xvEPA
Drifted States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Cntena and Standards Divwion
Washington DC 20460
EPA «0 5-60-062
October 1980
Water Quality
Criteria for
Heptachlor
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AMBIENT WATER QUALITY CRITERIA FOR
HEPTACHLOR
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
ii
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.I. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train. 8 ERC 2120
(0.0.C. 1976), modified, 12 ERC 1833 (0.0.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOH
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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Aquatic t:*e Toxicology
Vji '1 i arr A. Brunqs. EcL-f-3t
U.S. Environmental Protection Agency
'•'.anna1, i an Toxicology an£ Human Health Effects:
>,'. Br:ice Peiranc (author) HERL
'J.I. ir v • -"CM 'er: e' ^""ctect ~: :r> Agency
:^ N Gracy 'ace. mar.) ECAO-Cin
U.S. Environmental Protection Agency
Donna Sivulka (doc. mgr . ) ECAC-Cin
U.S. Environnental Protection Agency
Si Duk Lee, ECAC-Cin
J.S. Environmental Protection Agsncy
Shane Que Hee
University of Cincinnati
iJavid J. harser., E"3..-Gulf Breeze
U.S. EnvTronmenr..;1 ?rotect-,on Aa
Roy E. Albert, GAG*
i • f — • i ~>
i ^ •• *n *, i?y."ri'Tioo~"1 —'*• *"\ ^ Q .*"• ^ •.•'•• ^ ™ jj o ^
John Do'jll
University of Kansas
Kris Khanna, CDW
U.S. Environmental Protection Agenc
Fumio ttatsuinura
Michigan State University
Joseph Santodonato
Syracuse Research Corporation
Technical Supoort Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
?.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Oenessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, P. Gray, R. Swantack.
*CAG Participating Members: Elizabeth L. Anderson, Larry Anderson, Ralph Arnicar,
Steven Bayard, David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard haberman,
Chara1ingayya hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dnarrr V. Singh, and Todd W. Thorslund.
IV
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TABLE OF CONTENTS
Criteria Suawry
Introduction A-l
Aquatic Life Toxicology B-l
Introaution B-l
Effects B-2
Acute Toxicity B-2
Chronic Toxicity B-6
Plant Effects 8-8
Residues 8-9
Miscellaneous B-12
Summary B-14
Criteria B-15
References B-37
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-2
Inhalation C-7
Dermal C-9
Pharmacokinetics C-10
Absorption and Distribution C-10
Metabolism and Excretion C-12
Effects C-19
Acute, Subacute, and Chronic Toxicity C-19
Mutagenicity C-25
Teratogenicity C-25
Synergism and/or Antagonism C-26
Carcinogenicity C-27
Criterion Formulation C-42
Existing Guidelines and Standards C-42
Current Levels of Exposure C-42
Special Groups at Risk C-43
Basis and Derivation of Criteria C-44
References C-48
Appendix C-60
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CRITERIA SUMMARY
HEPTACHLOR
CRITERIA
Aquatic Life
For heptachlor the criterion to protect freshwater aquatic life as de-
rived using the Guidelines is 0.0038 ug/1 as a 24-hour average, and the con-
centration should not exceed 0.52 ug/1 at any time.
For heptachlor the criterion to protect saltwater aquatic life as de-
rived using the Guidelines is 0.0036 ug/1 as a 24-hour average, and the con-
centration should not exceed 0.053 u9/l at any time.
Human Health
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of heptachlor through Ingestion of contaminat-
ed water and contaminated aquatic organisms, the ambient water concentration
should be zero based on the non-threshold assumption for this chemical.
However, zero level may not be attainable at the present time. Therefore,
the levels which may result in incremental increase of cancer risk over the
lifetime are estimated at 10, 10"6, and 10~7. The corresponding
co g 6
recommended criterion are 2.J4 ng/1, 0.2F ng/1, and 0.02£ ng/1, respective-
ly. If the above estimates are made for consumption of aquatic organisms
on c
only, excluding consumption of water, the levels are Z.pt ng/1, 0.2J ng/1,
and O.OZ^ong/l, respectively.
vi
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INTRODUCTION
Heptachlor is a broad spectrum insecticide of the group of polycyclic
chlorinated hydrocarbons called cyclodiene insecticides. It was introduced
in 1948 as a contact insecticide under the trade names E 3314 and Velsicol
104. During the period from 1971 to 1975 the most important use of hepta-
chlor was to control soil insects for corn cultivation and other crop pro-
duction. Since 1975 both the applications and production volume of hepta-
chlor have undergone dramatic changes resulting from the sole producer's
voluntary restriction of domestic use, and the subsequent issuance by the
U.S. Environmental Protection Agency of a registration suspension notice for
all food crops and home use of heptachlor, effective August 1, 1976. How-
ever, significant commercial use of heptachlor for termite control or in
nonfood 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 C10H5C17, a molecular weight of 373.35, a
melting point of 95*C and a vapor pressure of 3 x 10~* mm Hg at 25*C (Met-
calf, 1955; Martin, 1972; Wlndholz, 1976). It has a solubility in water of
0.056 mg/1 at 25 to 29*C and Is readily soluble 1n relatively nonpolar sol-
vents (Metcalf, 1955). The chemical name for heptachlor 1s 1,4,5,6,7,8,8-
heptachloro-3a,4,7,7a-tetrahydro-4,7-methano1ndene. It is produced by means
of a D1el$-Alder addition reaction which joins cyclopentadlene to hexa-
cMorocycTopentadlerie (VMndholz, 1976).
Technical grade heptachlor has the typical composition of approximately
73 percent heptachlor, 21 percent trans(gamma) chlordane, 5 percent nona-
chlor, and 1 percent chlordene isomers (Martin, 1972). Technical heptachlor
is a tan, soft, waxy solid with a melting point range from 46 to 74*C. It
A-l
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has a vapor pressure of 4 x 10"4 mm Hg at 25*C and a density of 1.65 to
1.67 g/ml at 25*C.
In general, heptachlor is quite stable to chemical reactions such as
dehydrochlorination, autooxldation, and thermal decomposition. However, in
the environment, heptachlor undergoes numerous microbial, biochemical, and
photochemical reactions.
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 (Oavidow and Radomski, 1953a,b). It represents the
principal metabolite of heptachlor.
The photodecomposition of heptachlor to photoheptachlor has been demon-
strated 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.
Heptachlor epoxide has also been shown to undergo photodecomposition to
photoheptachlor epoxide (IIIB) when exposed to UV light or sunlight (Graham,
et al. 1973).
Heptachlor can also be biologically converted to chlordene, 3-chloro-
chlordene, 1-hydroxychlordene, chlordene epoxide, l-hydroxy-2, 3-epoxycnlor-
dene, and 2-chlorochlordene.
Tbt persistence of heptachlor and heptachlor epoxide in the environment
1s M»11 -known. Heptachlor also has been shown to be converted to the meta-
bolite, heptachlor epoxide, 1n various soils (Gannon and Bigger, 1958;
Lichtenstein, 1960; Lichtenstein, et «1. 1971; Nash and Harris, 1972} and
plants (Gannon and Decker, 1958).
A-2
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REFERENCES
Sensors, W.R., et al. 1971. Photolysis of solid and dissolved dieldrin.
Jour. Agric, Food Chem. 19: 65,
Davidow, 8, and J,U Radomskis 1953a« Isolation of an epoxide metabolite
from fat tissues of dogs fed heptachlor. Jour. Pharmacol. Exp. Ther.
107: 259.
Oavidow, 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 1n soil. Jour. Econ. Entomol. 51: 1.
Gannon, N. and G.C. Decker. 1958. The conversion of aldrin to dieldrin on
plants. Jour. Econ. Entomol. 51: 8.
Graham, R.E., et al. 1973. Photochemical decomposition of heptachlor epox-
ide. Jour. Agric. Food Chem. 21: 284.
Lichtensteln, E.P. 1960. InsecticidaT residues 1n various crops grown in
soils treated with abnormal rates of aldrin and heptachlor. Jour. Agric.
Food Chem. 8: 448.
Lichtensteln, E.P., et al. 1970. Degradation of aldrin and heptachlor in
field soils. Jour. AgHc. Food Chem. 18: 100.
A-3
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Lichtenstein, E.P., et al. 1971. Effects of a cover c /ersus soil cult-
ivation on the fate of vertical distribution of insects e residues in soil
7 to 11 years after soil treatment. Pestic. Monitor. -. 5: 218.
Martin, H., (ed.) 1972. Pesticide Manual, 3rd (ed.). Br. Crop Prot.
Counc., Worcester, England.
Metcalf, R.L. 1955. Organic Insecticides. Interscience Publishers, John
Wiley and Sons, Inc., New York.
Miles, J.R.H., et al. 1969. Metabolism of heptachlor and its degradation
products by soil microorganisms. Jour. Econ. Entomol. 62: 1334.
Nash, R.6. and W.G. Harris. 1972. Chlorinated hydrocarbon Insecticide
residues in crops and soil. Jour. Environ. Qual. 2: 269.
Windholz, M., (ed.) 1976. The Merck Index. Merck and Co., Inc., Rahway,
Mew Jersey.
A-4
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Aquatic life Toxicology*
INTRODUCTION
Heptachlor is a chlorinated hydrocarbon pesticide that has had wide us-
age in the United States as a crop insecticide. It has been widely used for
such purposes as fire ant and general insect control in much of the United
States. 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 freshwater organ-
isms. More recently, pertinent studies have been completed that demonstrate
acute and chronic toxicity and b1oaccumulat1on potential to saltwater organ-
isms. Most of these studies, however, were carried out under static condi-
tions with results based on unmeasured rather than measured concentrations.
In most instances tests used technical grade heptachlor as the toxicant.
Technical grade heptachlor usually consists of 72 percent heptachlor and 28
percent impurities; these impurities are primarily trans-chlordane, cis-
chlordane, and nonachlor. There are insufficient data to evaluate the rela-
tive toxicitles of the various grades of heptachlor and the Impact of the
impurities on the toxicity determinations. Because of the unknown contribu-
tion of the Impurities, all data Included In this document are reported 1n
concentrations of the actual material used for testing. Some authors used
technical material in testing and then calculated concentrations as 100 per-
cent heptachlor for data reporting. These data were converted back to con-
*The reader 1s referred to the Guidelines for Deriving Water Quality Crite-
ria for the Protection of Aquatic Life and Its Uses 1n order to better un-
derstand 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 calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
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centrations of technical grade heptachlor in this document.
Some reported studies have examined the Impact of water hardness and
temperature on acute toxicity of heptachlor. Variable results were found
regarding the effect of temperature on heptachlor toxicity, whereas water
hardness had little effect on toxicity to fathead minnows in a single
comparison.
Heptachlor epoxide is the most commonly found degradation product of
heptachlor. Both heptachlor and heptachlor epoxide have been reported in
fish residues. There are few data on the relative toxicity to aquatic or-
ganisms of these two materials. What data are available suggest that the
epoxide is not more toxic than heptachlor Itself.
EFFECTS
Acute Toxldty
In all but one case (Macek, et al. 1976)(Table 6), freshwater data on
acute toxicity were obtained in static tests, and in every case exposure
concentrations were unmeasured. Values for standard tests with fish and in-
vertebrate species are reported in Table 1, and some additional acute toxic-
ity data are given 1n Table 6. Ten freshwater invertebrate and eight fish
species have been tested.
Many of the authors cited 1n Table 1 reported values for numerous other
pesticides 1n addition to heptachlor. No clear relationship regarding the
toxicity of heptachlor compared to other pesticides was found. For example,
heptachlor 1$ substantially less toxic to the scud, Gammarus fasciatus, than
DOT and endrln; for the freshwater glass shrimp, however, there 1s little
difference 1n toxicity among the three pesticides (Sanders, 1972). For the
stonefly, Pteronarcys californlca, heptachlor 1s less toxic than endrln and
more toxic than DOT (Sanders and Cope, 1968). Katz (1961) found with
chinootc salmon and coho salmon that DDT and endrln are more toxic than
8-2
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heptachlor, whereas with rainbow trout, heptachlor is more toxic than DDT.
It is difficult to determine how many 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 the data in Table 1 that
heptachlor is generally highly toxic in an acute exposure.
LC50 values for invertebrate species range from 0.9 ug/l for a 96-hour
exposure with the stonefly, Pteronarcella badia, to 80 ug/1 for a 48-hour
exposure with the cladoceran, Simocephalus serrulatus (Table 1). Larvae of
the Fowler's toad were tested by Sanders (1970)(Table 6); the 96-hour LC5Q
is 440 ug/l.
Freshwater fish species are generally less sensitive to heptachlor than
are invertebrate species (Table 1). Ninety-six-hour LC50 values for fish
species range from 10.0 ug/1 for rainbow trout to 320 ug/1 for goldfish
(Table 1).
The Freshwater Final Acute Value for heptachlor, derived from the spe-
cies mean acute values listed in Table 3 using the procedure described in
the Guidelines, is 0.52 wg/1.
There is little information regarding the possible effect of water hard-
ness on the toxicity of heptachlor. The 96-hour LC50 values for fathead
minnows exposed to technical grade heptachlor in soft and hard water are 130
and 78 wg/1. respectively (Henderson, et al. 1959). It is difficult to for-
mulate any conclusions regarding hardness-related effects on the basis of
these tests.
Bridges (WeS^found that toxicity to redear sunflsh Increased at higher
temperatures (Table 6). Twenty-four-hour EC5Q values decreased (toxicity
increased) from 92 wg/l at 45*F to 22 Pg/l at 85*F. Macek, et al. (1969)
found essentially no difference in toxicity to rainbow trout when tested at
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1.6, 7.2, and 12.7'C (Table 1). Naqvi (1973) found 100 percent mortality of
tubificid worms, Sranchiura sowerbyi. at 2,500 ug/1 when tested at 4.4 and
32.2*C (Table 6); at 21.0'C no mortality occurred. Sanders and Cope (1966)
found that with the cladoceran, Simocephalus serrulatus, the 48-hour ECgo
values for heptachlor were 47 ug/l at 60*F and 80 ug/l at 70*F (Table 1).
Only one acceptable freshwater study was found that compared the rela-
tive toxicity of heptachlor to its common degradation product, heptachlor
epoxide. Frear and Boyd (1967), using an unspecified grade of material, de-
termined the 26-hour LC^Q for Daphnia magna to be 52 ug/1 for heptachlor
and 120 ug/1 for heptachlor epoxide (Table 6).
