i. REPORT wot
EPA/600/8-88/015
TECHNICAL REPORT DATA
(rUmt ntd Iiuavctioiu on tHt matt btfort cvmpitttotJ
2.
3. RECIPIENT'S ACCESSION NO.
PB88-179403/AS
1. TITLE AND SUBTITLE
Health Effects Assessment for Aldrin
I. REPORT DATE
. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
. PERFORMING ORGANIZATION REPORT NO.
PERFORMING ORGANIZATION NAME ANO ADDRESS
10. PROGRAM ELlMENTNO.
11. CONTRACT/GBANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE Of REPORT ANO PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
s. SUPPLEMENTARY NOTES
6. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The Intent 1n these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate: of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Croup
8. DISTRIBUTION STATEMENT
Public
10. SECURITY CLASS (This Rffort)
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS
Unclassified
22. PRICE
EPA
2220-1 (R««. 4-77) PRKVIOU» COITION i> OMOL.CTC
-------
EPA/600/8-88/015
Nay, 1987
HEALTH EFFECTS ASSESSMENT
FOR ALORIN
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
Protection Ag»<»
r
'^ 1670
-------
DISCLAIMER
This document has been reviewed in accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
I
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with aldrln.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary reflecting limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on line literature searches of the TOXLINE and the
CHEMFATE/OATALOG data bases. The basic literature searched supporting this
document 1s current up to Hay, 1986. Secondary sources of Information have
also been relied upon 1n the preparation of this report and represent large
scale health assessment efforts that entail extensive peer and Agency
review. The following Office of Health and Environmental Assessment (OHEA)
sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Aldrln/Olel-
drln. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Water Regulations and Standards, Washington, DC.
EPA 440/5-80-018. NTIS PB81-117301.
U.S. EPA. 1980b. Hazard Profile for Aldrln. Prepared by the
Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste, Washington, DC.
U.S. EPA. 1986b. CarclnogenlcHy Assessment of Aldrln and 01el-
drln. December 1986 Review Draft. Office of Health and Environ-
mental Assessment, Carcinogen Assessment Group, Washington, DC.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfD$o)
exposures.
111
-------
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980c) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfOg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained 1n U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenlcHy
RfO-s and RfO values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980c). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents to this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The risk assessment for aldrln Is based on positive results In three
carclnogenlclty bloassays using mice (NCI, 1977; Davis and FUzhugh, 1962;
Epstein, 1975; Davis, 1965). The U.S. EPA (1986a) calculated a human
carcinogenic potency factor (q-|*) of 17 (mg/kg/day)"1 based on a dose-
related Increase 1n the Incidence of hepatocellular carcinomas In male
86C3F1 mice and )n both male and female CH3 mice given aldrln In the diet
for up to 2 years. The geometric mean of the three potency estimates was
calculated as the best upper bound estimate on risk by U.S. EPA (1986b).
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . ,
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS ,
CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.2. REFERENCE DOSE (RfD)
Page
. . . 1
. . . 3
. . . 3
. . . 3
4
, , 4
. . . 4
, . . 4
. . . 5
. . . 5
. . . 6
. . . 6
. . . 6
. . . 7
7
. . . 9
. . . 9
. . . 9
. . . 9
. . . 9
, . . 9
, . . 15
. . . 15
, . . 16
, . . 17
. . 18
, . . 18
. . 18
V11
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TABLE OF CONTENTS
Page
6.3. CARCINOGENIC POTENCY (q-j*) 18
6.3.1. Oral 18
6.3.2. Inhalation 18
7. REFERENCES 22
APPENDIX: Summary Table for AldMn 28
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LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
LOAEL Lowest-observed-adverse-effect level
NFO Mixed function oxldase
OMPA Octamethyl pyrophosphoramlde
ppm Parts per minion
RfO Reference dose
RfD$ Subchronlc reference dose
TLV Threshold limit value
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
aldrln are presented In Table 1-1.
