemented gluten. They also found that weight gain,
microsomal proteins, and heptachlor metabolism were significantly
reduced in the animals fed unsupplemented gluten and that animals pair-
fed the casein diet had higher heptachlor epoxidase activities than
those fed the gluten diet. Therefore, they suggest that low protein
diets impair or slow heptachlor jfrom being metabolized to the more toxic
heptachlor epoxide. Weatherholtz, et al. (1969) reported that rats fed
protesin' deficient diets axe less susceptable to heptachlor toxicity and
also suggested that this observation may be due to reduced in vivo
conversion of the pesticide to the epoxide form.
Miranda and Webb also studied the effects of phenobarbital and
SXF525-A on these protein diet regimens [Miranda, et al. 1973; Miranda
and Webb, 1974). Their studies suggested an interaction of protein
inadequacy with drug metabolism and its reduction or inhibition of
heptachlor metabolism, but they believed further studies should be
carried out to clarify their findings.
Harbison C197S) studied the effects of phenobarbital (PB) on
neonatal rats. He found that PB potentiates the toxicity of heptachlor
in newborn rats. The heptachlor LD^q for a newborn is S31 nig/kg, but
the heptachlor LD-q for a newborn rat pretreated with PB was 133 mg/kg
with the LDjq for an adult male un-pretreated rat being 71 mg/kg.
Carcinogenicity. Various studies regarding the carcinogenicity of
heptachlor and heptachlor epoxide when administered to rats and mice
have been conducted by the Kettering Laboratory, the Food and Drug
Administration, Cabral, et al., International Research and Development
Corporation sponsored by Velsicol, and the National Cancer Institute.
C-26
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Two extensive reviews of these studies have been conducted by Epstein,
(1976) and by the U.S. EPA (1977} and should be referred to for more
specific information on each study. Tables 4* and S present summary data
reported by Epstein (1976), and include the original authors' conclusions,
any independent histological re-evaluation of the studies which have
been conducted, and Or. Epstein's comments on each study.
The 19S5 Kettering study on heptachlor in rats was an unpublished
study by the Kettering Laboratory under contract to the Velsicol Corpor-
ation. the U.S. EPA (1977) review of this study stated that the oral
dosages were 0, 1.5, 3.0, 5.0, 7.0, and 10.0 mg/kg of heptachlor adminis-
tered to a total of 120 male and 120 female Carworth Farm strain rats.
The length of dietary administration was 110 weeks with a 57 percent
mortality rate in the male groups and a 43 percent mortality rate in the
female groups. The reviews of the report state that the majority of the
deaths were due to incidental diseases, particularly respiratory (U.S.
£PA, 1977; Epstein, 1976). Tumors were found both in controls and in
exposed animals and the original authors interpreted their data as
indicating no significant difference between the incidence of tumors in
test and control groups (Epstein, 1976). Based on an independent
statistical analysis of the data from this study, Epstein (1976) concluded
that "the data in fact demonstrated a statistically significant incidence
of multiple site and other tumors in the higher level female test groups."
Another Kettering study was carried out for the Velsicol Corp. in
1959 by Witherup, at al. (1959). This investigation evaluated heptachlor
epoxide at dietary levels of 0, 0.5, 2.5, 5.0, 7.5, and 10 mg/kg adminis-
tered to CFN (Carworth Farms, Nelson) rats for 108 weeks. Each dosage
C-27
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Table 4-Summary of carcinogenicity data In ruts
(taken from Table II of Epstein, 1976, with permission)
Authors Strain Poranilation
lleptachlor (II);
epoxide (HE);
chlordane (C)
Concentrations (ppm) Carcinogenicity
Comments
II
110
Authors
conclusions
Independent
histological
re-evaluation
Kettering, CI1 II of unspecified
1955 purity
1.5; 3.0;
5.0; 7.0;
10.0
Tumor incidence Not undertaken
"proportionately"
distributed in
all test and
control groups
1. Test diets prepared
crudely and study
poorly documented.
2. Author's data demon-
strate statistically
significant increase
in malignant and any
tumors in multiple
sites in some female
test groups.
Kettering, CPN
1959
HE of unspecified
purity
0.5; 2.5;
5.0; 7.5;
10.0
Tumor incidence
"unrelated" to
HE content in
diets. Excess
hepatomas in
test animals is
acknowledged,
but discounted.