Many authors reported LC5Q values for freshwater fish species after
24, 48, and 96 hours of exposure to heptachlor. In general, toxicity in-
creased slightly with time, although considerable variation existed among
species. 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 relationship
of ICgg values to exposure time was more dramatic and variable for inver-
tebrate species. The range of values for the ratio of 96-hour/24-hour
LCg0 values was 0.06 to 0.56. Exposure time, therefore, can significantly
affect ICgQ values for invertebrate species exposed to heptachlor.
Heptachlor has been shown to be acutely toxic to saltwater fish and in-
vertebrate species. Many of the saltwater toxicity tests with heptachlor
have used technical grade material containing approximately 65 percent hep-
tachlor, with the remaining 35 percent being a mixture of trans-chlordane,
cis-chlordane, nonachlor, and related compounds. There are insufficient
saltwater data to evaluate relative toxicity of heptachjor and heptachlor
epoxide. However, the data available suggest that toxicity of the technical
material is mostly attributable to heptachlor and that toxicitles of hepta-
chlor and heptachlor epoxide are similar (Schlmmel, et al. 1976a). The tox-
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icity of the several chlordane isomers 1s discussed in the criteria document
for that compound and is, in general, 2 to 7 times less than that of
heotachlor.
Saltwater invertebrate species seem to be more sensitive than fish spe-
cies to heptachlor and heptachlor epoxide and demonstrate a greater varia-
bility in sensitivity between species (Table 1). Of the seven species
tested, the commercially valuable pink: shrimp is especially sensitive with
96-hour I_C50 values as low as 0.03 wg/l (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)(Tables 1
and 6). Ninety-six-hour ICgg values derived front static exposures or ex-
posures based on unmeasured concentrations probably underestimate toxicity
of heptachlor and heptachlor epoxide to Invertebrate species. For example,
the 96-hour LC^g of heptachlor for the grass shrimp based on a static ex-
posure using unmeasured concentrations is 440 gg/1 (Eisler, 1969), whereas
the result from a flow-through test with measured concentrations is 1.06
ug/l (Schimmel, et al. 1976a). A similar relationship is true for the
American oyster. Test results from a flow-through exposure with unmeasured
concentrations (Butler, 1963) were 27 and 30 ug/l and, using flow-through
procedures and measured concentrations, Schimmel, et al. (1976a) determined
a 96-hour EC5Q of 1.5 yg/1. Generally toxicity data obtained from static
tests or those 1n which concentrations were not measured yielded higher
acute values for heptachlor than other tests. The range of LC5Q values
for saltwater Invertebrate species is from 0.03 to 440 ug/l.
The 96-hour LCgo values (Table 1) derived from flow-through tests with
four saltwater fish species range from 0.85 to 10.5 ug/l (Korn and Earnest,
1974; Schimmel, et al. 1976a; Hanscn and Parrlsh, 1977). Results of static
exposures of eight fish species are more variable and yield higher LC5Q
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values than those from flow-through tests; i.e., 0.8 to 194 ug/l (Katz,
1961; Eisler, 1970a). LC50 values derived from tests using aeration,
static test procedures, or unmeasured concentrations probably underestimate
the toxicity of heptachlor (Schimmel, et al. 1976a; Goodman, et al. 1978).
The Saltwater Final Acute Value for heptachlor, derived from the species
mean acute values listed in Table 3 using the procedure described in the
Guidelines, is 0.053 ug/l-
Chronic Toxicity
The only available freshwater chronic study on heptachlor was that of
Macek, et al. (1976) using the fathead minnow (Table 2). 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, and 0.11
ug/l. 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/l or lower. Analytical difficulties were encountered during the
last 10 weeks of the 40-week exposure period. However, all effects found in
the study occurred during the first 60 days, and so the analytical difficul-
ties did not affect the reported chronic endpoint values. The chronic lim-
its of heptachlor for fathead minnows are 0.86 and 1.84 ug/l. Data on the
acute toxicity of heptachlor to fathead minnows indicate that this species
is generally somewhat less sensitive than other fish species. There are no
direct comparisons between the chronic results for fathead minnows and
96-hour LC50 values from tests conducted by the same author. However, by
using the species mean acute value for fathead minnows, an acute-chronic ra-
tio of 80 can be calculated for fathead minnows (Table 2).
No valid chronic test data were available for any freshwater inverte-
brate species. However, 1n general, invertebrate acute values are consider-
ably lower than fish acute values (Table 1); Indeed, some LC5Q values for
B-6
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Invertebrate species were lower than the chronic value for fathead minnows.
It is reasonable to expect, therefore, that some freshwater invertebrate
chronic values would be lower than the available freshwater fish chronic
value.
Insufficient data are available to calculate a Freshwater Final Chronic
Value for heptachlor.
A 28-day life-cycle toxicity test (Table 6) was completed with a salt-
water mysid shrimp, Hysidopsis bahia (U.S. EPA, 1980). Mortality of mysid
shrimp exposed to measured concentrations of 0.17, 0.64, 1.3, and 3.1 ug/1
was significantly greater than that in the control. Mortality of animals at
an intermediate low concentration of 0.33 ug/1 was not significantly differ-
ent from controls. Because of this anomaly in the data, the more conserva-
tive estimate of effect on mortality is used (0.64 i»g/l). Statistical anal-
ysis of data on cumulative number of offspring per female per day did not
reveal significant differences between the control and any test concentra-
tion. Therefore, cumulative mortality of test animals exposed to 0.64 ug/l
heptachlor was the most sensitive effect. Because this effect is based on
anomalous data, test results are included in Table 6 rather than Table 2.
The chronic toxicity of technical heptachlor to the sheepshead minnow
was measured 1n an 18-week partial life-cycle exposure begun with juveniles
(Hansen and Parrlsh, 1977). Survival was affected at concentrations of 2.8
ug/l and greater (Table 6). Embryo production was significantly decreased
at the lowest concentration tested, 0.71, and at test concentrations of 1.9
to 5.7 ug/l. An Intermediate test concentration, 0.97 yg/1, did not cause
reduced embryo production significantly different from controls. Because of
this anomaly 1n the data, test results were Included 1n Table 6 rather than
Table 2.
B-7
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The chronic toxicity of technical heptachlor to sheepshead minnows was
also measured in a separate 28-day early Tife-stage test. Hatching was un-
affected, but survival of fry was significantly reduced from that of con-
trols at measured concentrations of 2.24 to 4.3 ug/1 (Goodman, et al.
1978). Comparison of these data with that from the early life-stage portion
of the partial life-cycle exposure (Hansen and Parrish, 1977) shows survival
of fry was reduced at a similar concentration in both exposures (2.24 and
2.8 ug/1, respectively). Growth of fry in the early life-stage test (Good-
man, et al. 1978) was significantly reduced at concentrations of 2.04 ug/l
and above. No detrimental effects were observed at 1.22 ug/1- If observed
decreases in embryo production in the partial life-cycle test at 0.71 ug/l
are an anomaly, then the results from the ent>ryo-fry exposure predict the
results of a life-cycle toxicity test rather accurately.
Chronic values for saltwater species can be obtained from only the
sheepshead minnow early life-stage test (Table 2) and not the life-cycle
tests on this fish species and mysid shrimp (Table 6). The chronic value
from the early life-stage test is 1.58 ug/1, and the acute-chronic ratio is
3.9. If effects observed in the sheepshead minnow partial life-cycle test
at 0.71 ug/l and in the mysid shrimp life-cycle test at 0.17 ug/l are con-
sidered anomalies, the acute-chronic ratios calculated using these two tests
are 4.6 and 7.6, respectively. The range 1n acute-chronic ratios for the
three tests 1s remarkably narrow, less than a factor of two.
Plant Effects
Two 96-hour tests with a freshwater algal species, Selenastrum capricor-
nutum, have been conducted (Table 4). The EC5Q values obtained are 39.4
and 26.7 vg/1. It should be noted that the exposure concentrations of hep-
tachlor rapidly diminished during the course of the tests, and substantial
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amounts of hydroxychlordene were present and may have contributed signifi-
cantly to the toxic effect (Call and Brooke^ 1980).
Information on the sensitivity of saltwater aquatic plants is limited to
effects on five species of unicellular algae, or dinoflagellates and one
study on a natural phytoplankton community (Tables 4 and 6).
Effects of heptachlor on three species of marine unicellular algae, Iso-
chrysis galbana, Porphyridium cruentum. and Skeletonema costatum, are fairly
similar. The 96-hour ECgo values range from 93 to 273 wg/l. The EC5Q
for a fourth species, Dunaliella tertlolecta. is 8 to 24 times higher (Table
4).
Toxicity tests with the marine dinoflagellate, Exuviella baltica. show
effects of heptachlor at a concentration of 50 ug/1 (Table 6). Cell densi-
ty, chlorophyll £ per unit volume of culture, 14C uptake per cell, and
carbon fixation per unit of chlorophyll £ were reduced at this concentration
after seven days. The natural phytoplankton community study was a 4-hour
exposure at a single exposure concentration of 1,000 ug/1. This concentra-
tion of heptachlor caused a 94.4 percent decrease in productivity (Butler,
1963)(Table 6).
Residues
The only appropriate residue studies on freshwater species are those re-
oorted by Veith, et al. (1979). These studies used 32-day exposures of fat-
head minnows to heptachlor and heptachlor epoxide (Table 5). Bioconcentra-
tion factors (BCF) are 9,500 for heptachlor and 14,400 for heptachlor
epoxide.
Andrews, et al. (1966} reported the results of tests in which bluegills
held in plastic pools were fed food containing heptachlor at either 25.0,
10.0, 5.0, or 0.0 mg/kg/day (Table 6); tests were run in duplicate. Effects
on survival, histopathology, and growth were monitored. In general, adverse
B-9
-------
effects were found at a feeding rate of 10 mg/kg/day. In order to determine
a maximum dally dietary Intake level for wildlife, a value of 7.1 mg/kg/day
(the geometric mean of 5 and 10 mg/kg/day) was calculated.
Data on the bioconcentration of heptachlor and heptachlor epoxide from
water Into the tissues of saltwater organisms are given 1n Tables 5 and 6.
The only 8CF values available at steady-state for heptachlor and heptachlor
epoxide are those for fish species (Table 5).
The three studies (Schlmmel, et al. 1976b; Hansen and Parrish, 1977;
Goodman, et al. 1978) listed 1n Table 5 used technical heptachlor containing
65 percent heptachlor, 22 percent trans-chlordane, 2 percent cis-chlordane,
2 percent nonachlor, and 9 percent other unidentified compounds. Goodman,
et al. (1978) and Hansen and Parrish (1977) measured both heptachlor and
trans-chlordane in the exposure water. Schlmmel, et al. (1976b) measured
only heptachlor 1n the exposure water. Each study measured concentrations
of heptachlor, heptachlor epoxide, trans-chlordane, and c1s-chlordane in ed-
ible tissues or whole fish. Therefore, several calculations of 8CF values
are possible, and these are given In Table 5.
Spot exposed for 24 days to technical grade material reached a maximum
concentration of heptachlor 1n whole body after three days (Schimroel, et al.
1976b). In the same exposure, maximum levels of heptachlor epoxide were
reached 1n whole fish after 17 days. Whole body residues were generally 1.6
times higher than residues 1n edible portions of fish. After a 28-day peri-
od of depuration, less than 10 percent of the maximum amount of heptachlor
remained 1n tissues; 1t was either lost or metabolized to the epoxide
(Schimmel, et al. 1976b).
Juvenile sheepshead minnows exposed 1n two separate exper- ts for 28
days to technical grade material had similar BCF values, I.e., 4,667 and
5,700 (Hansen and Parrish, 1977; Goodman, et al. 1978). Adult sheepshead
B-10
-------
minnows exposed to technical grade material for 126 days accumulated hepta-
chlor and heptachlor epoxide to a much greater extent, an average 37,000
times that 1n the exposure water (Hansen and Parrish, 1977). The BCF values
derived in the above studies are from effect, as well as safe concentra-
tions, and they appear similar.
The only BCF values considered appropriate for heptachlor for the deri-
vation of a Final Residue Value were those based on the concentration of
heptachlor in water and the total concentration of heptachlor and heptachlor
epoxide in tissue. Dividing a BCF value by the percent lipid value for the
same species provides a BCF value adjusted to 1 percent lipid content; this
resultant BCF value is referred to as the normalized bioconcentration fac-
tor. The geometric mean of the appropriate normalized BCF values for hepta-
chlor for freshwater and saltwater aquatic life is 5,222 (Table 5).
Dividing the U.S. Food and Drug Administration (FDA) action level of 0.3
mg/kg for edible fish and shellfish by the geometric mean of normalized BCF
values (5,222) and by a percent lipid value of 15 for freshwater species
(see Guidelines) gives a freshwater residue value of 0.0038 »g/l based on
marketability for human consumption (Table 5). Dividing the FDA action
level (0.3 mg/kg) by the geometric mean of normalized BCF values (5,222) and
by a percent lipid value of 16 for saltwater species (see Guidelines) gives
a saltwater residue value of 0.0036 ug/l. Also based on marketability for
human consumption, using the FDA action level and the highest appropriate
BCF for edible portion of a consumed species (3,435 for spot for saltwater),
a saltwater residue value of 0.087 wg/l 1s obtained (Table 5). No
appropriate BCF value for edible portion of a consumed species Is available
for freshwater. The Freshwater Final Residue Value 1s 0.0038 u9/L The
Saltwater Final Residue Value is the lower of the two calculated residue
8-11
-------
values and is 0.0036 ug/l. It should be pointed out that the Final Residue
Values may be too high because the average concentration in a high lipid
species will be at the FDA action level.
Miscellaneous
Macek, et al. (1976) reported an incipent LC5Q of 7.0 ug/l for a
10-day exposure of the fathead minnow (Table 6). This incipient LCr0 was
derived using flow-through testing procedures by determining when no addi-
tional significant mortality (less than 10 percent) wa-s observed at any con-
centration during a 48-hour period. A linear regression equation was calcu-
lated by converting test concentrations and corresponding mortalities into
logarithms and probits, respectively. This equation was then used to deter-
mine the incipient LCgQ. Due to analytical difficulties, however, actual
concentration measurements were not made; rather, concentration values were
based on nominal values.