Considering Its relatively low vapor pressure and high K value,
adsorption of aldrln to airborne partlculates may occur. Vapor phase aldrln
may react with hydroxyl radicals with an estimated half-life of <1 hour
(HSOB 1986). Available data Indicate that volatilization, oxidation by
hydroxyl radicals, bloconcentratlon and adsorption to sediments will be
significant 1n water (HSOB, 1986). The aquatic half-life of 34 days for
aldrln 1s based on a study with lake water (Zoetemann et a!., 1980). In
both soil and water, dleldrln Is reported to be a major degradation product
of aldrln (Callahan et al., 1979; Sanborn et al., 1977). The half-life of
aldrln In soil was estimated from persistence data (Adams, 1967) and the
observation that after five annual applications of aldrln to soil, 95%
disappeared In 1 year (Sanborn et al., 1977).
0096h -1- 09/25/86
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TABLE 1-1
Selected Chemical and Physical Properties and Half-lives for Aldrln
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
B1oconcentrat1on factor;
Soil adsorption
coefficient:
Half-lives:
Water
Soil
309-00-2
chlorinated
pesticide
364.93
2.31xlC-5 mm Hg
at 20°C
2.7x10-* mg/l
at 20°C
3.01-7.40
109 to 10*.
various aquatic
organisms
407-28,200
34 days (lake)
3-7 months
Sanborn et al., 1977
Sanborn et al.. 1977
Lu and HeteaIf, 1975;
BMggs, 1981
Callahan et al.,
1979
SablJIc. 1984
Zoetemann et al., 1980
Adams. 1967;
Sanborn et al., 1977
0096h
-2-
12/17/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Qualfe and FUzhugh (1967) reported that aldMn was readily absorbed
from the gastrointestinal tract. No quantitative data for absorption were
available.
2.2. INHALATION
Pertinent data concerning the absorption of aldrln from the respiratory
tract could not be located In the available literature.
0096h -3- 09/25/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. NCI (1977) conducted subchronlc range-finding studies with
rats and mice. Groups of five male and five female Osborne-Mendel rats and
equal numbers of B6C3F1 mice were fed diets containing aldrln In 2-fold
Increasing concentrations from 40-320 ppm (rats) or 2.5-80 ppm (mice) for 6
weeks followed by a 2-week observation period. In rats, some mortality and
depression of body weight gain occurred at 160 and 320 ppm, but no such
effects occurred at 40 and 80 ppm. All mice exposed to 40 and 80 ppm died,
while two of those at 20 ppm died. No body weight effects occurred In any
group. No other parameters of toxlclty were monitored In these studies.
In a long-term oral toxlclty study using dogs, FHzhugh et al. (1964)
orally treated 12 mongrel dogs with aldrln at dosages of 0.2, 0.5, 1 or 5
mg/kg/day (presumably In the diet), 6 days/week for up to 25 months. Gross
toxic effects, Including weight loss and convulsions, occurred at >0.5
mg/kg/day. Fatty degenerative changes In liver and kidney, and bone marrow
changes (reduced cellularUy) occurred at >1.0 mg/kg/day. No adverse
effects were observed at >1.0 mg/kg/day or at 0.2 mg/kg/day. In another
study. Del:hmann et al. (1968) fed three groups of six male beagle dogs
capsules containing 0.6 mg/kg aldrln, 0.3 mg/kg aldrln plus 12 mg/kg DDT, or
24 mg/kg DDT only, 5 days/week for 10 months. Signs of Intoxication (hyper-
excHabllHy, tremors, anorexia) and some mortality occurred In both groups
receiving aldrln.
3.1.2. Inhalation. Subchronlc Inhalation data could not be located In
the avallaole literature.
0096h -4- 12/17/86
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3.2. CHRONIC
3.2.1. Oral. Jager (1970) monitored workers at a pesticide manufacturing
plant and reported that 33.2 vg/kg/day can be tolerated by workers for up
to 15 years. The route of exposure was presumed to be oral. Some workers
could tolerate twice this level without any signs of Intoxication.