Also unusual
malignant tumors
in wales and
females
llepatocarcino-
genic and
multiple site
malignant '
tumors
1. test diets prepared
crudely and study
poorly documented.
2. Kettering data statis-
tically significant,
for incidence of total
tumor-bearing animals
and for liver and
pituitary tumors.
3. Histological re-eval-
uation showed
hepatocarcinomas.
4. Ilepatocarcinogenicity
statistically signi-
ficant.
Kettering, CD
1966
Mixture of 25% HE 5,
(99.9% pure), and
75% II (96.0 % pure)
0; 7.5; 10; 12.5
Incidence of
tumors
"qualitatively
and quantita-
tively similar"
in test and
controls.
Not undertaken 1.
2.
Study poorly document-
ed and methodologi-
cally unsound; female
rats only tested.
Unacceptable as
carcinogenicity test.
-------
Table (continued)
(taken from Table II of Epstein, 1976, with permission)
Authors Strain Formulation
lleptachlor (II);
epoxide (HE);
chlordane (C)
Concentrations (ppm)
II
110
Carcinogenici ty
Authors
conclusions
Comments
Independent
histological
re-evaluation
Cabral,
et al.,
1972
Wistar II Analytic Grade
96.8% pure
Total
dosage
50
mg/kg
Technical II;
consisting
of 74* II and
ca 26% alpha
C
Not carcinogenic Not undertaken 1. Perinatal dosage only.
2. Author's datn demon-
strate statistically
significant increase
in endocrine tumors
in males and rare
"lipomatous" renal
tumors in 2 test
females.
NCI,
1975
Osborne-
Mendel
Males
38.9;
77.9
Females
18.9;
37.8
Final Report
pending
Not undertaken
1. Relatively small
number negative
controls; uncertain-
ties in dosage; high
mortality in high
dosage test groups.
2. NCIdata shows excess
hepatic nodules in
males and females.
-------
Table S Summary of carcinogenicity data in mice
(taken from Table I of Epstein, 1976, with permission)
Authors Strain Formulation
lleptachlor (II);
epoxide (HE);
chlordane (C)
Concentrations (ppm)
II
lie
Carcinogenicity
Authors
conclusions
Comments
Independent
histological
re-evaluation
Davis,
(FDA), 1965
C3II
II and HE of
unspecified
purity
10
10
"Benign hepato-
mas" induced by
II and by IIU
II and HE both
hepatocarcino-
genic
1.
2.
CD-I Mixture of 25%
II and 75% HE
1.0; 5.0; 10.0
FDA data poorly
documented.
FDA data statisti-
cally signflcant
for tumor incidences.
3. Histological re-eval-
uation demonstrated
hepatocarcinogenic-
ity.
4. Ilepatocarcinogenic
effects statistically
significant.
IRDC data statisti-
IRDC,
1973
Dose related
nodular hyper-
plasia at 5.0
and 10.0 ppm
Hepatocarcino-
genic
1.
2.
B6C3F1 Technical II; Males:
consisting 6.1; 13.8
of 74% II, Females
and ca. 26% C 9.0; 18
Not undertaken IT
cally significant
excess of nodular
hyperplasias.
Histological re-eval-
uation found liepato-
carcinomas.
Ilepatocarcinogenicity
statistically signi-
f leant.
Relatively small
number negative
controls; non-concur-
rent experiments;
uncertainties in
dosage.
Revised data statis-
tically significant
for hepatocarcino-
genicity.
NCI,
1975
Final report
pending
2.
-------
group consisted of 2S males and 25 females. Mortality in males ranged
from 32 percent for the controls to 52 percent at the dosage level of
2.5 mg/kg of diet and in the females ranged from 24 percent in controls
to 52 percent at a dose level of 7.5 mg/kg of diet. They stated, however,
that the increased mortality in the groups fed heptachlor epoxide was
not significant. They also stated that the earliest tumor was discovered
during the 13th month and that animals dying before that were examined,
but were not included among the numbers capable of bearing tumors. The
authors concluded that the tumor incidence was unrelated to the heptachlor
epoxide content in the diet, although they acknowledge an excess of
hepatomas in the test animals (Epstein, 1976). An independent statistical
analysis of this data indicated that all the heptachlor epoxide dose
levels except the 0.5 mg/kg level in the males, were significant at the
P = 0.05 probability level.