Andrews, et al. (1966) studied the impact of a single application of
technical grade heptachlor in several earthen ponds (Table 6). Initial con-
centrations as technical grade heptachlor in the test ponds ranged from 17.4
to 69.4 ug/l. Residue levels measured in stocked bluegills were not propor-
tional to dosage. Time to peak residue levels depended on concentration,
with the lower concentrations peaking within 24 hours. Residue concentra-
tions at all test levels decreased to below detectable limits by the end of
84 days. Although the data were not usable for calculating 8CF values in
this document, maximum BCF values, based on peak residue levels for total
heptachlor, heptachlor epoxlde, and related compounds, compared to initial
dose concentrations of technical grade heptachlor, ranged from 638 to 1,326
ug/l. The highest BCF value was for fish in one of the intermediate level
ponds.
B-12
-------
l£ vitro measurements of the effect of heptachlor on biochemical activi-
ty have also been reported by several authors (Table 6). The value of these
data for criteria derivation is limited, however, since no environmental
dose relationships were tested or derived.
A study by O'Kelley and Deason (1976) Investigated the effect of hep-
tachlor on the growth of 20 algal species isolates from Black Warrior River,
Alabama (Table 6). Exposures were conducted in FW-1 algal media spiked with
10, 100 and 10,000 wg/1 heptachlor. Effects on growth were determined by
comparison with control values after two weeks of exposure. Variable spe-
cies responses were found. At all three concentrations the majority of the
species exhibited 51 to 110 percent growth compared to controls. At 10 and
100 u9/l there were no species that grew at less than 50 percent of con-
trols. At 1,000 wg/1 two species grew at less than 50 percent of controls,
but there was also one species that grew at 151 to 190 percent of controls.
The values for particular species were not specified.
Other saltwater BCF data (Table 6} available for heptachlor and hep-
tachlor epoxide are based on short-term exposures and are probably not
steady-state values (Wilson, 1965; Schimmel, et al. 1976a). These values
are also measured at effect exposure concentrations. Two shrimp species,
pink shrimp and grass shrimp, showed less bloconcentratlon in 96-hour expo-
sures to technical heptachlor than did another invertebrate species, the
American oysUr (BCF values ranged from 200 to 700 for the shrimp and from
3,900 to 8,500 for oysters). A BCF of 17,600 was obtained in a separate
10-day exposure of oysters to technical heptachlor (Wilson, 1965). The BCF
values for three fish species exposed for 96 hours to technical heptachlor
ranged from 2,800 to 21,300.
Exposure to heptachlor as the technical material and to analytical grade
heptachlor (99 percent pure heptachlor) gave comparable BCF values for two
B-13
-------
species tested. The pink shrimp had BCF values of 200 to 300 when exposed
to technical material and from 300 to 600 when exposed to analytical grade
heptachlor. The spot had BCF values from 3,000 to 13,800 when exposed to
technical material, as compared to 3,600 to 10,000 1n an exposure to analy-
tical material.
Table 6 contains no saltwater effect data at lower concentrations than
those summarized in previous tables, except for the work of Hansen and Par-
Msh (1977) and U.S. EPA (1980), which were discussed earlier.
Summary
Acute toxidty data are available for 18 freshwater invertebrate and
fish species. Species mean acute values range from 0.9 to 78 ug/l for in-
vertebrate species and from 13.1 to 320 ug/1 for fish species. A single
life-cycle test has been conducted with the fathead minnow, providing a
chronic value of 1.26 pg/1 and an acute-chronic ratio of 80 for this spe-
cies. No chronic data are available for any freshwater Invertebrate species.
Steady-state bioconcentration factors for fathead minnows are 9,500 for
heptachlor and 14,400 for heptachlor epoxlde. Adverse effects on bluegills
were observed at a feeding rate of 10 mg/kg/day. EC5g values of 39.4 and
26.7 ug/l are available for a freshwater algal species, although hydroxy-
chlordene was present 1n the test solutions and may have contributed signif-
icantly to the observed toxlcity.
Acute toxidty data are available for 19 species of saltwater organ-
Isms. The range of species mean acute values 1s from 0.04 to 194 wg/l. The
96-hour LC5- values for pink shrimp from flow-through tests with measured
concentrations are 0.11 ug/l using technical heptachlor and 0.03 wg/1 using
99 percent pure heptachlor. Three saltwater chronic toxidty tests have
been conducted, but the only acceptable one was an early life-stage test
with the sheepshead minnow which resulted 1n a chronic value of 1.58 Mg/l
8-14
-------
and an acute-chronic ratio of 3.9. If the acute-chronic ratio for penaeid
shrimp is similar to that of the tested species, then chronic effects might
be expected to occur at concentrations less than 0.008 ug/1. EC5Q values
for four saltwater algal species range from 93 to 2,260 ug/1.
The saltwater bioconcentration data show that uptake of heptachlor is
fairly rapid, reaching a maximum in one study in three days. However, hep-
tach^or is readily metabolized in fish to heptachlor epoxide. The relative
amount of heptachlor epoxide in tissues increased with length of exposure,
with the maximum amount occurring by day 17. After a 28-day depuration, ap-
proximately 90 percent of the heptachlor was either eliminated or degraded
to heptachlor epoxide.
Freshwater and Saltwater Final Residue Values of 0.0038 and 0.0036 pg/1,
respectively, were derived. However, these Final Residue Values may be too
high because the average concentration 1n a high lipid species will be at
FDA action levels.
CRITERIA
For heptachlor the criterion to protect freshwater aquatic life as de-
rived using the Guidelines is 0.0038 ug/1 as a 24-hour average, and the con-
centration should not exceed 0.52 vg/1 at any time.
For heptachlor the criterion to protect saltwater aquatic life as de-
rived using the Guidelines is 0.0036 tfg/l as a 24-hour average, and the
concentration should not exceed 0.053 ug/1 at any time.
B-15
-------
Table 1. Acute M!«M for heetacfclor
Specie*
H**M*I«
CftMlc.1
"ssr
Specie* Heea
Acute Velve
(•a/1) Referea
ce
FRESHWATER SPECIES
Cledooeraa,
Capital* sifjn*
CladocerM,
Dephala put ex
Cladoceran.
Slaocephalus serrulatus
Cladoceran,
SlMOcephalus serruletus
Scud,
GaaMcu* faaclatus
Scud,
Ceaswus tasclatu*
Scud.
GMHMTUS lecustrls
Crayfish,
Glass shrlap.
StoMcf ly.
Stonefly,
S tenet ly,
Pteronarcys ca 1 1 lorn 1 ca
Coho salami,
Oncorhynchus Msutch
Chinook salajon.
S, U
S, U
S, 0
s. u
s. u
s, u
s, u
s. u
s, u
s. o
s, u
s, u
s, u
s, u
Heptachlor (99$)
Unspecified
grade
grade
Technical
heptachlor 1 72 ft
Technical
heptachlor (72|)
Technical
heptechlor (72$)
Technical
heptechlor (72|)
Technical
heptachlor (72$)
Technical
heptachlor (72$)
Technical
heptachlor (72$)
Technical
heptachlor (72$)
Technical ••
heptachlor (72$)
Technical"
70
42
47
00
96
40
29
7.0
1.0
2.0
0.9
I.I
01.9
24.0
70 MaceK. et at. 1976
42 Sander* i Cope, 1966
Sanders 1 Cope, 1966
61.3 Sanders 1 Cope, 1966
Sanders. 1972
47.3 Sanders, 1972
29 Sanders, 1969
7.0 Sanders, 1972
1.0 Sanders, 1972
2.0 Sanders t Cope, I960
0.9 Sanders 4 Cope, I960
I.I Sanders & Cope, 1966
01.9 Kotz, 1961
24.0 Katl. 1961
Oncorhynctms tshaoytscha
heptachlor (72*)
B-16
-------
I.
Spaclaa
Rainbow trout,
Satan oalrfearl
Rainbow trout.
Salao oalrdnarl
Rainbow trout,
Satan oalrdnarl
Rainbow trout,
Salao oalrdnarl
Goldfish.
Carats lu> auratus
Fathead Minnow,
Plawphalaa proa* las
Fathaad •Innow,
Pla*Ohala» proa* laS
Guppy,
PoocllU rotlculata
BliMglll,
LapOMlt •acrodilrus
Raoaar lunflsh,
LapoaiU •Icrolophus
Aawlcan oymtar,
Cra««oatraa virgin lea
/tear lean oystar,
Cratioatraa virgin lea
Aawlcan oyttar,
Cra»so«traa virgin lea
Mathod*
S, U
S. U
S, U
S. U
S, U
S. U
S. U
S, U
S. U
S, U
FT, U
FT. U
FT. M
Cttaalcal
Technical"
haptachlor (72J)
Technical""
haptacttlor (72|)
Tachnlcal"**
haptachlor (72|)
Tachnlcal""
haptachlor (72|)
Tachnlcal
haptachlor (721)
Tachnlcal
haptachlor (72|)
Tachnlcal
haptachlor (72|)
Tachnlcal
haptachlor (72<)
Tachnlcal
haptachlor (72|)
Tachnlcal1"
haptachlor (72
-------
Tabla I. (ConttMMd)
Mysld thrlap,
Mysldopsls kali 1 a
Sand shrlap,
Crangon saptaswplnos*
Harailt crab,
Pagurus long I carpus
KoraaA shrlap,
Palaaann aacrodactylu*
Grass snrlap,
Palaaaonatat vulgar Is
Grass shrlap,
Palaaswfiatat vulgar Is
Pink shrlap.
Panaaus duoraruai
Pink shrlap.
Panaaus duoraruai
Pink shrlap.
Panaaus duorarusi
Aawlcan aal.
Angullla rostrata
Snaapshaad •Innoii,
Cyprlnodon varlagatus
Shaapshaad Minnow,
Cyprlnodon yarlagatus
MuMlohog,
Fundulus hataroclltus
Strlpad klllltlsh.
Hathod*
FT, M
S, U
S. U
S, U
S, U
FT, M
FT, M
FT. M
FT, M
S, U
FT, M
FT. M
S. U
S, U
Cha.lcal
Haptachlor
Haptachlor1*
Haptach lor6
Haptachlor
Haptach torb
Tacnnlcalc
haptach lor
Tachnlcalc
haptach lor
Haptachlor
Haptachlor
apoxlda <99J>
Haptachlor6
Tachnlcalc
haptach lor
Tachnlcalc
haptach lor
Haptach tor"
Itoptochlor6
LC90/ECM
3.4
e
55
14.5
440
1.06
0.11
0.03
0.04
10
3.66
10.3
50
32
Acut* Valua
(MO/1) Rafaranca
3.4 U.S. EPA, I960
a Elslar, 1969
55 Elslar, 1969
14.5 Schoattgar, 1970
Elslar, 1969
1.06 SchlaMal, at al.
I976a
SchlaMl, at al.
I976a
0.057 SchlaMal, at al.
I976a
0.04 SchlajMl, at al.
I976a
10 Elslar. I970a
SchlaMal, at al.
I976o
6.22 Hansan 1 Parrlsh,
1977
50 Elstar, I970a
32 Elster, I970a
fundulut aajalIt
B-18
-------
Table I. (Coatlmted)
Specie*
Atlantic silver*! da,
Menldla apaldla
Threesplne stickleback,
Gasterosteus aculeatus
Threesplne stickleback,
Gaiterosteus aculeatus
Striped bass.
Moron* saxatllls
Plnflsh.
Laaodon rnoefcoldes
Spot.
LelostoBiis xanthurus
Spot.
lelostoejus xanttturus
Bluehead.
ThallassoM bltasclatuai
Striped aullet.
Muflll ceohalus
Northern puffer,
Spheeroldes aaculatus
Met!
s,
s.
s,
fT.
FT,
FT.
T,
s.
S,
s.
hod"
U
U
U
u
M
M
M
U
U
U
Cbeplcal
Heptachlor6
Technical
heptachlor (12%)
Technical
heptachlor (72%)
Heptachlor
Technical0
heptach lor
Technical0
heptach lor
Hsptachlor
Heptach lor b
Heptach lor b
Haptachlorb
LCM/EC90
(Nfl/D
3
Ml. 9
IM.9
3
3.77
0.85
0.86
0.8
194
188
Species Mean,
Aoite Vain*
(wo/0
3
112
3
3.77
0.86
0.8
194
188
Reference
Elsler. 1970s
Katz, 1961
Kati. 1961
Korn s Earnest, 1974
SchlMiel, et al.
I976a
Schleael, et al.
I976a
SchlajMl, et al.
I976a
Elsler, I970a
Elsler. 1970s
Elsler. (970a
• S • ctatlc, FT • flow-through, U • unmeasured, M * Measured
•• Author converted fro* technical grade (.12%) to lOOf active Ingredient. For the purpose of this criterion
document. LC50 was converted beck to technical (rede.
•••Authors converted fro* technical grade of unspecified percent heptachlor to lOOf active Ingredient. For this
criterion document It Mas assumed that the technical grade mat 12% and LC50 values «ere converted back to
technical grade.
• ECM: aeount of cheacal estlMted to reduce shell growth by 90%.
b Entoool. Soc. A*, reference standard.
c Technical Material: 65| heptachlor. 22$ trans-chlordane, 2% cls-chlordane. 1% nonnchlor. and 9$
unidentified conpounds.
B-19
-------
Taala 2. CtM-oalc walwaa for ha? tax* lor
Chroalc Valw
fRESMfATER SPECIES
FathMd alnnoM, LC Haptachlor 0.66-1.64 1.26 Mac**. «t al. 1976
laa propala*
SALTMATER SPECIES
ELS TacMlcal" 1.22-2.04 1.56 GoodMn, at al. 1976
• LC • llta cycl* or pwtUI IIU cycU. ELS • Mrly !!«•
MtwUli 65| iwptachlor. 22$ tr»*»-chlordww, 2% cI»-chIonian*, ami <2| nonachlor
Acut*-Ct«ronlc Ratio*
Acuta Chronic
Spaclat <»g/l) (J*fl/D Rjjtlp
•Inncw, H>l 1.26 80
Pla»phala« proaalai
6.22 1.56 5.9
CyprlnoooM varlagatut
B-20
-------
Tab I* 3. Specie* M>n acute v*lue* a*d acute-cfcroftlc ratio* tor heptechlor
te
17
16
13
14
13
12
II
10
Specie*
d^lce,"
Specie* Mae*
Acute Value
(WO/I)
Specie* Maee
Acute-Chronic
Ratio
FRESHWATER SPECIES
Goldfish.
Carasslut auratus
Guppy,
Poecllla ratlculata
Fathead Minnow,
Goto Mlaon,
Oncorhynchut Mtutch
Cladoceran,
Oaphnla eagna
Cladoceran,
Sl«oceph*lu> serrutatu*
Scud,
GaeMrus tasclatus
Cladoceran,
Oaplmta pule*
Scud,
Gaewwws lacu»trl*
Blueglll,
lepoils awcrochlrus
Chinook talmon,
Oncorhynchus tshaoytscha
Redear sunflth.