Treon and Cleveland (1955) conducted a study In which groups of 40 male
and 40 female Carworth rats were fed diets containing aldMn at 0, 2.5, 12.5
or 25 ppm for 2 years. Mortality of females was significantly Increased
relative to controls at all concentrations tested; however, the authors
questioned the validity of this observation because of unusually low mortal-
ity of the control In this experiment. Relative liver weights of males fed
2.5 ppm and females fed 12.5 ppm were significantly greater than controls.
Delchmann et al. (1970) fed groups of 30 male and 30 female Osborne-
Mendel rats diets containing 0, 20, 30 or 50 ppm aldrln for 2 years.
Tremors and convulsions were observed 1n a few rats 1n all treated groups,
and the number affected was dose-related. The Hfespan of high-dose females
was shortened, and relative liver weights were Increased In male rats at 30
and 50 ppm.
FHzhugh et al. (1964) fed groups of 12 male and 12 female Osborne-
Nendel rats diets containing 0. 0.5, 2, 10, 50, 100 or 150 ppm aldrln for 2
years. Survival was reduced at >50 ppm. Increased relative liver weights
and microscopic liver lesions occurred at all doses. The liver lesions were
minimal In rats fed 0.5 ppm aldrln and pronounced at >50 ppm.
Hodge et al. (1967) summarized available aldrln toxldty studies and
attempted to define thresholds for various effects 1n different species.
The most sensitive effect of aldrln was Increased relative liver weight In
rats, which occurred at a concentration of 0.5 ppm In the diet for 2 years.
0096h -5- 09/25/86
-------
'H1stopatholog1cal liver effects occurred at 2 ppro aldrln In the diet for 2
years, but not at 0.5 ppm. This 1s In contrast to the observation by
FUzhugh et al. (1964) who noted minimal liver lesions In rats fed diets
containing 0.5 ppm aldrln for 2 years. In dogs, Increased relative liver
weights and hlstopathologlcal liver effects occurred at 3 ppm aldrln In the
diet for 15 months, but not at 1 ppm. A dietary concentration of 10 ppm for
2 years caused hlstopathologlcal changes In the liver of mice.
Host of the Information concerning chronic oral toxldty of aldrln 1s
provided by studies that are primarily concerned with the potential for
cardnogenldty. These studies are discussed In more detail 1n Section 4.2.
3.2.2. Inhalation. Avar and Czegledl-Janko (1970) studied occurrence of
neurological signs and symptoms In a group of 15 male workers occupatlonally
exposed to aldrln for <5 years. Some workers with whole blood dleldrln
concentrations 0.10 ppm had signs of aldrln poisoning, but others had no
signs at higher blood levels (0.25 ppm). In three severely affected men,
symptoms ceased within 7 months after cessation of exposure. Dleldrln, the
epoxlde of aldrln. Is the predominant metabolite of aldrln 1n animals.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Treon and Cleveland (1955) reported results of a 3-genera-
tlon study 1n which aldrln was fed to groups of Carworth rats at dietary
concentrations of 0, 2.5, 12.5 or 25 ppm. At 12.5 or 25 ppm, aldrln caused
reduced numbers of pregnancies, and Increased pup mortality during the
suckling period. Effects at 2.5 ppm were described as "slight to moderate."
Litter size was unaffected at any concentration.
Hodge et al. (1967) and Clegg (1979) summarized several studies concern-
Ing reproductive effects of aldrln. Clegg (1979) reported that postnatal
survival was decreased In the F. . F,. and F_. generations of mice fed
0096h -6- 09/25/86
-------
3, 5 or 10 ppro aldrln In the diet. Hodge et al. (1967) attempted to define
thresholds For reproductive effects. Estrus cycles of rats were disturbed
when they were fed aldrln at a dietary concentration of 20 ppm, but not at 5
ppm. In dogs. 8 ppm aldrln In the diet caused Increased pup mortality.
None of the studies summarized by Hodge et al. (1967) Indicated that aldrln
caused any teratogenlc effects In rats or dogs.