Re-evaluation of tissue slides of the 1959 Kettering study by Dr.
Melvin D. Reuber indicated that there was an increase in hyperplastic
nodules and carcinomas of the liver in the treated animals when compared
to control animals (U.S. EPA, 1977). He also found a greater incidence
of carcinomas in females than in males, as the Kettering data had also
indicated. In addition, he found highly malignant tumors in brain,
thyroid, adrenal, kidney, lung, bone, and genital organs. Reuber
concluded that because carcinomas of the liver in the untreated rats
were infrequent, the presence of 23 liver carcinomas among 215 treated
-8
rats indicates that heptachlor epoxide is carcinogenic in rats at P<10
(U.S. EPA, 1977).
C-31
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Dr. Williams (U.S. EPA, 1977) also re-evaluated the Kettering
tissue slides, and he concluded that the study demonstrated an increased
incidence of cancer in the livers of treated rats and an increase in
hyperplastic nodules in the males only at the 10 mg/kg level. He
considered the seven liver malignancies in the treated animals versus no
malignancies in controls, to be strongly suggestive of a carcinogenic
effect (U.S. EPA, 1977). Williams like Kettering and Reuber, also
diagnosed a range of unusual malignant tumors in treated animals (Epstein,
1976).
The slides were re-evaluated by three other independent pathologists
(Drs. Stewart, Squire and Popper) and all three diagnosed a higher
incidence-of carcinomas than that reported by the Kettering workers who
found only two (U.S. EPA, 1977; Epstein, 1976).
In 1966 the Kettering Laboratory produced another unpublished
report dealing with the administration of a mixture of 75 percent
heptachlor and 25 percent heptachlor epoxide to female CD rats at doses
of 0, S.0, 7.5, 10.0, and 12.5 mgAg in the diet (Jolley, et al. 1966).
After 104 weeks of exposure various lesions in the pituitary gland,
adrenal gland, mammary gland, and the liver were found but considered by
the original investigators to be ,,spontaneous', because these lesions
were found both in control and treated groups. The lesions of the
pituitary glands and adrenal glands were considered hypertrophies rather
than neoplasms. The lesions of the mammary gland were diagnosed as
adenomas or fibroadenomas of mammary glands. The liver lesions were
referred to as "clusters.of enlarged hepatic cells" (Epstein, 1976y calls
it centrilobular hepatocytcmegaly), with cytoplasmic degranulation and
C-32
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clusters of enlarged irregular vacuolated cells filled with lipid and
distributed randomly in the lobules. They concluded that the experimental
diet caused the changes in the liver which were qualitatively similar to
but quantitatively different from lesions in control rats. Epstein,
(1976) suggested that a re-evaluation of the liver histology in all test
and control groups is necessary before the significance of these and
other possible lesions can be assessed.
In 1965 FDA completed a 2 year study of heptachlor and heptachlor
epoxide fed to CJfeb/Fe/J mice (Davis, 1965). Three groups of 100 males
and 100 females per group were fed 10 mg of heptachlor per kg of diet,
10 mg heptachlor epoxide per kg of.diet, or a control diet. During the
2 year period survival rates of 34 percent, 30 percent, and 9.5 percent
were reported for the control group and the heptachlor and heptachlor
epoxide fed animals, respectively. Over the test period 30 control mice
had benign tumors only and 21 controls had malignant tumors; heptachlor-
treated mice had 51 benign tumors only and 10 malignant tumors; heptachlor
epoxide-treated mice had 8S benign tumors only and 15 malignant tumors.
Statistics were not run on this data by FDA because of incompleteness in
the number of samples and. the "arbitrariness of microscopic diagnoses"
(Davis, 1965). Davis stated that the incidence of hepatic hyperplasia
and benign hepatomas was approximately doubled in the test groups, but
concluded that heptachlor and heptachlor epoxide do not have a significant
effect on. the incidence of malignant tumors.
The tissue slides from the 1965 FDA study were re-evaluated by Dr.