Lepoals ailcrolopnus
Ra 1 ntxw trout ,
SatMo galrdnarl
Technical
Technical
heptachlor
Technical
haptachtor
Technical
haptachlor
Technical
heptach lor
Technical
heptachlor
Technical
heptachlor
Technical
heptachlor
Technical
heptachlor
Technical
heptachlor
Technical
heptach lor
Technical
haptachlor
Technical
haptacMor
320
146
101
81.9
76
61.3
47.3
42
29
26
24
23.6
13.1
60
B-21
-------
TafcU 5. (Co*tlMw4)
ft«**
«***MBM*^
5
4
3
2
1
19
18
17
16
14
13
12
CraytUh.
Orconactas nals
Stonaf ly.
Claassanla sabulosa
Glass shrlap.
Stonaf ly.
Ptaronarcys calif or a lea
Stonaf ly.
Ptaronarcall* bad la
Strlpad aullat.
Mug II capnalus
Northarn put far,
Sphaaroldaa ••culatus
Thraasplna stlcklaback.
Gastarostaus aculaatus
Har«lt crab.
PaguTMS loaglcarpus
Mavldiog,
Fuadu 1 us hataroc 1 1 tus
Strlpad kllllflsli,
Fundulus Mjalls
KoraM sir lap.
PalaajKM atscrodactylus
African aal.
Cha.le.1"
TachAlcal
haptadtlor
Technical
lM0t«d»lor
TacMtlcal
haptacti lor
Technical
haptacfclor
Tachnlcal
haptacklor
SALTWATER SPCCIES
Haptadilor*11
HaptachlorttlB
Tachnlcal
haptachlor
Haptachlor*"
Haptachlor""
Haptachlor"*
Maptachlor
Haptachlor»M
Sfaclas Naaa
AcMt* Val«M
lHfl/1)
7.8
2.8
1.8
I.I
0.9
194
188
112
55
50
32
14.5
10
AcHta-Cnroalc
Ratio
-
Angullla rottrata
B-22
-------
Table 5. CContlMied)
Raafc*
It
10
9
•
7
6
5
4
3
2
I
Sand shrlep,
Crangon sept*
fcplnosa
Sheapshead »lnnow,
Cyprlnodon varleoatus
PinfisJi.
lagodon rhoaboldes
Mysld *hrl«p.
bahla
Atlantic
Myiljla •anldla
Strlp*d bass.
Horonm saxatllls
Aawrlcan oystar,
Crassostraa vlrglnlca
Grass shrlap,
Palaaannata* vulgarts
Spot,
Lalostcwus xanthurus
Bluatwad,
Thallassoaa blfasclatu*
Pink shrlap,
Pacwwis duorarua
Haptacttlor'1*
Tachnlcal*""1
haptach lor
haptach lor
Haptach lor
Haptach lor««*
Haptacltlor
Tachnlcal
haptach lor
Haptachlor****
Haptach lor""
(Both technical
and
Haptach lor**"
Haptachlor*•»•
(Both technical
and
Specie* Mean
Acute Value
related co*pounds unless noted otharnlse.
•** Entoeol. Soc. A*, reference standard.
B-23
-------
7wi« 5.
Mt«rl«l> 6iJ h*pt«* tor. 22J trant-dilordM*. 2% cU-dtlorten*, 21
, (Hd 9
FlMl Acut* VcliM for h«ptaci«lor • 0.92 no/1
Saltvatcr FlMl Acwt* VI|IM for lMpt*chlar - 0.055 pg/l
-------
Tab la 4. Plant valua* for kaptachlor
Sjpaclas
Mga,
SaTanaftrwji caprlcornutua)
AIM.
SalaMCtruB caprlcornutua)
Alga,
Ow«a Malta tartlolacta
Alga.
Itochrysls galbana
Porphyrldlu* cruantua)
Alga.
Sfcatatonaa* costatua
Chaailcal
Haptachlor
Haptachlor
Haptachlor
Maptach lor
(99|)
Haptachlor
i99t)
Haptach lor
(99*)
Effact (fig/I} Rafaranca
FRESHWATER SPECIES
96-hr EC50, 39.4« Call & Brooka, I98O
growth Inhibition
96-hr EC50, 26.7" Call t Brooka, 1980
growth Inhibition
SALTWATER SPECIES
EC5O, raductlon 2,260 U.S. EPA. I960
In growth a*
•aasurad by
abcorbanca
EC50, raductlon 157 U.S. EPA, I960
In growth as
•aacurad by
absorbanca
ECSO, raductlon 273 U.S. EPA, I960
In growth as
•aaaurad by
aborbanca
EC50, raductlon 93 U.S. EPA, 1900
In growth as
•aasurad by
absorbanca
• Ta*t solutions of haptachlor oontalnad froai 6 |ig/l hydroxychlordana In tha lowact fast concantratIon
of S.6 Mfl/l to 29 Mfl/l hydroxydi lordana In tha hi ghat t tattad conoantrat Ion of 37 pa/1.
B-25
-------
TabU 9. RaaldMM tor feeetachlor
Fathead Minnow,
PlMOhale* proa* la*
Fathead elnacw,
Pleaphele* nroMlat
Sheepxhaad •JAAOV
(Juvenile),
Cyprlnodon varlegattt»
Sheep t heed Minnow
(Juvenile).
Cyprlnooon verleoetu*
Shaepshead minmau
(Juvenile),
(Juvenile).
Cyprlnodon varlegetut
SheepBhead a)lnnon (adult).
(Juvenile).
Cyprlnodon verleoatu«
Spot,
Spot.
Lelostoew* xanthurw*
Spot.
lelo»t
-------
Table 9. (CoatI
tlpld
Specie* Tissue (|)
Spot. Whole body 1.1b
Lelostoaus Kenthurus
Spot, Edible tissue
Lei oft tows xaethunie
Spot, Whole body 1. lb
LelostoiMS xanthurus
Chemical
Technical
heptach lor**
Technical
heptach lorc
Technical
heptachlorc
Bloconcentratlon Iteration
Factor
-------
Tatle 9. ICmtl
BeoMtrlc MM of appropriate normalized BCf values (*ee text) • 9,744/1.1 • 5,222
Marketability for (MM ooMuaptloni FDA ectloe level for fl*h MM) thai Kith - 0.3 agAg
PM-ovot llpld valu* for froalMatcr ip«c)M (••• Gu)d«lln»») - 1
Pmrc^nt llpld valua for HltMfar ip«cl«» <»•• Guld«lln«t) « 16
FrMh«at«ri
Saltwater;
0.5
• 0.0000038
5,222* 15
0.3
5,222 x 16"
0.0036 i*fl/l
0.0000036 a«Ag - 0.0036
Uftlftfl tilglMtt appropriate BCF for edible portion of a coMuaed tpecles
Saltwateri Spot - 4.6M (ScfclaMl, et al. I97«b)
0.3 - 0.000087 a«Ag - 0.007
J,435
FraaHHater FlMl Aeeldue Value - O.O034
Seltweter Final Reel due Value " 0.0036 ng/1
B-28
-------
Tabla ft. Othar 4ata for fcaptachlor
SfMClMI
Cnaaical Duration Elf act
FRESHWATER SPECIES
(pa/I)
Twenty riMT •tgal Haptachlor 2 »M Raduction in growth 70* of
•paclaa tsolataa
MuMirous
Miscellaneous
Invertebrates
Cladoceran,
Cladoceraa,
Depnnla ••flM
Tublficld HOTM,
Brencfclura Huarfayl
Tublficld «ar*>,
flUTMICllillf 9 MMHWbyl
Tublficld ttorai.
BrancMiura •ovarbyl
CrayfUh,
ProcaMbarut clarfc.ll
in hvptachlor-
ftplkad FW-I algal
•adla
Haptachlor 171 days tOOf Mortality In
24 hrs; raturnad
to narMi popula-
tion (aval* by
day 14
Haptachlor % hrs LC50
Haptachlor 26 hrs LC50
apQKtda
Haptachlor 72 hrs lOOf Mortality
at 4.4 C
Haptachlor 72 hrs Of Mortality at
21.0 C
Haptachlor 72 hrs tOOt Mortality
at 32.2 C
Haptachtor Varlabla TIMS to daath
aftar consul Ing
spaciac
frair to
1-901 o»
controls
10 no/I
52.1
92
120
2,900
2,500
2,900
2
Rafare>£»
O'Kallay and Da**cn,
1976
Andraws, at al. 1966
Fraar 4 Boyd, 1967
Frav A Boyd, 1967
Maqv), 1973
Naqvi, 197}
Maqvl, 1973
Crayfish,
ProcaMbaru* clarfcl'
B-29
-------
Tabla 6. (CoatlMiad)
Spacla*
Glass shrlap.
Palaaaonataa kad|afcansl«
Fowlar's toad (larva),
Bufo woodhousll lowlarl
Bullfrog (larva).
Ran* cataabalana
Rainbow trout,
Salao flalrdnarl
Rainbow trout.
Sal an galrdnarl
Atlantic salMon (juvanlla).
Sal MO salar
Fathaad Minnow,
PlMaphala* pr caw las
Moaqultoflsh,
GaMbusIa afflnls
Mosqultof Ish,
GaMbusIa afflnls
LapoMls Macrochlrus
Bl,*gltl,
Cna.lcal
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Haptach lor
Duratloa
24 hr*
96 hrs
46 hrs
15 Mln
15 Mln
24 hrs
10 days
48 hrs
36 hrs
171 days*
171 days*
Effact
LC50
LC50
eof Mortality In
cagas subaargad
ponds dosad with
aaulslflabla
concantrata
67| Inhibition
of MaK-ATPasa
3I| Inhibition
of My-ATPasa
Changa In taapar-
atura salactlon
Inclplant LC50
64$ Mortality In
cagas tubaargad In
ponds dosad with
aaulslflabla
concantrata
LC5O
>90f Mortality
Growth and
Rawilt
40.6
440
0.5
Ibc/acra
37.350
3,735
No affact
up to 25
7.0
0.5
Ibs/acra
70
69.4
No affact
Rafaranca
Naqvl & farguson,
1970
Sandars, 1970
Hulla. 1963
Davis, at al. 1972
Davis, at al. 1972
Patarson. 1976
Macek. at al. 1976
Mulla. 1963
Boyd & Karguson, 1964
Andrews, at al. (966
Andrews, at al. 1966
LapoaU MacrocMrus
(-•product Ion
whara fish
survl vad
B-30
-------
Tabla «* (CMtfMMd)
BliMglli.
Lapo»U
Bliwglll.
«»croc»n«»
BliMglli,
ocMfut
BluaglH,
LaooaU •acrocMnit
••crochlrut
Haptachlor
Haptachlor
lor
Ouratloa
171 days*
171
171
t7t
29 »ln
29 Bin
96 hr»
96 hrt
Effact
Tlssua •cctaw-
latloM
•orUllty
gro*>th d»cr*M
lltltM
69-691 Inhi-
bition of NaK-
49-471 Inhi-
bit Ion of HaK-
LCSO of topta-
cMor as aaulsl-
flabla eonoan-
trata U toft
vatar
LC90 of hapta-
chlor as a«ulsl-
Mabla conoan-
trata In hard
I. 1966
of 1.326*
Initial data
concaNtratlon;
ratwrn to
noraal aftar
M days
10
•0A0/day
Andrawt. at al. 1966
9 to 29 AAdrai*. at al. 1966
AcciMMlatlon Andraa*. at al. \966
paakad and
•ubaaquantly
dacllMad to
undatactabla
(avals by
day 112
19.600 CutkoMp. at al. 1971
16.200 Cutkoap. at al. 1971
22 Handarson, at al.
I960
IB Handarson, at at.
I960
B-31
-------
Tabla 6. (Coatlauad)
Spacla*
Bluaglll,
•acrodtlrua
Bluafllll,
LapoaiU •acrochlru*
Bluvglll,
lapoals aacrochtru*
Bluaglll.
Lapoalt aMcrochlrui
Bluaglll,
Lapoals Mcrochlrua
Radaar suntUh,
•Icrolopttus
Radaar iunfl*h.
Radaar auntlsh,
•Icrolophu*
Radaar tunflsh,
Laoo»l> •Icrolophot
«lcrolot>hu»
Natural phytoplankton
coMwnltlas
Chemical
Heptach lor
Haptachlor
Haptachlor
Haptachlor
Haptach lor
Haptachlor
Haptachlor
Haptach lor
Haptachlor
Haptach lor
Duration
Unspaclflad
Unspaclflad
Unspaclflad
Unspaclflad
Unspecified
24 hra
24 hr»
24 hr»
24 hr»
24 hr»
RattilT
Effect
-------
Taal* 6.
Saacla*
Olnoflagallata,
Exuvlalla fcftltlca
AawtcM oystar,
Crasftoatraa vlrglalca
Aaarlcaa oystar,
Crassofttraa virgin lea
Mysld shrlap,
Mysldopsls bahla
Graft* shrlap,
Pataaaonataa vulgarls
Graft* shrlap,
Palaaaonatas vulgarls
Graft* shrlap.
Palaaswnatas vulgar Is
Palaaannrtas vuloarls
Grafts shrlap,
PalaasKXMtaa vulgarls
Palaamonataa vulgarls
Palaasnnatas vulgarls
Chaalcal
Tachnlcal
Technical
haptachlor*"*
Tachnlcal
haptadilor""
Haptachtor
Haptachlor*
Haptachlor*
Haptachlor*
Haptachlor*
Haptachlor*
Haptachlor*
Haptach lor*
Duration
7 days
10 days
96 hrs
28 days
48 hrs
48 hrs
48 hrs
48 hrs
48 hrs
48 hrs
48 hrs
48 hrs
Eftact
^•^•M^KBM
Raduoad call dan-
slty, chlorophyll a
par unit yolua* of
cultura, '*C
uptaka par call and
carbon fixation par
unit of chlorophyll
B loconcantrat Ion
factor " 17,600°
B loconcantrat Ion
factor - 3,900 to
Raducad survival
50-75| Mortality
12 gAg salinity
25-5OS Mortality
18 gAg salinity
29-901 Mortality
24 gAg salinity
29-901 Mortality
30 oAfl salinity
29-901 Mortality
36 gAg salinity
0-291 Mortality
IOC
Of Mortality
19 C
29-50| Mortality
20 C
Raault
-------
Tabla 6. (Coatlauad)
Spaclas
Grass shriMp,
Grass shrlap,
Palaasonatas vulgar Is
Grass shrlap,
Palaaaonatas vulgar Is
Pink shrlap.