Ottolenghl et al. (1974) conducted a study In which pregnant golden
hamsters or CD-I mice were given single oral doses of 50 or 25 mg/kg,
respectively. Hamsters were treated on days 7, 8 or 9 of gestation and mice
on day 9. Treatment on day 7 or 8 caused a significant Increase In fetal
deaths In hamsters. Reduced fetal weight occurred In treated hamsters.
Hamsters treated on day 8 had the highest Incidence of anomalies (open eye,
webbed foot, cleft palate, etc.) Teratogenlc effects also occurred In
treated mice.
3.3.2. Inhalation. Data concerning teratogenlc or reproductive effects
of aldrln In Inhalation exposures could not be located In the available
literature.
3.4. TOXICANT INTERACTIONS
U.S. EPA (1980a) noted that since aldrln 1s metabolized by hepatic HFOs,
any Inducer or Inhibitor of these enzymes would affect the metabolism of
aldrln. Delchmann et al. (1968) found that tissue DOT concentrations were
Increased In dogs given DDT and aldrln compared with those given DDT alone;
no explanation was given for this observation. Rats pretreated with a diet
containing 250 ppm hexachlorobenzene for 4 weeks retained less radioactivity
from an Intraperltoneal Injection of 5 mg/kg radlolabeled aldrln than rats
that were not pretreated with hexachlorobenzene (Clark et al., 1981).
0096H -7- 12/17/86
-------
'Williams et al. (1967) reported that aldrln pretreatment by tntraperHoneal
Injection reduced the acute oral toxldty of Banol and Mobam. two carbamate
Insecticides. Trlolo and Coon (1966) and Trlolo et al. (1970) found that
aldrln pretreatment reduced the toxlclty of parathlon and paraoxon. Aldrln
failed to protect against the antlchlolnesterase effects of OHPA and
neostlgmlne (Trlolo and Coon, 1966).
0096h -8- 09/25/86
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding cardnogenlclty of aldrln to
humans from oral exposure could not be located 1n the available literature.
4.1.2. Inhalation. Versteeg and Jager (1973) reported results of a study
of 233 pesticide workers at a plant 1n Holland. These workers were exposed
to aldrln and dleldMn for up to 12.3 years, with a mean exposure of 6.6
years and an average time since the end of exposure of 7.4 years. Van
Raalte (1977) published a follow-up study on these workers, and reported
that no Increase In Incidence of any type of cancer was observed. U.S. EPA
(1980a) has criticized these studies because of the small sample size, short
exposure time and short observation period.
4.2. BIOASSAYS
4.2.1. Oral. The available data from cardnogenlclty bloassays with
aldrln are summarized 1n Table 4-1. Negative results were obtained In three
carclnogenlclty studies with Osborne-Hendel rats (Delchmann et al., 1970;
FHzhugh et al., 1964; NCI, 1977). In contrast, the NCI (1977) study using
mice yielded positive results as did the Davis (1965) and Davis and FHzhugh
(1962) studies. U.S. EPA (1980a) noted that mice appear to be the species
most susceptible to carcinogenic effects of aldrln. The U.S. EPA (1986b)
evaluated these studies and felt that the Delchmann et al. (1970) study was
an Inadequate test of cardnogenlclty; therefore, this study will not be
further discussed.
In the NCI (1977) study using rats, groups of SO male and 50 female
Osborne-Hendel rats were fed diets containing 30 or 60 ppm aldrln for 74
weeks, followed by a 37- to 38-week observation period. Hatched controls
consisted of 10 rats/sex, and pooled controls used for statistical analyses
0096h -9- 01/29/87
-------
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'consisted of matched controls plus 58 untreated males and 60 untreated
females from other studies. Hyperexcllability and reduced body weights
relative to controls occurred In treated rats during the second year of the
study. The combined Incidence of folUcular cell adenoma and carcinoma of
the thyroid was Increased In male and female rats, but this Increase was
significant only In low-dose males (14/38, p=0.001) and low-dose females
(10/39, p*0.009) when compared with pooled controls (4/48 males and 3/52
females). Cortical adenoma of the adrenal gland was Increased 1n the
low-dose females (8/45) but not 1n high-dose females (1/48) compared with
pooled controls (0/55, p=0.001). In the absence of significant Increases 1n
any tumor relative to matched controls, NCI (1977) concluded that none of
the observed tumors In rats could be associated with aldrln treatment.