Reufaer. He found liver carcinomas in 64 out of 87 male mice (75 percent)
and 57 out of 78 female mice (74 percent) ingesting heptachlor; in 73 out
C-33
-------
of 79 male mice (92 percent) and 77 out of 31 female mice (95 percent)
ingesting heptachlor epoxide; and in 22 out of 73 control male mice (30
percent) and in 2 out of S3 control female mice (4 percent) (Reuber,
1977 b). He also stated that the affected treated animals often had
three to four carcinomas per liver with a size of 3 to 5 an, while
affected control animals had only solitary carcinomas of a size 5 mm or
less. Reuber concluded that heptachlor and heptachlor epoxide diets
caused the development of a highly significant incidence of carcinomas
of the liver which were capable of invasion and metastasis.
Four other independent pathologists (Drs. Stewart, Squire, Williams,
and Sternberg) were asked to review slides from 19 animals that Reuber
had diagnosed as having hepatic carcinomas. Drs. Stewart, Squire and
Sternberg agreed with Dr. Reuber that the 19 animals had heptatic carcin-
omas (U.S. EPA, 1977-). Or. Williams diagnosed eight carcinomas, 10
nodules or hyperplastic nodules, and one dysplastic area. However, Or.
Williams considers that hyperplastic nodules are induced only by carcin-
ogens, therefore he considers them evidence of a carcinogenic effect on
the liver (Epstein, 1976).
Cabral, et al. (1972) conducted a study using 95 Wistar rats force
fed heptachlor in com oil by gastric intubation. Heptachlor was adminis-
tered at a level of 10 mg/kg of body weight five times on alternating
days beginning at 10 days of age. It was observed that the incidence of
tumors in males occurred at different sites and was not reproducible,
while the tumors in females were in the adrenal, thyroid, and pituitary
glands and were comparable in both control and treated groups. In the
treated females, 9 of 28 rats developed 12 tumors in various organs,
C-34
-------
including five mammary tumors and two renal lipomatous tumors. In the
control group, 4 of 27 females developed four tumors, two of which were
located in the breast. They concluded, that "in view of the different
locations of the tumors and the lack of reproducibility of the findings
among males, the results are not considered as evidence of carcinogen-
icity of heptachlor under the present experimental conditions." Epstein
(1976) on the other hand, concluded that the study does show a statis-
tically significant incidence of endocrine tumors in males.
In 1975 the International Research Development Corp. (IRDC) completed
an unpublished 18 month study using CD-I mice on a treatment diet
mixture of 75 percent heptachlor epoxide and 25 percent heptachlor. The
study was designed using one negative control, one positive dietary
control of 2-Acetamidofluorene at 250 mg/kg, and three dietary treatment
groups of 1.0, 5.0, and 10.0 mg/kg, respectively. Each group contained
100 males and 100 females. After 6 months on these treatments 10 males
and 10 females were sacrificed from each group. It was found that the
liver weights were significantly increased in the 5.0 and 10.0 mg/kg
treatment groups in males and in the 10.0 mg/kg treatment group in
females (IRDC, 1973). Also, the livers from males fed the 1.0, 5.0, and
10.0 mg/kg diets and from females fed the 5.0 and 10.0 mg/kg diets
showed a dose related incidence and severity of hepatocytomegaly. A
large number of compound related liver masses (nodular hyperplasias)
were seen in mice that died during the study period or that were sacrificed
at the end of the test period. These masses were thought to be extensions
of the hepatocytomegaly lesions (IRDC, 1973). The mice fed the 1.0
mg/kg diet were considered to be free of compound-related nodular
C-35
-------
hyperplasia, since the incidence of the lesion was similar to the
untreated controls. No lesions were found suggestive of a compound
effect in any tissue other than the liver and no mention was made of any
carcinomas in any heptachlor epoxide/heptachlor test group.
Reuber also re-evaluated the histological material from the IRDC
study (U.S. EPA, 1977; Epstein, 1976). His findings indicated a signi-
ficant increase in the incidence of liver cancers induced by the heptachlor
epoxide/heptachlor mixture in males in the S.O mg/kg group and in both
males and females in the 10.0 mg/leg group. The incidence in these
groups was comparable to or higher than the incidence in the positive
(2-acetamedofluorene, 250 mg/kg) controls. It has been indicated that
the majority of lesions diagnosed as nodular hyperplasias by IRDC, were
diagnosed by Reuber as carcinomas (Epstein, 1976). It is interesting to
note though that both IRDC and Reuber diagnosed a similar number of
carcinomas in the positive controls, the discrepancies in diagnoses seem
largely restricted to the test groins at the 5.0 and 10.0 mg/Tcg levels
(Epstein, 1976).