Panaaus duoraruai
Pink shrlap,
Panaaus duoraruM
Pink shrlap.
Panaaus duoraniM
Pink shrlap,
Panaaus duoraruM
Blua crab (juvanlla),
Calllnactas sapldus
Shaapshaad Minnow,
Cypr Inodon varlagatus
Shaapshaad Minnow,
Cypr Inodon varlagatus
MuMMlchog,
Fundulus hataroclltus
MuMBlchog.
Fundulus hataroclltus
MuMlchog,
Fundulus hataroclltus
MuaMlchog.
Cha»Jcal
Haptach lor"
Haptach lor'
Tachnical
haptachlor110*
Tachnical
haptachlor***
Tachnical
Haptach lor
(99|)
Haptach lor
apoxlda (99$)
Tachnical
haptachlor'""'
Tachnical
haptachlor"""
Tachnical
haptachlor""'"'
Haptach lor*
Haptacnlor*
Haptach lor"
Haptach lor"
Duration
48 hrs
48 hrs
96 hrs
48 hrs
96 hrs
96 hrs
96 hrs
48 hrs
96 hrs
126 days
96 hrs
96 hrs
96 hrs
96 hrs
ftaault
Cffact (MO/U
75-100$ Mortality 400
25 C
75-100$ Mortality 400
50 C
B 1 oconcantr at Ion
factor • 500 to 700b
EC50i loss of 0.3
aqulllbrluM
B loconcantrat Ion -
factor - 200 to 300*
B loconcantrat Ion
factor - 300 to 600°
B loconcantrat Ion -
factor • 200 to l,700d
EC50t loss of 63
aqul HbrluM
B loconcantrat Ion
factor • 7,400 to
Dacraasad aabryo 0.71
production
0-29$ Mortality 50
12 0A0 salinity
0-29$ Mortality 50
18 gAg salinity
50-75$ Mortality 50
24 gAg salinity
25-50$ Mortality 50
Rafaranca
Elslar, 1969
Elslar, 1969
SchlMMl. at al.
I976a
Butlar, 1963
SchlMMal, at al.
I976a
SchlM»al, at al.
I976a
SchlMMl. at al.
I976a
Butlar, 1963
SchlMaal, at al.
I976o
Hansan t Parrlsh,
1977
Elsler. I970b
Elslar, 19706
Els lor, I970t>
Elsler, I970b
Fundulus hataroclltus
30 gAg salinity
B-34
-------
Table 6.
Species
MuMMlcnog,
Fundulus heteroclltus
MuHtlchog,
Fundulus heteroclltus
HuMMlchog.
Fundulus heteroclltus
MuM»lchog.
Fundulus hetaroclltus
Duration
R*f*r
ilchog,
Fundulus heteroclltus
MuMBlcnog,
Fundulus hetaroclltus
ilchog,
Fundulus heteroclltus
Plnflsh,
LaoodOK rhoMboldes
Spot.
NMtlUITUS
Spot,
KMthurus
Mhlte Mullet (Juvenile).
Mug! I coreMa
H^ttachlor*
H»pt«cl)lor*
Heptachlor4 96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
Heptachlor" 96 hrs
Heptachlor* 240 hrs
96 hrs
96 hrs
96 hr»
Technical
H»pt«chlor
(99f|
25-50J aorta II ty
36 gAg salinity
Of*ortallty
IOC
0| Mortal Ity
ISC
0-23J Mortality
20 C
50-751 Mortal Ity
25C
0-25< Mortality
30 C
LC90
Bloconcantrat Ion
factor - 2.600 to
factor
7.700b
Technical 48 hrs
heptachlor"*
6 loconcantrat 1 on
factor - 3,000 to
I3,800b
6 loconoantrat Ion
factor • 3,600 to
IO,000C
LC90
90 Els lor, 19706
50 Elslar, I970b
90 Elslar, I970b
90 Elslar, I970b
90 Elsler, 19706
90 Elsler, 19706
II Elsler, 19706
SchlM*el. et al.
I976a
SchlMMl. et al.
I976a
SchlMJMl, et al.
I976a
Butler. 1963
• Tasted In ponds, dosed on day t only. Authors dosed with technical grade heptachlor and reported as tig/1
active Ingredient. For the purpose of this document, values are reported as |ig/< technical grade heptachlor.
•• Tested In small pools. Technical grads heptachlor Mas Incorporated Into fish food only and fad (or duration
of test.
B-35
-------
Tatle t, (Continued)
••• Technical Material: contains 741 heptachlor end 26% other chaalcalt. Including trans-chlordane, cls-ch lor dene,
nonach.lor, and others*
••••T*ctwlc*l MtwUI: contains 65* Iwptachlor, 22| trans-chlordWM, 2$ cls-chlordan*, 2% nonachlor, and 9t
othart*
• Haptachlor; Entoawl. Soc. Aaw rafaranca standard.
** ConcantratIon of haptacMor In vhola body dlvldad by concentration of naptachlor In Mater. Ogaols* aMposad
to tachnlcal haptacnlor <65J naptachlor, 22$ trans-chlordana, 2f cls-cttlordana. and 2f nonachlor).
c Concantratlon of naptachlor In whola body dlvldad by concentration of naptachlor In water. Organise exposed
to analytical-grade naptachlor (99? naptachlor).
Coacantratlon of haptacnlor epoxlde In whole body dlvldad by concentration of haptachlor epoxlde In water.
lsM exposed to haptachlor epoxlde (99J)
B-36
-------
REFERENCES
Andrew, A.K., et al. 1966. Some effects of heptachlor on bluegills (Lepom-
is macrochirus). Trans. Am. F1sh. Soc. 95: 297.
Boyd, C.E. and D.E. Ferguson. 1964. Susceptibility and resistance of mos-
quito 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. In: C.M. Tarzwell (ed.), Biologi-
cal Problems in Water Pollution, 3rd Seminar 1962. U.S. Publ. Health Serv.
999-WP-25. p. 247.
Butler, P.A. 1963. Commercial fisheries Investigations, pesticide-wildlife
studies: A review of F1sh and Wildlife Service Investigations during
1961-1962. U.S. Oept. Inter. F1sh and WUdl. C1rc. 167: 11.
Call, O.J. and L.T. Brooke. 1980. Memorandum to R.C. Russo. July 17.
Cutkomp, L.K., et al. 1971. ATPase activity 1n fish tissue homogenates and
inhibitory effects of DOT and related compounds. Chew. Blol. Interactions.
3: 439.
Davis, P.W., et al. 1972. Organochlorlne Insecticide, herbicide and poly-
chorlnated blpnenyl (PCB) Inhibition of NaK-ATPase In rainbow trout. Bull.
Environ. Contam. Toxlcol. 8: 69.
B-37
-------
Eisler, R. 1969. Acute toxlcitles of insecticides to marine decapod crus-
taceans. Crustaceana. 16: 302.
Eisler, R. 1970a. Acute toxlcitles of organochlorine and organophosphorous
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Wild!. Tech. Pap. 46.
Eisler, R. 1970b. Factors affecting pesticide-induced toxicity in an es-
tuarine fish. U.S. Dept. Inter. 8ur. Sport Hsh. Wild!. Tech. Pap. 45.
Frear, O.E.H. and O.E. Boyd. 1967, Use of Daphnia magna for the microbio-
assay of pesticides. I. Development of standardized techniques for rearing
Daphnia and preparation of dosage-mortality curves for pesticides. Oour.
Econ. Entomol. 60: 1228.
Goodman, L.R., et. al. 1978. Effects of heptachlor and toxaphene on labo-
ratory-reared embryos and fry of the sheepshead minnow. Proc. 30th Annu.
Conf. Conf. S.E. Assoc. Game Fish Conm. 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.
Hansen, D.J. 1980. Memorandum to C.E. Stephan. July.
Hansen, D.J. and P.P. Parrlsh. 1977. Suitability of Sheepshead Minnows
(Cyprinodon varlegatus) for Life-Cycle Toxicity Tests. _Irr. F.L. Meyer and
J.L. Hamelink (eds.). Toxicology and Hazard Evaluation. ASTM STP 634, Am.
Soc. Test. Mater, p.117.
B-38
-------
Henderson, C., et al. 1959. Relative toxicity of ten chlorinated hydro-
carbon Insecticides to four species of fish. Trans. Am. F1sh. Soc. 88: 23.
Henderson, C., et al. 1960. The Toxicity of Organic Phosphorus and Chlori-
nated Hydrocarbon Insecticides to F1sh. I_n: C.M. Tarzwell (ed.), Biological
Problems in Water Pollution, 2nd Seminar 1959. U.S. Pub!. Health Serv.,
R.A. Taft Sanitary Eng. Center, Tech. Rep. WGO-3. p. 76.
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Katz, M. 1961. Acute toxicity of some organic Insecticides to three spe-
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Korn, S. and R. Earnest. 1974. Acute toxicity of twenty insecticides to
striped bass, Morone saxtHis. Calif. F1sh Game. 60: 128.
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B-39
-------
Magani, B. et al. 1978. Effects of chordane and heptachlor on the marine
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Naqvi, S.M.Z. 1973. ToxicUy of twenty-three insecticides to a tubificid
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Naqvi, S.M.Z. and D.E. Ferguson. 1970. Levels of Insecticide resistance in
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B-40
-------
Sanders, H.O. 1972. Toxicity of some insecticides to four species of mala-
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Schimmel, S.C., et al. 1976b. Heptachlor: Uptake, depuration, retention
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B-41
-------
Yeith, G.O., et al. 1979. Measuring and estimating the bioconcentration
factor of chemicals 1n fish. Jour. Fish. Res. Board Can. 36: 1040.
Wilson, A.J. 1965. Chem. assays. Annu. Rep. Bur. Commercial Fish. Biol.
Lab., Gulf Breeze, Florida. U.S. Bur. Cornm. Fish. Circ. 247: 6.
Yap, H.H. et al. 1975. lr\_ vitro inhibition of fish brain ATPase activity
by cyclodiene insecticides and related compounds. Bull. Environ. Contam.
Toxicol. U: 163.
B-42
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from 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 around the
U.S., 15 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 detection limit
for heptachlor was in the range of 0.002 to 0.010 ug/1, but was
only 0.075 ug/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 detect-
able, found levels of heptachlor ranging from 0.001 to 0.035 ug/1,
and heptachlor epoxide levels ranging from 0.001 to 0.020 ug/1,
with a mean concentration for both of 0.0063 ug/1 (U.S. EPA,
1976) . They added 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
ug/1 for both heptachlor and heptachlor epoxide. Another survey
conducted by th« U.S. Geological Survey of 11 western U.S. streams
showed heptachlor levels ranging from 0.005 ug/1 to 0.015 ug/1
when found and heptachlor epoxide levels ranging from 0.005 to
0.010 ug/1 when found, with one sanple showing 0.090 ug/1
heptachlor epoxide (Brown and NishioJca, 1967).
C-l
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Ingestion from Food
Food can add significantly to man's exposure to heptachloc
and heptachlor epoxide. This occurs through biomagnification of
heptachlor/heptachlor epoxide through the food chain. For ex-
ample, the U.S. EPA (1976) cited data from Hannon, et al. (1970),
who reported that average heptachlor/heptachlor epoxide residues
in the Lake Poinsett, S. Dakota ecosystem were: 0.006 ug/1 for
water; 0.8 ug/kg for bottom sediment; 1.0 ug/kg for crayfish; 1.1
ug/kg for plankton-algae; 8.0 ug/kg for fish; and 312.0 ug/kg for
aquatic insects. Additionally, there is an approximate 10-fold to
15-fold increase in heptachlor residues found in body fat, milk
butterfat, and the fat of eggs and livestock as compared to resi-
due levels found in normal food rations (U.S. EPA, 1976).
Since 1964, the Food and Drug Administration (FDA) has re-
ported pesticide residues in their Total Diet Study, sometimes
called the "Market Basket Study" (Johnson and Manske, 1977).
Their "market basket* of food, which is collected in each of
several geographic areas, represents the basic 2-week diet of 16-
to 19-year-old males, statistically the nation's highest per
capita consumers. The foods analyzed in these studies were pre-
pared in the manner in which they would be normally served and
eaten. Th« latest published study covers food collected from
August 1974 to July 1975 in 20 different cities (Johnson and
Manske, 1977). Their results showed that only 3 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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TABLE i
Heptachlor Epoxide Residues in Pood*
positive composites
Pood
I
II
VIII
Class
Dairy Products
Meat, Pish,
and Poultry
Garden Pruits
Average
Concentration
ppra
0.0004
0.001
Trace
Total
Number
11
13
1
Number
Reported
as Trace
5
4
1
Range ppra
0.0006-0
0.001-0.
Trace
.003
0003
*Source< Johnson and Nanake, 1977
C-3
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Nisbet (1977) calculated the average daily intake of hepta-
chlor epoxide from the FDA's Market Basket Study standardized diet
and estimated that the daily intake of heptachlor epoxide ranged
from 1 to 3 ug/day between 1965 and 1970, and from 0.29 to 0.64
ug/day between 1971 and 1974. Nisbet questioned the calculated
decrease in residue levels observed between the two time periods,
because 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 methodologies and
he regarded the total Diet Survey for heptachlor epoxide as only
semi-quantitative. He stated 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 (USDA) Food Surveillance
Program found heptachlor epoxide residues greater than 0.03 mg/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 ad-
dition 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, et al. 1969). Results were reported
as mg/kg (wet weight whole fish) and ranged from 0.01 to 8.33
rag/kg when found. It must be noted that these results represent
C-4
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the whole fish, not just the portions that man eata, so it is pos-
sible that much of the residues are accumulated in the uneaten
portion (Henderson, et al. 1969).
A bioconcentration factor (BCF) relates the concentration of
a chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the
per capita consumption of fish and shellfish, the weighted average
percent lipids of consumed fish and shellfish, and a steady-state
BCF for the chemical.
Data from a recent survey on fish and shellfish consumption
in the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion
of the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
Several laboratory studies, in which percent lipids and a
steady-state BCP were measured, have been conducted on heptachlor.
The mean of the BCP values, after normalization to 1 percent
lipids, is 3,747 (see Table in Aquatic Life Toxicology, Section
B). An adjustment factor of 3 can be used to adjust the mean nor-
malized BCP to the 3.0 percent lipids that is the weighted average
C-5
-------
for consumed fish and shellfish. Thus, the weighted average bio-
concentration factor for heptachlor and the edible portion of all
freshwater and estuarine aquatic organisms consumed by Americans
is calculated to be 11,200.