In the FUzhugh et al. (1964) study, as described by U.S. EPA (1986b),
aldrln (>99% purity) was administered to 12 male and 12 female Osborne-
Hendel rats In the diet at dose levels of 0, 0.5, 2, 10, 50, 100 or 150 ppm
for a period of 2 years. The rats were 3 weeks of age when aldrln diet was
started.
There was no significant effect on growth rate. However, survival was
markedly decreased 1n aldrln groups .Jt 50 ppm or more. Increases 1n llver-
to-body weight ratio were reported at all dose levels and were statistically
Increased from controls (p<0.05) at 10 ppm and greater In males and at all
dose levels for females. Chronic nep.lrltls, which occurred more commonly In
males than females, was reported for Mgh-dose levels.
Only 68% of all animals were examined hlstologlcally. Total tumor Inci-
dence (all doses combined) In aldMn-treated animals was 36% compared with
an Incidence 1n controls of 18%. However, the Increase was particularly
large among rats at the lower dosage levels. The lower Incidence at higher
doses may have been related to the decreased survival at the high doses.
0096h -12- 01/30/87
-------
There was no predominant tumor type with tumors In various organs Including
the lungs, breast and lymphoretlcular system. Although no hepatomas or
hepatocellular carcinomas were diagnosed, a high Incidence of "chlorinated
Insecticide" lesions were observed at 50 ppm and above.
In the NCI (1977) mouse study, groups of 50 male and 50 female B6C3F1
mice were fed diets containing 3 or 6 ppm (females) or 4 or 8 ppm (males)
for 80 weeks followed by a 10- to 13-week observation period (NCI, T977).
Matched controls consisted of 10 untreated females and 20 untreated males;
pooled controls consisted of matched controls plus 79 untreated females and
92 untreated males from other experiments. There was a significant dose-
related Increase In the Incidence of hepatocellular carcinomas 1n male mice
(matched controls 3/20, pooled controls 17/92, low-dose 16/49, high-dose
25/45) when compared with matched controls (p=0.001) or pooled controls
(p<0.001). NCI (1977) concluded that aldrln was carcinogenic to male B6C3F1
mice, causing hepatocellular carcinomas.
Davis and FUzhugh (1962) alluded to a previous 2-year aldrln mouse
feeding study that raised the suspicion of tumor1gen1c1ty of aldrln although
the results were considered Inconclusive because the majority of the animals
were not available for pathologic examination. No reference was provided
and no further Information could be found on that study.
In this study, as reviewed by U.S. EPA (1986b). a group of 215 C3HeB/Fe
mice were fed a dietary mixture containing 10 ppm aldrln (purity not speci-
fied) for a period of up to 2 years. The control group consisted of 217
mice. The number of mice/sex was not given, but they were approximately
equally divided by sex. Mice that died during tne experiment were necrop-
sled, as were all 2-year survivors. The extent of pathology examination was
not clear. Tissues from animals with gross lesions and from some grossly
0096h -13- » 01/30/87
-------
normal mice were preserved. After fixation, the tissues were reexamlned and
were selected for microscopic study. Slides were prepared from all gross
lesions 1n which neoplasla was suspected, from lungs of mice that had
hepatic masses, and also from some animals that had gross pneumonia, Intus-
susceptions, or certain other Incidental gross abnormalities. No breakdown
was provided as to actual tissues examined.
The average survival of the aldrln-treated groups was -2 months less
than controls. Intercurrent diseases, pneumonia and Intestinal parasitism
were present and may have Influenced the long-term survival rate.