Five additional pathologists reviewed slides from the IRDC study
(two of the pathologists were consultants to the Velsicol Corporation)
and found that the IRDC study had substantially underdiagnosed the
number of carcinomas present (Epstein, 1976). Epstein (1976) concluded
that the IRDC study demonstrated that the heptachlor epoxide/heptachlor
mixture induced a dose-related incidence of nodular hepatic hyperplasias,
and also demonstrated the hepatocarcinogenicity of heptachlor epoxide/
heptachlor as evidenced by the histological re-evaluations.
C-36
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The National Cancer Institute CNCI) released a preliminary report
on the Gulf South Research Institute study on heptachlor in 197S. These
preliminary findings have been reviewed by both Epstein Q1976) and the
U.S. EPA (1977], In 1977 the NCI released a final report which reported
on contract work conducted first by the Gulf South Research Institute
and more currently by Tracor Jitco Inc. (NCI, 1977). Both Osborne-
Mendel rats and B6C5F1 mice were used to test the possible carcino-
genicity of technical-grade heptachlor.
Groups of 50 rats of each sex were administered low and high doses
of heptachlor for SO weeks and then observed for 50 weeks. The doses of
heptachlor to both males and females were lowered several times during
the study due to toxic effects, and the time-weighted average doses used
were 38.9 and 77.9 mg/kg of heptachlor in the diet for male rats and
2S.7 and SI.3 mg/kg for female rats. Matched controls consisted of 10
untreated rats of each sex and pooled controls consisting of SO untreated
male and SO untreated female rats from similar bioassays of five other
compounds. All surviving rats were killed at 110 to 111 weeks and no
hepatic tumors were observed. Neoplasms were found in test animals or
with increased frequency when compared to control groups, but the nature,
incidence, and severity of the lesions observed p-rovide no clear evidence
of a carcinogenic effect of heptachlor in 0sborne-Mendel rats as reported
by the pathologists.
In the second part of the NCI study, groups of SO mice of each sex
were administered heptachlor at low and high doses for 30 weeks and then
observed for 10 weeks. The dose for males was reduced once while the dose
for females was reduced twice due to toxic effects. The time-weighted
C-37
-------
aveTage dosages in the diet were 6.1 and 13.3 mg/kg of heptachlor for
male nice, and 9 and 13 mg/kg of heptachlor for female mice. Matched
controls consisted of 10 of each sex of untreated mice and pooled controls
consisted of 90 untreated male and 70 untreated female mice from similar
bioassays of five other compounds. Results of hepatocellular carcinomas
in both male and female mice were found to show a highly significant
dose-related trend. Twenty-six percent of matched male controls and 20
percent of matched female controls developed hepatic carcinomas; IS
percent of the pooled male controls and 4 percent of pooled female
controls developed hepatic carcinomas; 24 percent of the low dose males
and 6 percent of the low dose females developed hepatic carcinomas; and
72 percent of the high dose males and 71 percent of the high dose females
developed hepatic carcinomas. It was concluded that heptachlor is
carcinogenic in mice livers under the conditions of this assay at the
high dosages given.
C-38
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CRITERION FORMULATION
Existing Guidelines and Standards
Agency
Published Standard
Reference
Occup. Safety
Health Admin.
Am. Conf. Gov.
Ind. Hyg. (TLV)
Fed. Republic
Germany
Soviet Union
World Health
Organ.**
U.S. Pub. Health
Serv. Adv. Comm.
500 jig/m^* on skin from air
500 pg/nH inhaled
500 pg/m^ inhaled
10 pg/m^ ceiling value
inhaled
0.5 pg/kg/day acceptable
daily intake in diet
Recommended drinking water
standard (1968) 18 pjg/l of
heptachlor and 18 pq/1
heptachlor epoxide
Natl. Inst. Occup.
Safety Health, 1977
Am. Conf. Gov. Ind.