Infants are exposed to heptachlor and heptachlor epoxide
through mothers' mil* (Savage, 1976), cows' milk (Ritcey, et al.
1972; Johnson and Manske, 1977), and commercially prepared baby
foods (Lipscotnb, 1968). A recent nationwide study, conducted dur-
ing 1975-1976, indicates that 63.1 percent of the 1,936 mothers'
milk samples possessed heptachlor epoxide residues (Savage/ 1976).
The adjusted mean fat concentration for heptachlor epoxide in the
mothers' milk, with levels above the 1 ug/1 sensitivity level, was
91*36 ug/1 with a range of 15.24 to 2,050 ug/1. Therefore, it
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 (Sav-
age, 1976). Whole cows' milk and evaporated milk did not show a
trace of heptachlor epoxide in the U.S. FDA's 1974-1975 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 ug/1 in evaporated milk (Ritcey, et
al. 1972). C owner cially 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 (Lipscorab, 1968). Therefore, it appears that infants raised
C-6
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on mothers' millc run a greater risk of ingesting heptachlor epox-
ide than if they were fed cows' milk and/or commercially prepared
baby food.
Ritcey, 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 mg/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 resi-
due 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 lesser ex-
tent 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 (Nis-
bet, 1977).
Nisbet (1977) has reported air surveys where agricultural
fields have been treated with technical heptachlor (2 Ib/acre).
The air above and downwind from the fields showed heptachlor con-
centrations as high as 244 ng/m3 immediately after application.
C-7
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After three weeks the concentrations remained as high as 15.4
ng/ra3. One survey reported heptachlor concentrations as high as
600 ng/m3 in air over a treated field, with the field showing
high concentrations in the air throughout the growing season, at
least from May to October (Nisbet, 1977). 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 from 1972 to
1974 of Stoneville, Miss., which is reported as one of the highest
pesticide usage areas of the U.S. due to intensive cotton produc-
tion. They found heptachlor in 62 percent of their monthly sam-
ples, with an average level of 0.25 ng/m3 and a maximum concen-
tration of 0.8 ng/m3. Heptachlor epoxide was found in 36 per-
cent of the monthly samples at an average level of 0.21 ng/m3
and a maximum concentration of 9.3 ng/ra3 (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 epox-
ide in any of the localities. The localities showing residues
were Iowa City, Iowa and Orlando, Florida with maximum heptachlor
levels of 19.2 ng/m3 and 2.3 ng/m3, respectively.
Niab«t (1977) calculated the typical human exposure to hepta-
chlor to b* 0.01 ug/individual/day based on an ambient air mean
concentration of 0.5 ng/m3 and breathing 20 m3 of air per day.
He stated further that even in Jackson, Miss., which has a mean
air level as high as 6.3 ng/m3, the average individual would
C-8
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inhale only 0.13 ug/day of heptachlor. The significance of these
figures is dependent upon the efficiency of lung absorption of
heptachlor and heptachlor epoxide which has not been reported for
humans (Nisbet, 1977). Based on the information presented here,
it appears that inhalation is not a major route for human exposure
to heptachlor and its metabolites. However, an experiment by
Arthur, et al. (1975) using rabbits, although controversial (Nis-
bet, 1977), suggests that inhalation may be a significant route of
exposure even at ambient levels as low as 1.86 ng/m3.
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 der-
mally exposed. Razen, et al. (1974) found that chlordane, a com-
pound structurally similar to heptachlor, could be found on a
man's skin two years after occupational exposure. Gaines (1960)
found that rats dermally exposed to technical grade heptachlor had
LD5Q values of 195 rag/kg for males and 250 ing/kg for females,
while the LDsQ values for orally exposed rats were 100 rag/kg
for males and 162 mg/kg for females. Xylene was used as the ve-
hicle to dissolve and apply the heptachlor/ with the solution ap-
plied at a rate of 0.0016 ralAg body weight.
It i» significant to note that the U.S. EPA suspended most
uses of heptachlor effective August 1, 1976, including most agri-
cultural, hone, and garden uses of technical grade heptachlor.
C-9
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PHARMACOKINETICS
Absorption and Distribution
Heptachlot and/or heptachlor epoxide are both readily ab-
sorbed from the gastrointestinal tract (Radomski and Davidow,
1953; Mizyukova and Kurchatov, 1970; Matsumura and Nelson, 1971).
Mizyukova and Kurchatov (1970) showed pure heptachlor reaches all
organs and tissues of female rats within one-half to one hour
after a single dose (120 mg/kg) of heptachlor was delivered
directly into the stomach. After four hours the metabolite of
heptachlor (heptachlor epoxide) was found in the blood, liver, and
fatty tissue. After a few days the concentration of heptachlor in
all organs and tissues decreased, while at the same tine there was
a rapid increase in heptachlor epoxide levels. By the end of one
month, only traces of heptachlor could be found in the fatty tis-
sue, chiefly in the form of its metabolic products. Heptachlor or
its metabolites could not be found in the blood or kidneys. How-
ever, a small amount of heptachlor epoxide was found in the liver.
After three to six months the level of heptachlor epoxide in fatty
tissues became stabilized.
Radomski and Davidow (1953) used both dogs and rats. In
rats, after two months on a diet of 30 to 35 mg/kg of heptachlor,
the highest concentration of heptachlor's metabolite (heptachlor
epoxide) vaa found in the fat, with markedly lower amounts in the
liver, kidney and muscle, with none being detected in the brain.
Female dogs, dosed at 1 mg/kg daily for a period from 12 to 18
months, showed the same heptachlor epoxide distribution as did the
rats, except the dog livers appeared to contain more heptachlor
010
-------
epoxide than the kidneys and muscles. The lowest detectable con-
centration of heptachlor epoxide in this study was 0.6 ing/kg.
The degree to which heptachlor or heptachlor epoxide is ab-
sorbed by inhalation has not generally been reported (Nisbet,
1977). Arthur, et al. (1975) conducted a now controversial study
where they exposed white rabbits to the ambient air of Stoneville,
Miss., an area of high pesticide use. Their controls were housed
indoors at Mississippi State University, an area of low pesticide
use. They found that between July 1972 and October 1972 the
heptachlor epoxide level in the rabbits' adipose tissue from
Stoneville was 0.039 mg/kg, while only 0.016 mgAg was found in
the same tissue in rabbits from Mississippi State. The heptachlor
epoxide level in air at Stoneville was reported to be 1.86
ng/m3, while the Mississippi State University 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 respira-
tory intake of heptachlor for rabbits in Stoneville, Miss, as
0.002 ug/day. These data, even though controversial, indicate
that heptachlor epoxide can be absorbed to a significant degree
after inhalation, as determined by rabbit adipose tissue resi-
dues.
Several studies released in the late 1960's indicate that the
human placenta does not provide adequate protection against chlo-
rinated hydrocarbon pesticides such as heptachlor epoxide (Selby,
et al. 1969; Zavon, et al. 1969; Curley, et al. 1969). Selby, et
Oil
-------
al. (1969) found that women who had high levels of heptachlor or
heptachlor epoxide in their blood also had high levels of both in
their placenta. They also reported heptachlor epoxide distribu-
tion between the placenta and maternal blood in a ratio of 5.8:1
(placenta ppbrmaternal blood ppb) based on the geometric means of
54 placental and 53 maternal blood samples. Polishuk, et al.
(1977b) has shown that heptachlor epoxide was higher in the ex-
tracted 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
children showed that heptachlor epoxide levels paralleled the con-
centrations 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 var-
ied greatly, but were within the range observed in adults. There-
fore, any exposure of heptachlor or heptachlor epoxide to the
mother will also expose the fetus to heptachlor epoxide.
Metabolism and Excretion
Early studies (Radomski and Davidow, 19S3; Davidow and Radom-
ski, 1953) show. that both the rat and the dog metabolize ingested
heptachlor rapidly by epoxidation (Figure 1) 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 in the fat tissue. In this
study, the female rats accumulated approximately six times as much
heptachlor epoxide in their fat tissue as did the males.
C-12
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HEPTACHLOR
HEPTACHLOR EPOXIDE
FIGURE 1
013
-------
Matsumura and Nelson (1971) fed four male albino rats 10
mg/kg of 99 percent pure heptachlor epoxide for 30 days (approxi-
mately 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 (1970) found that the excretion of the nonstored
heptachlor and its metabolites occurs within the first five days,
chiefly through the gastrointestinal tract and to a smaller extent
in the urine.
One very important route of excretion of heptachlor and hep-
tachlor epoxide in females is through lactation (Jonsson, et al.
1977). This study indicates that milk is a primary excretory
route for heptachlor and its metabolites. Generally, heptachlor
epoxide concentration in mothers' milk is a good indicator of the
body burden of heptachlor epoxide stored in the lactating mothers'
body {Jonsson, et al. 1977; Strassman and Kutz, 1977). Polishuk,
et al. (1977a) found that overweight women excreted lower quanti-
ties of pesticides, such as heptachlor epoxide, in their milk than
did women of normal weight. They also found that women front ages
20 to 29 years old excreted higher pesticides levels in their milk
than did women from the ages 30 to 39, even though the younger
women had lower pesticides levels in their plasma.
In * human milk study of 53 samples collected from two Penn-
sylvania regions during 1970, Kroger (1972) found all of the
samples contained heptachlor epoxide at an average concentration
of 0.16 mg/1. Savage, et al. {1973} performed a similar survey in
Colorado in 1970-1971 with 40 human milk samples, and found 25
014
-------
Cl
Cl
\
—OH
HEPTACHLOR
FECAL METABOLITE
FIGURE 2
015
-------
percent of the samples contained heptachlor epoxide at levels
ranging from trace amounts to 5 ug/1. Strassman arid Kutz (1977)
conducted a study in Arkansas and Mississippi in 1973-1974 of 57
milk samples and found heptachlor epoxide residues in 35.1 percent
of the samples with 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.
Savage (1976) reported the results of an extensive study con-
ducted during 1975 involving 1,436 human milk samples from
selected sites within the continental U.S. He found that only 2
percent showed heptachlor residues, but 63.1 percent of the
mothers' milk samples showed heptachlor epoxide residues ranging
from 15.24 to 2,050 ug/1 on a fat adjusted basis, with a mean con-
centration of 91.36 ug/1. Savage also found that 11 percent of
the high residue group of women were either occupationally exposed
or lived in households where a 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
p
heptachlor epoxide in human milk from other countries include:
Ritcey, «t al. (1972); Polishuk, et al. (1977a); 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 is an addition
C-16
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to the body burden which already exists due to exposure _in utero
(PolishuX, et al. 1977b; 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 of the
exposure to heptachlor and heptachlor epoxide (Kutz, et al. 1977).
Biopsied human adipose tissue was used by Burns (1974) to study
the heptachlor epoxide levels in 302 hospital patients from 1969
to 1972 in the lower Rio Grande Valley in Texas. During the study
period, he found 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 heptachlor
epoxide has been published by Kutz, et al. (1977). Tissues were
collected during postmortem examinations, and from surgical exci-
sions and rejected samples collected from patients known or sus-
pected of pesticide poisoning, cachectic patients, and patients
institutionalized for extended periods. The samples were obtained
within the coterminous 48 states, and the sampling sites were ran-
domly selected to be representative of the U.S. populations. The
5-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/Xg (Table 2).
In addition to the storage of heptachlor epoxide in human
adipose tissue, a minor component (trans-nonachlor) of both tech-
nical heptachlor and technical chlordane has also been found
(Sovocool and Lewis, 1975). They studied nine composite human fat
samples from nine census divisions of the U.S. and found eight of
C-17
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TABLE 2
H«ptachloc Epoxide Residues in Human Adipose Tissue*
Survey Year
(fiscal)
1970
1971
1972
1973
1974
Sample
Size
1412
1615
1913
1095
898
Percent
Positive
94.76
96.22
90.28
97.72
96.21
Geometric
Mean (mgAg)
0.09
0.09
0.08
0.09
0.08
Maximum
Value tag /kg
10.62
1.53
1.21
0.84
0.77
*Source: Kutz, et al. 1977
C-18
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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 epox-
ide and oxychlordane. These data indicate 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 (Curley, et al. 1973; Wasserman, et
al. 1974; Abbott, et al. 1972; Wasserman, et al. 1972) have re-
ported heptachlor epoxide residues in human adipose tissue in
other countries.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Heptachlor and its metabolites have L^so values ranging
from 6 mg/kg to 531 mg/kg (Table 3) depending upon the animal
species, toxicant used, and the mode of administration. Radomski
and Davidow (1953) were the first to report that heptachlor epox-
ide is two to four times more toxic than heptachlor itself when
given intravenously in mice. 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 photoheptachlor epoxide {III Bl (Ivie, et al.
1972), which is formed by exposure of heptachlor epoxide to ultra-
violet light or sunlight in the presence of a photosensitizer on
plants. Ivie, et al. (1972) reported the LD50 values for male
Swiss-Webster mice to be 18 mgAg for heptachlor epoxide; 36 mg/kg
C-19
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TABLE 3
Heptachlor and Heptachlor Metabolites
Organism
Sex fc Strain
Mouse
(Swiss-Webster)
Compound
Heptachlor
epoxide
Route
of
Administration
i.p.
LD50
(rag/kg)
IB
Reference
Ivie,
et al.
1972
Mouse
(Swiss-Webster)
Mouse
(Swiss-Webster)
Photo-heptachlor
epoxide II
Photo-heptachlor
epoxide (III B)
i.p.
i.p.
* - assumed to be rag/kg body weight
M - male
F - female
N - neonate
i.p. « intraperitoneally
36
6
Ivie, et al. 1972
Ivie, et al. 1972
Rat (M-Sherman)
Rat (F- Sherman)
Rat (M-Sherman)
Rat (F-Sherman)
Rat (M-Sprague-
Dawley)
Rat (N-Sprague-
Dawley)
Mouse
Rat
Hamster
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
oral
oral
dermal
dermal
i.p.