Results, reported for both sexes combined, Indicated a statistically
significant (p<0.001) Increase In the Incidence of hepatomas (hepatic cell
adenomas) 1n the treated animals as compared with controls. Only one other
tumor (lung) was reported In the aldrln group. The Incidence of hepatomas,
based on necropsled mire, was 23% In the aldrln group and 7% In controls.
The hepatic cell adenomas were described as expanding nodules of hepatic
parenchymal tissue, usually with altered lobular architecture, and morpho-
logically ranging from very benign lesions to borderline carcinomas. The
authors concluded that aldrln had significantly Increased the Incidence of
hlstologlcally benign liver tumors. Dr. M. Reuber conducted an Independent
revaluation of the liver lesions and considered most of the hepatomas to be
liver carcinomas. Ors. Popper, Farber and Flrmlnger concurred with Reuber's
evaluation (Epstein, 1975). The value of this study was compromised by the
poor survival rate, lack of detailed pathology, loss of a large percentage
of the animals to the study, and failure to treat the results In males and
females separately. Despite these Inadequacies, the study revealed evidence
for hcpatocardnogenlcHy of aldrln 1n C-H mice.
0096h -14- 01/30/87
-------
As a followup to the previous study, Davis (1965), as reviewed by U.S.
EPA (1986b), administered aldrln (purity not specified) at 0 or 10 ppm In
the diet to groups of 100 male and 100 female C_H mice for 2 years. The
pathology examination was similar to that conducted In Davis and FUzhugh
(1962). Again, survival 1n the treated group was reduced compared with the
control group, although no breakdown of data by sex and by time of death was
given. There was no Indication as to the time of tumor detection or deaths
1n treated versus control groups. The Incidence of hepatic hyperplasla and
benign hepatomas 1n the aldrln group was approximately double that of
controls, whereas the number of hepatic carcinomas was about the same. Dr.
Reuber also reevaluated the liver lesions from this study and concluded that
most of the hepatomas were actually carcinomas. Drs. Popper, Farber and
Flrmlnger concurred In Reuber's diagnosis (Epstein, 1975).
Some of the same deficiencies seen In the 1962 FDA study were also
evident 1n this one; namely, a lack of detailed pathology examination and
failure to present data according to sex. However, the survival at 18 or 24
months was acceptable In the controls. The evidence for an oncogenlc
response (whether benign or malignant) 1s substantial In male and female
C3H mice.
4.2.2. Inhalation. Carc1nogen1c1ty bloassays for aldrln 1n which Inhala-
tion exposures were used could not be located In the available literature.
4.3. OTHER RELEVANT DATA
U.S. EPA (1980a) noted that data concerning mutagenlclty of aldrln were
limited, but that the data concerning dleldrln might be sufficient since
aldrln Is readily converted to dleldrln In both in vivo and in vitro
systems. Several studies reviewed by U.S. EPA (1980a) Indicated that
aldrln/dleldrln gave predominantly negative results 1n mutagenlclty assays
0096h -15- 01/30/87
-------
with microorganisms. In a review of several studies, Ashwood-Smlth (1981)
noted that aldrln was generally not mutagenlc In bacterial assays, and that
most mammalian studies were difficult to Interpret because of a lack of
positive controls or a dose-response relationship. A more recent review by
Khan and Oev (1982) stated that aldrln was not mutagenlc 1n bacteria and
yeast.
4.4. WEIGHT OF EVIDENCE
Aldrtn can be placed tn EPA Group 82, Probable Human Carcinogen, using
the U.S. EPA (1986a) guidelines for carcinogen risk assessment. This
category applies to compounds for which there Is sufficient evidence of
cardnogenlclty In animals In the absence of human data. In this case, the
sufficient animal evidence consists of a definitive malignant tumor response
In Independent studies that Included different strains of the same species
(mouse) (U.S. EPA, 1986b).
Aldrln was classified by IARC (1982) 1n Group 3, chemicals that cannot
be classified as to their potential carclnogenlclty In humans. The database
provides limited evidence of carclnogenlclty In animals and Inadequate
evidence of carclnogenlclty In humans.