Hyg.f 1971
Winell, 1975
Winell, 1975
Natl. Acad. Sci., 1977
Natl. Acad. Sci., 1977
* Time weighted average
** Maximum residue limits in certain foods can be found in Food Agric.
Organ./World Health Organ. 1977, 1978
C-39
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Current Levels of Exposure
Various investigators have detected heptachlor and/or
heptachlor epoxide in the major river basins of the United
States with a mean concentration of 0.0063 pg/1 (U.S. EPA,
1976) for those instances of detection. Food can add to
man's exposure to heptachlor and metabolites through biomag-
nification in the food chain. The FDA showed that in their
market basket study covering August 1974-July 1975 for 20
different cities (Johnson and Manshe, 1977) three of 12 food
classes contained residues of heptachlor epoxide ranging from
0.0006 to 0.003 ppm. A national study by the U.S. Department
of Interior in 1967-1968 reported that heptachlor and/or hep-
tachlor epoxide were found in 32 percent of the 590 fish sam-
ples examined (Henderson, 1969) with whole fish residues of
from 0.01 to 8.33 mg/kg. Schimmel, et al. (1976) reported an
average bioconcentration factor of 12,000 for the sheepshead
minnow which will subsequently be used in risk calculations
as being representative of fish bioconcentration potential.
Nisbet (1977) calculated the typical human exposure to
heptachlor to be 0.01 jig/individual/day based on an ambient
air mean concentration of 0.5 ng/m^ and breathing 20
of air per day. He states further that even in Jackson,
Miss., which has a mean air level as high as 6.3 ng/m^, the
average individual would inhale only 0.13 pg/day of hepta-
chlor. The significance of these figures is dependent upon
the efficiency of lung absorption which does not appear to be
reported for humans (Nisbet, 1977). Based on this, it appears
that inhalation is not a major route for human exposure to
heptachlor.
C-40
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Special Groups at Risk
Infants have been exposed to heptachlor and heptachlor
epoxide through mothers' milk (Savage, 1976) cows' milk (Rit-
cey, et al. 1972), and commercially prepared baby foods (Lips-
comb, 1968). It appears that infants raised on mothers' milk
run a greater risk of ingesting haptachlor epoxide than if
they were fed cows' milk and/or commercially prepared baby
food. Nisbet (1977) found that persons living and working in
or near heptachlor treated areas had a particularly high inha-
lation exposure potential.
Basis and Derivation for the Criterion
Heptachlor has been shown to exhibit numerous toxicolo-
gical effects in animal systems. Acute toxicity of hepta-
chlor and its metabolites has LD50 values ranging from 6 to
531 mg/kg depending upon the animal test system. Heptachlor
is generally classified as a neurotoxin because it produces
abnormal stimulation of the central nervous system when ani-
mals are exposed to high doses. Other effects on animal en-
zyme systems are referenced throughout the literature. Muta-
genicity was not demonstrated with Salmonella typhimurium in
the Ames assay; however, oral doses of heptachlor caused domi-
nant lethal changes in male rats as demonstrated by an increase
in the number of resorbed fetuses in intact pregnant rats.
Heptachlor administered to rats caused a marked decrease in
litter size, both in several litters of one generation as
well as in successive generations.
C-41
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Studies concerning the carcinogenicity of heptachlor and
heptachlor epoxide when administered to rats and mice have
been conducted by the Kettering Laboratory, the Food and Drug
Administration, Cabral, et al., International Research and
Development Corporation, and the National Cancer Institute.
Heptachlor or its metabolites have induced hepatocellular
carcinomas in three chronic mouse feeding studies and hepta-
chlor epoxide has produced the same response in one rat study
although no response was observed in four additional rat
studies.
The weight of evidence for carcinogenicity is sufficient
to conclude that heptachlor is likely to be a human carcino-
gen. As carcinogens are generally assumed to have a non-
threshold dose/response characteristic, the carcinogenic
effect is the most significant exposure effect from which to
estimate an ambient water quality criterion value. A linear,
non-threshold mathematic model is used in estimating human
health risks associated with the ingestion of heptachlor (see
appendix for model). Using the described model, the concen-
tration of heptachlor in water may be calculated assuming an
additional individual lifetime risk of 1/100,000, the inges-
tion of 2 1/day of water and 18.7 grams/day of contaminated
fish products, a representative fish bioaccumulation factor
of 12,000, and data for hepatocellular carcinoma incidence in
the FDA female mouse. The calculation yields a concentration
of 0.23 nanograms per liter as the desired ambient criterion
level to maintain an additional risk of one cancer per 100,000
exposed individuals.