I.p.
oral
oral
oral
100
162
195
250
71*
531*
70
105
100
Gaines, 1960
Gaines, 1960
Gaines, 1960
Gaines, 1960
Harbison, 1975
Harbison, 1975
Gak, et al. 1976
Gak, et al. 1976
it
Gak, et al . 1976
C-20
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for the intermediate photo metabolite photoheptachlor epoxide
[II]; and 6 mg/kg for photoheptachlor epoxide [III B]. Gaines
(1960) conducted acute ^050 studies using oral doses of hepta-
chlor in the Sherman strain of rat and found L&SO values of
100 rag/kg in males and 162 mg/kg in females, while the acute der-
mal LDso of heptachlor in males was 195 tag/kg and 250 mg/kg
for females. Harbison (1975) used neonatal and adult (120 to
150 g) Sprague-Dawley rats to show that the newborn rat is more
resistant to heptachlor than the adult. The intraperitoneal
LD5Q for the adult male rats was 71 mg/kg*, but was 531 mg/kg*
for newborn rats. Gak, et al. (1976) reported heptachlor L05Q
values for the mouse, rat, and hamster to be 70 mg/kg, 105 mg/kg,
and 100 mg/kg of body weight, respectively.
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. St.
Omer (1971) studied the convulsions produced by heptachlor in rats
and found that the intensity of the convulsions was directly cor-
related 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 to rat« significantly elevated their brain acetyl-
choline content, with some decrease in acetylcholine concentration
*assumed to be mg/kg body weight.
021
-------
during the period of severest seizure activity. They suggested
that these changes in the brain level of ammonia and acetylcholine
during heptachlor exposure may be part of the mechanism of convul-
sion induction. Hrdina, et al. (1974) administered heptachlor
chronically for 45 days to rats and found the acetylcholine level
in the cerebral 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 rag/kg) produced body hypo-
thermia.
Changes in the energy linked functions of the mitochondria
have been studied by Pardini, et al. (1971) and Settlemire, et al.
(1974). Pardini, et al. (1971) reported that heptachlor (1 umole/
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 de-
pressed the mitochondrial activity of NADH-oxidase to 8.6 percent
of uninhibited controls, while again heptachlor epoxide had no
effect. They speculated that since heptachlor did not interact at
any step in the electron transport chain after cytochrome C, 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 lower concentrations of hep-
tachlor caused dramatic changes in the membrane of mouse mitochon-
dria. They stated that th« increase in respiration (oxidation of
succinate), observed when ADP and heptachlor were added, was prob-
ably caused by increased permeability of membranes to succinate,
022
-------
or by confornational changes of such a nature that the intrinsic
activity of the respiratory chain was increased.
Induction of liver raicrosomal enzymes by heptachlor and hep-
tachlor epoxide has been reported by Kinoshita and Kempt (1970)
and Den Tonkelaar and Van Esch (1974). Kinoshita and Kempf (1970)
found heptachlor and heptachlor epoxide to be very persistent in-
ducers in rats of phosphorothioate 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 Tonkelaar and Van Esch
(1974) found that dietary heptachlor significantly induced aniline
hydroxylase, aminopyrine demethylase, and hexobarbital oxidase in
rats at levels of 2 to 50 mg/kg, 2 to 50 mg/kg» and 5 to 50 mg/kg,
respectively. Both groups reported that approximately 1 mgAg 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 (GPT) and aldolase (ALD)
in the serum of rats. Histologic examinations of the livers re-
vealed 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 hepta-
chlor stimulated the metabolism of estrone by liver microsomal
enzymes and inhibited the increase in uterine wet weight in
treated female rats.
C-23
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Several studies have been conducted concerning the effects of
heptachlor on glucose hoiueostasis in the rat (Kacew and Singhal,
1973; 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, phosphoenolpyruvate carboxykinase,
fructose 1,6-diphosphatase, and glucose 6-phosphatase, an eleva-
tion 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 the cyclic AMP-adenylate cyclase system in liver
and kidney cortex.
Dvorak and Halacka (1975) studied the ultrastructure of the
liver cells of pigs after the administration of small doses (2 to
5 mg/kg of 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
reticulun. With higher doses and a longer duration of administra-
tion of heptachlor/ a greater occurrence of liver lysosomes was
also observed.
Reuber (1977a) found that C3fi male and female mice fed 10
mg/kg of heptachlor or heptachlor epoxide developed hepatic vein
thrombosis. Heptachlor caused IS percent of the females and 10
C-24
-------
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 7 mice of the 39 that exhi-
bited 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 5 rag/kg given to male rats caused
dominant lethal changes as demonstrated by a statistically sig-
nificant increase in the number of resorbed fetuses in intact
pregnant rats. They confirmed this by finding a significant in-
crease in the incidence of abnormal mitosis, abnormalities of
chromatids, pulverization, and translocation of chromosomes in the
bone marrow cells of their experimental animals. They concluded
from the results mentioned above that rat fetuses in early and
late stages of embryonic development could be adversely affected
by heptachlor. Ahmed, et al. (1977) used SV-40 transformed human
cells (VA4) in culture to show that both heptachlor and heptachlor
epoxide induced unscheduled DNA synthesis in this system when
metabolically activated with homogenized rat liver supernatant.
Teratogenicity
Mestitzova (1967) found that heptachlor administered to rats
in food at 6 mg/kg body weight caused a marked decrease in litter
C-25
-------
size, both in several litters of one generation as well as in suc-
cessive generations. The author also stated that the life span of
suckling rats was significantly shortened, with the death rate be-
ing 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. Mestit-
zova stated that the sequence of occurrence of the cataracts ex-
cluded the possibility of recessive genetic traits or a vitamin a
deficiency as the causative factor.
Synergism and/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 un-
supplemented 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 to rats fed unsupplemented gluten. They also
found that weight gain, microscmal proteins, and heptachlor metab-
olism were significantly reduced in the animals fed unsupplemented
gluten and that animals pair-fed the casein diet had higher hepta-
chlor epoxidase activities than those fed the gluten diet. There-
C-26
-------
fore, they suggested that low protein diets impaired or slowed
metabolism of heptachlor to the more toxic heptachlor epoxide.
Weatherholtz, et al. (1969) reported that rats fed protein defi-
cient diets were less susceptable to heptachlor toxicity and also
suggested that this observation may have been due to reduced i_n
vivo conversion of the pesticide to the epoxide form.
Miranda and Webb also studied the effects of phenobarbital
and SKF525-A on these protein deficient diets (Miranda, et al.
1973; Miranda and Webb, 1974). Their studies suggested an inter-
action of protein inadequacy with drug metabolism and with inhibi-
tion of heptachlor metabolism, but they believed further studies
should be carried out to clarify their findings.
Harbison (1975) studied the effects of phenobarbital (PB) on
neonatal rats. He found that PB potentiates the toxicity of hep-
tachlor in newborn rats. For heptachlor, 1*^50 values for a
newborn rat, for a newborn pretreated with PB, and for an adult
male untreated rat, were 531 mg/kg» 133 mg/kg, and 7 mg/kg, re-
spectively.
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 FDA, Cabral, et
al. 1972, International Research and Development Corporation
(IRDC) sponsored by V«lsicol, and the National Cancer Institute
(NCI). Two extensiv* reviews of the»« studies have been conducted
C-27
-------
by Epstein (1976) and by the U.S. EPA (1977) and should be con-
sulted foe more specific information on each study. Tables 4 and
5 present summary data reported by Epstein (1976), and include the
original authors's conclusions, any independent histological re-
evaluation of the studies which have been conducted, and Dr.
Epstein's comments on each study.
The 1955 Kettering study on heptachlor in rats was an unpub-
lished study by the Kettering Laboratory under contract to the
Velsicol Corporation. The U.S. EPA (1977-) review of this study
stated that the oral dosages of heptachlor administered in the
diet were 0, 1.5, 3.0, 5.0, 7.0, and 10.0 rag/kg. These dosages
were administered 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 inci-
dental diseases, particularly respiratory diseases (U.S. EPA,
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 conducted for the Velsicol Corp.
in 1959 by Witherup, et al. (1959). This investigation evaluated
C-28
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TABLE 4
Summary of Carcinogenlclty Data in Hat**
Author*
lettering,
1955
Strain formulation
lieptachlor (H)|
•poxlde (HE),
Cfclordase (C>
cr U at uMpaclfied
parity
Concentrations (ppm)
H HE C
1.5, 3.0,
&.O) 1.0)
10.0
Carcinogen! city
Authors Independent
Conclusions Histological
De-evaluation
Tumor Incidence Not undertaken
"proportionately*
distributed in
all tests and
control groupe
Comments
1. Test diets prepared
crudely and study
poorly documented.
2. Author's data demon-
strate statistically
significant increase
in •alignant and any
tumors in multiple
sites in some female
tetter ing, CFN HE of unspecified - Of 0.5) - Tumor Incidence
19S9 purity 2.5, S.O) "unrelated" to
1.S) 10.0 H8 content in
diets. Vice as
hepatomaa in test
animal* 1* ac-
knowledged, but
discounted. Also
unusual malignant
tumor* in males
and females
Hapatocarcino-
genlc and mul-
tiple site ma-
lignant tumors
1. Test diets prepared
crudely and study
poorly documented.
2. Kettering data stalls
tlcally significant, -
for incidence of tota
tumor-bearing animals!
and for liver and pi-
tuitary tumors.
J. Histological re-eval-
uation showed hepato-
carcincaaa.
4. ttepatocarcinogsnlclty
statistically slgni-
cant.
Kettertng,
CD Mixture of 25%
HI (»«.»» pure),
and 75% N |9e.0%
pure)
S.O, 1.5, 10) 12.5
Incld*nc« of tu-
•ors •qualita-
tively and quan-
titatively simi-
lar * in test and
controls.
Not undertaken 1.
Study poorly docu-
mented and methodolog
cally unsound) femalel-
rats only tested.
Unacceptable as car-
cinogeniclty teat.
C-29
-------
TABLE 4 (Continued)
Author*
StrainFormulation
Concentration* (PP*)'
Carcinogenic 1ty
•enta
Cabral, »t
•1. 1973
tfeptachlor (H);
Epoilde (HBh
Chlordane (C)
Hlatar H Analytic Grade
96. •% pure
H
Total
doaage
SO »g/kg
HE C Author*
Concluaiona
Mot carcinogenic
Independent
Hlatolo9lcal
Re-evaluation
Not undertaken
1.
2.
Perinatal doaage only.
Author 'a data de»on-
atrate atatlatlcally
al9nl(leant Increaae
1a endocrIne tua>or a
in *alea and rare
•llpoBatoua" renal
twaora in 2 teat fe-
•alea.
NCI, 1977
Oaborne- Technical Hi
Hendel conaiating of
741 H and ca
2ft% alpha C
Halea 3i.9j
77. ».
Peaalea
25. 7| 51. 3
Carcinogenic
under condi-
tlona at
aaaay**
Not undertaken 1. Relatively aaiall num-
ber negative control*)
uncertainties in doe-
aqai high Mortality
in high doaage teat
group*.
NCI data ehowe eiceae
hepatic nodule* in
•alee and temalee.
* Sourcei Kpetein, If7*
•*The conclusion* oC NCI atate that there 1* no clear evidence of carcinogenic effect of heptachlor.
C-30
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TABLE S
SuMary of Catclnoganlclty Data In Nice*
Author* Strain Poraiulation Concentration* tppai) Carclnoqenlcitv ~ Cwnirnt*
Haptachlor (H), H
Ipoalde (H£)t
Cblordana (C)
HE C Author*
Conclualona
Hiatological
He-evaluation
Davli,
C3N H and HI of un-
•p«olCl«d purity
10
10
•Benign* h*pa-
tcMMB induced
by M And HI
H and He both
h«p*tocarclno-
9«nlc
1. PDA data poorly docu-
FDA data atatiatl-
cally •Igniftcaiit for
tuator incidancaa.
Miatotoglcal ra-«val~
uatlon daaionatratad
hcpatocarclnoganiclty .
Hapatocatcinogantc
at(«ct« •tatlatlcally
I BBC,
197)
CD-I Mlitur* of 25% 1.0| 5.0f 10.0
H and 7SI
Doaa ralatad
nodular hypar-
plaaia at 5.0
and 10.0 ppa
Ha pa t oca t c I no-
ganic
1. I HOC data atatlatl-
cally aignlflcant
accaaa of nodular
hyparplaalaa.
Hlatologlcal r«-«val-
uatlon found ha|>atcr-
eate I noaaa.
H«patocarcinog«nicity
•tatlatlcally algnl-
fleant.
NCI, 1977 MC3rl
Tachnlcal Hi
cona latino,
ol 74% H,
and ca, 2««C
Halaa t.
13.•
ra»alea
Carcinogenic
under condi-
tion* oC
aaaay
Not under taken
Relatively aaalI nu»-
bar n«9atlva control*
noii-concurrant eipet 1 -
•entai uncartalntlea
in doaaga.
Davlaad data atatla-
tically aigniflcant
(or tvapa
9«ftjclty.
•Sourcei Bpataln, If7a
C-31
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heptachlor epoxide at dietary levels of 0, 0.5, 2.5, 5.0, 7.5, and
10 rag/kg administered to CFN (Carworth Farms, Nelson^ rats for 108
weeks. Each dosage group consisted of 25 males and 25 females.
Mortality in males ranged from 32 percent for the controls to 52
percent at 2.5 mgAg of diet, and in the females ranged from 24
percent in controls to 52 percent at 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 the
earliest tumor was discovered during the 13th month and 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 acknowledged 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 » 0.55 probability level.
Re-evaluation of tissue slides by Dr. Melvin D. Reuber of a
1959 unpublished Kettering study indicated that there was an in-
crease in hyperplastic nodules and carcinomas of the liver in the
treated animals when compared to control animals (O.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 28 liver carcinomas among 213 treated rats indicated
C-32
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that heptachlor epoxide is carcinogenic in rats at P<10~8
(U.S. EPA, 1977).