0096h -16- 01/30/87
-------
5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (19SOa) derived cancer-based ambient water quality criteria for
aldrln using a potency factor calculated from data for Incidence of hepato-
cellular carcinomas In male mice In the MCI (1977) bloassay. The q * for
aldrln was 11.45 (mg/kg/day)"1. The resulting criteria corresponding to
an Incremental Increase of lifetime cancer risk of 10~5, 10~» and 10"7
are 0.74, 0.074 and 0.0074 ng/a, respectively, for exposure to contami-
nated water and 1ngest1on of contaminated aquatic organisms. The criteria
are 0.79, 0.079 and 0.0079 ng/J, 1f only consumption of contaminated
aquatic organisms Is considered. Because aldrln Is rapidly metabolized to
dleldrln 1n fish, these criteria were calculated by application of a factor
based on the carcinogenic potency of dleldrln as well as that of aldrln.
ACGIH (1986) recommended a TLV of 0.25 mg/m3 for aldrln. This value
was designed to protect against liver Injury, but ACGIH (1986) noted that It
had only limited supporting data. The OSHA (1983) standard Is also
0.25 mg/m3.
0096h -17- 01/29/87
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE OOSE (RfD$)
Because aldrln 1s classified as a carcinogen, no RfD- (formerly AIS)
values for oral or Inhalation exposures will be calculated.
6.2. REFERENCE OOSE (RfD)
Because aldrln 1s classified as a carcinogen, no RfD (formerly AIC)
values for oral or Inhalation exposures will be calculated.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. U.S. EPA (1986b) performed a quantitative carclnogenlcHy
risk assessment for aldrln. The following text was adapted from this recent
document.
Three data sets are suitable for quantitative risk estimation. These
are both male and female C.H mice In the Davis (1965) study as reevaluated
*3
by Reuber and cited 1n Epstein (1975), and male B6C3F1 mice 1n the NCI
(1978) bloassay.
Using these data sets and the linearized multistage model of Crump (U.S.
EPA, 1980c), three potency eslmates, ranging from 23 down to 12 (mg/kg/
day)'1, with a geometric mean of 17 (mg/kg/day)"1 were calculated.
Because humans may be as sensitive as the most sensitive animal species, the
potency for the general population 1s estimated at 17 (mg/kg/day)'1.
These estimates are plausible upper bounds for the Increased cancer risk
from aldrln, meaning that the true risk 1s not likely to exceed these
estimates and may be lower.
Review of the CBI file for aldrln did not reveal any Information that
would affect this assessment.
6.3.2. Inhalation. Inhalation data for aldrln were Insufficient to
perform a quantitative risk assessment.
0096h -18- 05/06/87
-------
TABLE 6-1
Cancer Data Sheet for Derivation of q-j*
Compound: aldrln
Reference: NCI, 1978; U.S. EPA, 1986b
Species, Strain, Sex: mice, B6C3F1, male
Body weight: 0.035 kg (measured)
Length of exposure (le) » 80 weeks
Length of experiment {Le) - 90 weeks
Llfespan of animal (L) = 90 weeks
Tumor site and type: hepatocellular carcinomas
Route, vehicle: oral, diet
Experimental Doses
or Exposures Transformed Dose
(ppro In diet) (mg/kg/day)
0 0
4 0.52
8 1.04
Incidence
No. Responding/No. Tested
or Examined
17/92
16/49
25/45
Human q-|* « 12 (mg/kg/day)'
0096h -19- 01/29/87
-------
TABLE 6-2
Cancer Data Sheet for Derivation of q-j*
Compound: aldrln
Reference: Davis, 1965; U.S. EPA, 1986b
Species, Strain, Sex: mice, 38, female
Body weight: 0.030 kg (assumed)
Length of exposure (le) = 2 years
Length of experiment (Le} = 2 years
Tumor site and type: liver, carcinoma
Route, vehicle: oral, diet
Experimental
Dose (ppm)
Transformed
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)
Incidence
No. Responding/
No. Examined
0
10
0
1.3
0
0.104
2/53
72/85
Human q-j* * 23 (mg/kg/day)'
009(>h
-20-
01/30/87
-------
TABLE 6-3
Cancer Data Sheet for Derivation of q-|*
Compound: aldrln
Reference: Davis and Fltzhugh, 1962; U.S. EPA, 1986b
Species, Strain, Sex: mice, C3H, male
Body weight: 0.030 kg (assumed)
Length of exposure (le) - 2 years
Length of experiment (Le) * 2 years
Tumor site and type: liver, carcinoma
Route, vehicle: oral, diet
Experimental
Dose (ppm)
0
10
Transformed
Dose (mg/kg/day)
0
1.3
Human Equivalent
Dose (mg/kg/day)
0
0.104
Incidence
No. Responding/
No. Examined
??//:i
75/91
Human q-j* « 18 (mg/kg/day)'1
0096h
-21-
01/29/87
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Documentation of the Threshold Limit Values, 4th ed. Cincinnati, OH. p. 17.