C-42
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Basis for the Criterion
The proposed criterion for heptachlor/heptachlor epoxide
in drinking water was derived from the extrapolation of the
data presented in the carcinogenicity section of this docu-
ment using a linear, non-threshold model. The extrapolation
methodology can be found in the Methodology Document.
From this extrapolation the calculated dose of hepta-
chlor/heptachlor epoxide in drinking water was found to be
0.23 nanogram per liter.
Under the Consent Decree in NRDC v. Train, criteria are
to state "recommended maximum permissible concentrations (in-
cluding where appropriate, zero) consistent with the protec-
tion of aquatic organisms, human health, and recreational ac-
tivities." Heptachlor is suspected of being a human carcino-
gen. Because there is no recognized safe concentration for a
human carcinogen, the recommended concentration of heptachlor
in water for maximum protection of human health is zero.
Because attaining a zero concentration level may be in-
feasible in some cases and in order to assist the Agency and
States in the possible future development of water quality
regulations, the concentrations of heptachlor corresponding
to several incremental lifetime cancer risk levels have been
estimated. A cancer risk level provides an estimate of the
additional incidence of cancer that may be expected in an
exposed population. A risk of 10"^ for example, indicates
a probability of one additional case of cancer for every
100,000 people exposed, a risk of 10~® indicates one addi-
tional case of cancer for every million people exposed, and so
forth.
C-43
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In the Federal Register notice of availability of draft
ambient water quality criteria, EPA stated that it is
considering setting criteria at an interim target risk level
of 10~5, 10-6 or 10~7 as shown in the table below.
Exposure Assumptions Risk Levels and Corresponding Criteria (1)
(per day)
0 10~7 10~6 10"5
2 liters of drinking water 0 0.0023 ng/1 0.023 ng/1. 0.23 nq/1
and consumption of 18.7
grams fish and shellfish. (2)
Consumption of fish and 0 0.0023 ng/1 0.023 ng/1 0.23 ng/1
shellfish only.
(1) Calculated by applying a modified "one-hit" extrapola-
tion model described in the Methodology Document' to the
animal bioassay data presented in Appendix I. Since the
extrapolation model is linear at low doses, the addi-
tional lifetime risk is directly proportional to the
water concentration. Therefore, water concentrations
corresponding to other risk levels can be derived by
multiplying or dividing one of the risk levels and
corresponding water concentrations shown in the table by
factors such as 10, 100, 1,000, and so forth.
C-44
-------
(2) 98 percent of the heptachlor exposure results from the
consumption of aquatic organisms which exhibit an aver-
age bioconcentration potential of 5,200-fold. The re-
maining 2 percent of heptachlor exposure results from
drinking water.
Concentration levels were derived assuming a lifetime
exposure to varius amounts of heptachlor, (1) occurring from
the consumption of both drinking water and aquatic life grown
in waters containing the corresponding heptachlor concentra-
tions and, (2) occurring solely from consumption of aquatic
life grown in the waters containing the corresponding hepta-
chlor concentrations.
Although total exposure information for heptachlor is
discussed and an estimate of the contributions from other
sources of exposure can be made, this data will not be fac-
tored into amibient water quality criteria formulation until
additional analysis can be made. The criteria presented,
therefore, assume an incremental risk from ambient water
exposure only.
C-45
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I
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APPENDIX I
Derivation of Criterion for Heptachlor
The lifetime carcinogenicity study of heptachlor epoxide
at 10 ppm in the diet of C3Heb/Fe/J strain mice resulted in
liver carcinomas in females in 77 of 81 treated animals and 2
of 54 controls (Davis, 1965). Using a fish bioaccumulation
factor of 5,200, the water concentration estimated to result
in a lifetime risk of 10"^ is calculated from the extra-
polation model using the following parameters:
nt =77 le = 104 weeks
NT = 81 d = 10 x 10-6 x 0.13 x 10=6 mg
nc = 2 food per day/kg body weight
NC = 54 =1.3 mg/kg/day
Le = 104 weeks w = 0.030 kg
L = 104 weeks
R = 5,200
The result is that the water concentration corresponding
to a lifetime risk of 10"^ is 0.23 (0.233) nanograms/liter.
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