Dr. Williams (U.S. EPA, 1977) also re-evaluated the Kettering
tissue slides and concluded that the study demonstrated an in-
creased 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 malign«fncies in the treated
animals versus no malignancies in controls to be strongly sugges-
tive 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 pa-
thologists (Drs. Stewart, Squire, and Popper) and all three diag-
nosed 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 unpub-
lished report dealing with the administration of a mixture of 75
percent heptachlor and 25 percent heptachlor epoxide to female CO
rats at doses of 0, 5.0, 7.5, 10.0, and 12/5 mg/kg 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 the lesions were found in both control
and treated groups. The lesions of the pituitary and adrenal
glands were considered hypertrophies rather than neoplasms. The
lesions of the mammary gland were diagnosed aa adenomas or fibro-
C-33
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adenomas of mammary glands. The liver lesions were referred to as
"clusters of enlarged hepatic cells* (Epstein (1976) calls it cen-
trilobular hepatocytomegaly) with cytoplasmic degranulation and
clusters of enlarged irregular vacuolated cells which were filled
with lipid and distributed randomly in the lobules. They con-
cluded 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 C3Heb/Pe/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 ani-
mals, respectively. Over the test period, 30 control mice had
benign tumors and 21 controls had malignant tumors; heptachlor-
treated mice had 51 benign tumors and 10 malignant tumors; hepta-
chlor epoxide treated mice had 85 benign tumors and 13 malignant
tumors. Statistics were not performed on this data by PDA because
of incompleteness in the number of samples and the "arbitrariness
of microscopic diagnoses" (Davis, 1965). Davis stated that the
incidence of hepatic hyperpiasia and benign hepatomas was approxi-
mately doubled in the test groups, but concluded that heptachlor
034
-------
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. Reuber. He found liver carcinomas in 64 of 87 male mice
(74 percent) and 57 of 78 female mice (73 percent) ingesting hep-
tachlor; in 73 of 79 male mice (92 percent) and 77 of 81 female
mice (95 percent) ingesting heptachlor epoxide; and in 22 of 73
control male mice (30 percent) and in 2 of 53 control female mice
(4 percent) (Reuber, 1977b). He also stated that the affected
treated animals often had three to four carcinomas per liver with
a size of 3 to 5 on, while affected control animals had only soli-
tary 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 ani-
mals that Reuber had diagnosed as having hepatic carcinomas. Drs.
Stewart, Squire, and Sternberg agreed with Dr. Reuber that the 19
animals had hepatic carcinomas (U.S. EPA, 1977). Dr. Williams
diagnosed eight carcinomas/ 10 nodules or hyperplastic nodules,
and one dysplastic area. However, Dr. Williams considers that
hyperplastic nodules are induced only by carcinogens, 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 corn oil by gastric intubation. Hepta-
C-35
-------
chlor was administered at a level of 10 rag/kg of body weight five
times on alternating days beginning at 10 days of age. It was ob-
served 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, including five mam-
mary 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 dif-
ferent locations of the tumors and the lack of reproducibility of
the findings among males, the results are not considered as evi-
dence of carcinogenicity of heptachlor under the present experi-
mental conditions." Epstein (1976) on the other hand, concluded
that the Cabral, et al. (1972) study does show a statistically
significant incidence of endocrine tumors in males.
In 1973, the IRDC completed an unpublished 18-month study
using CD-I mice on a treatment diet containing a mixture of 75
percent heptachlor epoxide and 25 percent heptachlor. The study
was designed using one negative control, one positive dietary con-
trol of 2-acetamidofluorene at 250 mg/kg, and three dietary treat-
ment group* of 1.0, 5.0, and 10.0 mg/kg, respectively. Each group
contained 100 males and 100 females. After six months on these
treatments 10 males and 10 females were sacrificed from each
group. It was found that the liver weights were significantly in-
creased 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
C-36
-------
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 in-
cidence and severity of hepatocytomegaly. A large number of com-
pound 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 ex-
tensions of the hepatocytomegaly lesions (IRDC, 1973). The mice
fed the 1.0 mg/kg diet were considered to be free of compound-
related nodular hyperplasia, since the incidence of the lesion was
similar to the untreated controls. No lesions were found sugges-
tive 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 significant increase in the incidence of liver cancers induced
by the heptachlor epoxide/heptachlor mixture in males in the 5.0
mg/kg group and in both males and females in the 10.0 mg/kg group.
The incidence in these groups was comparable to or higher than the
incidence in the positive (2-acetajnidifluorene, 250 mg/kg} con-
trols. It has been indicated that the majority of lesions diag-
nosed as nodular hyperplasias by IRDC, were diagnosed by Reuber as
carcinoam* (Epstein, 1976). It is interesting to note that though
both IRDC and Reuber diagnosed a similar number of carcinomas in
the positive controls, the discrepancies in the diagnoses seem
largely restricted to the test groups at th« 5.0 and 10.0 mgAg
(Epstein, 1976).
C-37
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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 un-
derdiagnosed the number of carcinomas present (Epstein, 1976).
Epstein (1976) concluded that the IRDC study demonstrated the hep-
tachlor epoxide/heptachlor mixture induced a dose-related inci-
dence of nodular hepatic hyperplasias, and also demonstrated the
hepatocarcinogenicity of heptachlor epoxide/heptachlor as evi-
denced by the histological re-evaluations.
The NCI released a preliminary report on the Gulf South Re-
search Institute study on heptachlor in 1975. These preliminary
findings were reviewed by both Epstein (1976) 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 Insti-
tute and more currently by Tracer Jitco Inc. (NCI, 1977). Both
Osborne-Mendel rats and B6C3F^ mice were used to test the pos-
sible carcinogenicity of technical-grade heptachlor.
Groups of 50 rats of each sex were administered low and high
doses of heptachlor for 80 weeks and then observed for 30 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 rag/kg of heptachlor
in the diet for male rats and 25.7 and 51.3 mg/kg for female rats.
Matched controls consisted of 10 untreated rats of each sex and
pooled controls consisted of 50 untreated male and 50 untreated
female rats from similar bioassays of five other compounds. All
surviving rats were killed at 110 to 111 weeks and no hepatic
C-38
-------
tumors were observed. Neoplasms were found in test animals at in-
creased frequency when compared to control groups, but the nature,
incidence, and severity of the lesions observed provide no clear
evidence of a carcinogenic effect of heptachlor in Osborne-Mendel
rats as reported by the pathologists.
In the second part of the NCI study, groups of 50 mice of
each sex were administered heptachlor at low and high doses for 80
weeks and then observed for 10 weeks. The dose for males was re-
duced once, while the dose for females was reduced twice due to
toxic effects. The time-weighted average dosages in the diet were
6.1 and 13.8 mg/kg of heptachlor for male mice, and 9 and 18 rag/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 car-
cinomas; 18 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.
Epidemiological studies conducted to date have uncovered no
evidence of increased cancer mortality among workers occupation-
C-39
-------
ally exposed in the manufacture of chlordane and heptachlor (Shin-
dell/ 1977; Wang and MacMahon, 1979a,b) . Wang and MacMahon
(1979a) investigated mortalities in a cohort of professional
pesticide applicators. There were 311 deaths between 1967 and
1976 in the population of 16,126 males, giving a standard mortal-
ity rate (SMR) of 84. SMRs for cancers of the lung, liver and
bladder did not differ significantly from 100 at the 95 percent
confidence level. In fact, SMRs for termite control operators,
exposed routinely to heptachlor and chlordane, were somehwat lower
than SMRs for general pesticide operators, who received much less
exposure to heptachlor and chlordane.
Wang and MacMahon (1979b) reported on 1,403 white male
workers who were employed for at least three months in the manu-
facture of chlordane and heptachlor in two U.S. plants between
1946 and 1976. Their study observed 113 deaths from the study
group, compared to 157 expected, giving a standardized mortality
ratio of 72. They also observed no overall excess of deaths from
cancer, even in workers followed for 20 or more years from entry
into the occupation. A small nonsignificant increase in lung can-
cer deaths was seen (12 observed, 9.0 expected), which was not
distributed by duration of exposure or latency in any pattern sug-
gesting an etiologic role. Unfortunately, cigarette smoking data
were not available for this exposed population. The Wang and Mac-
Mahon (1979b) data would indicate that chlordane and heptachlor do
not increase the cancer mortality anong these workers, but the
C-40
-------
authors express that "the study population is too small and the
period of followup too short to translate this into a statement
that there is no excess risk of cancer associated with exposure in
man."
C-41
-------
CRITERION FORMULATION
Existing Guidelines and Standards
Source
Published Standard
Reference
Occup. Safety
Health Admin.
An. Conf. Gov.
Ind. Hyg.
Fed. Republic
Germany
USSR
World Health
Organ.**
U.S. Pub. Health
Serv. Adv. Conn.
500 ug/m3*
500 ug/m3 inhaled
(TLV)
500 ug/m3 inhaled
10 ug/m3 ceiling
value inhaled
0.5 ug/kg/day accept-
able daily intake in
diet
Recommended drinking
water standard (1968)
18 ug/1 of heptachlor
and 18 ug/1 heptachlor
epoxide
Natl. Inst. Occup.
Safety Health, 1977
Am. Conf. Gov. Ind.
Hyg., 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
Current Levels of Exposure
Various investigators have detected heptachlor and/or hepta-
chlor epoxide in the major river basins of the United States at a
mean concentration of 0.0063 ug/1 (U.S. EPA, 1976) for those in-
stances of detection. Food can be a significant factor in man's
exposure to heptachlor and metabolites through bionagnification in
C-42
-------
the food chain. The FDA showed that in their "market basket
study" covering August 1974 to July 1975 for 20 different cities
(Johnson and Manshe, 1977), 3 of 12 food classes contained resi-
dues of heptachlor epoxide ranging from trace amounts in the gar-
den fruits class to 0.0006 to 0.003 ppm in the dairy products and
the meats, fish, and poultry classes, respectively. A national
study by the U.S. Department of Interior in 1967 to 1968 reported
that heptachlor and/or heptachlor epoxide were found in 32 percent
of the 590 fish samples examined (Henderson, et al. 1969), with
whole fish residues from 0.01 to 3.33 mg/kg.
Nisbet (1977) calculated the typical human exposure to hepta-
chlor to be 0.01 ug/individual/day, based on a mean ambient air
concentration of 0.5 ng/m3 and a respiratory volume of 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/m3, the average in-
dividual would inhale only 0.13 ug/day of heptachlor. The sig-
nificance of these figures is dependent upon the efficiency of
lung absorption, which does not appear to have been reported for
humans (Nisbet, 1977). Based on this research, it appears that
inhalation is not a major route for human exposure to heptachlor.
Special Groups at Risk
Infants have been exposed to heptachlor and heptachlor epox-
ide through mothers' milk (Savage/ 1976), cows' milk {Ritcey, et
al. 1972), and commercially prepared baby foods (Lipscomb, 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
C-43
-------
persona living and working in or near heptachlor treated areas had
a particularly high inhalation exposure potential. =
Basis and Derivation of Criteria
Heptachlor has been shewn to exhibit numerous toxicological
effects in animal systems. Heptachlor and its metabolites have
LD50 values ranging from 6 to 531 rag/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 animals are exposed to high doses. Other ef-
fects on animal enzyme systems are referenced throughout the
literature. Mutagenicity was not demonstrated with Salmonella
typhimurium in the Ames assay; however, oral doses of heptachlor
caused dominant 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.
Studies concerning the carcinogenicity of heptachlor and hep-
tachlor epoxide when administered to rats and mice have been con-
ducted by the Kettering Laboratory, the FDA, Cabral, et al. 1972,
the IRDC, and the NCI. Heptachlor or its metabolites have induced
hepatocellular carcinomas in three chronic feeding studies in mice
and heptachlor 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 carcinogencity is sufficient to
conclude that heptachlor is likely to be a human carcinogen. As
C-44
-------
carcinogens are generally assumed to have a nonthreshold dose/
response characteristic, the carcinogenic effect is the most sig-
nificant exposure effect from which to estimate an ambient water
quality criterion value. A linearized multistage model, as dis-
cussed in the Human Health Methodology Appendices to the October
1980 Federal Register notice which announced the availability of
this document, is used in estimating human health risks associated
with the ingestion of heptachlor. Using the described model, the
concentration of heptachlor in water may be calculated from the
incidence data for hepatocellular carcinoma* in the NCI B6C3F]_
mouse study, by assuming an additional individual lifetime risk of
1/100,000, the daily ingestion of 2 liters of water and 6.5 grams
of contaminated fish products, and a weighted average biocconcen-
tration factor of 11,200.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate/ zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." Heptachlor
is suspected of being a human carcinogen. Because there is no
recognized safe concentration for a human carcinogen/ the recom-
mended concentration of heptachlor in water for maximum protection
of human health is zero.
Because attaining a zero concentration level may be infeas-
ible in sc*« 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
C-45
-------
level provides an estimate of the additional incidence of cancer
that may be expected in an exposed population. A risk of 10~5
for example, indicates a probability of one additional case of
cancer for every 100,000 people exposed, a risk of 10~6 indi-
cates one additional case of cancer for every million people ex-
posed, and so forth.
In the Federal Register notice of availability of draft am-
bient water quality criteria, EPA stated that it is considering
setting criteria at an interim target risk level of 10~5,
10~^, or 10"^ as shown in the table below.
Risk Levels
Exposure Assumptions and Corresponding Criteria (1)
(per day)
0 10~7 10'6 10-5
2 liters of drinking 0 0.02^0ng/1 0.2^ng/1 2.^€ ng/1
water and consumption QQ
of 6.5 grams fish
and shellfish. (2)
Consumption of fish 0 0.02Jf/ng/l 0.2#ng/l 2.J« ng/1
and shellfish only
(1) Calculated by applying a linearized multistage model as
described above to the animal bioassay data presented in
the Appendix. Since the extrapolation model is linear
at low doses, the additional lifetime risk is directly
proportional to the water concentration. Therefore,
water concentrations corresponding to other risk levels
can b« 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
C-46
-------
(2) Ninety-seven percent of the heptachlor exposure results
from the consumption of aquatic organisms which exhibit
an average bioconcentration potential of 11,200-fold.
The remaining 3 percent of heptachlor exposure results
from drinking water.
Concentration levels were derived assuming a lifetime expo-
sure to various amounts of heptachlor, (1) occurring from the con-
sumption of both drinking water and aquatic life grown in waters
containing the corresponding heptachlor concentrations and (2)
occurring solely from consumption of aquatic life grown in the
waters containing the corresponding heptachlor concentrations.
Although total exposure information for heptachlor is dis-
cussed and an estimate of the contributions from other sources of
exposure can be made, these data will not be factored into ambient
water quality criteria formulations until additional analysis can
be made. The criteria presented, therefore, assume an incremental
risk from ambient water exposure only.
C-47
-------
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C-52
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C-59
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APPENDIX
Derivation of Criterion £or Heptachlor
Heptachlor fed to B6C3F^ mice for nearly a lifetime induced
hepatocellular carcinomas wtih high frequency in both sexes at two
doses (NCI, 1977). The data for males and additional parameters,
as shown below, were used to calculate the criterion:
Dose (rcg/kg/day) Incidence (I responding/* tested)
0.0 5/19
0.79 11/46
1.79 34/47
le - 546 days w - 0.036
Le « 630 days R - 11,200
L * 630 days
With these parameters the carcinogenic potency for humans,
q]_*, is 3.37 (mg/kg/day P1. The result is that the water
concentration corresponding to a lifetime risk of 10~5 is
2.8 ng/1.
• US OOVIKHIUKT PMNTWC OrrlCI HBO -?C-G:S,O»]
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