Adams, R.S., Jr. 1967. The fate of pesticide residues 1n soil. J. Minn.
Acad. Scl. 34: 44-48.
Ashwood-Smlth, M.O. 1981. The genetic toxicology of aldMn and dleldMn.
Mutat. Res. 86(2): 137-154.
Avar, P. and G. Czegledl-Janko, 1970. Occupational exposure to aldrln:
Clinical and laboratory findings. Br. J. Ind. Med. 27(3): 279-282.
BMggs. G.G. 1981. Theoretical and experimental relationships between soil
adsorption, octanol-water partition coefficients, water solubilities,
bloconcentratlon factors, and the parachor. J. Agrlc. Food. Chem. 29: 1052.
Callahan, M.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-related
Environmental Fate of 129 Priority Pollutants. U.S. EPA, Washington, DC.
EPA 440/4-79-029A.
Clark, O.E., G.W. Ivle and B.J. Camp. 1981. Effects of dietary hexachloro-
benzene on 1n vivo blotransformatlon. J. Agrlc. Food Chem. 29(3): 600-608.
Clegg, D.J. 1979. Animals reproduction and cardnogenldty studies In
relation to human safety evaluation. Dev. Toxlcol. Environ. Sc1. 4: 45-59.
0096h -22- 01/29/87
-------
Davis, K.J. 1965. Pathology report on mice for aldrln. dleldrln, hepta-
chlor, or heptachlor epoxlde for two years. Int. Food. Drug Admin. (Cited
In U.S. EPA. 1980a)
Davis, K.J. and O.G. FHzhugh. 1962. Tumorlgenlc potential of aldrln and
dleldrln for mice. Toxlcol. Appl. Pharmacol. 4: 187-189.
Oelchmann, W.B., M. KepHnger, I. Dressier and F. Sala. 1968. Retention of
dleldrin In the tissues of dogs fed aldrln and DDT Individually and as a
mixture. Ind. Med. Surg. 37(7): 548.
Delchmann. W.B., W.E. MacDonald, E. Blum, et al. 1970. Tumor 1 gen1c1ty of
aldrfn, dleldrln and endrln In the albino rat. Ind. Med. Surg. 39(10):
426-434.
Epstein, S.S. 1975. The carclnogenldty of dleldrln. Part I. Sc1. Total
Environ. 4: 1-52.
FUzhugh, O.G., A.A. Nelson and H.L. Qualfe. 1964. Chronic oral toxlclty
of aldrln and dleldrln 1n rats and dogs. Food Cosmet. Toxlcol. 2: 551-562.
Hodge. H.C.. A.M. Boyce, W.B. Delchmann and H.F. Krayblll. 1967. Toxicol-
ogy and no-effect levels of aldrln and dleldrln. Toxlcol. Appl. Pharmacol.
10(3): 613-675.
HSDB (Hazardous Substance Data Bank). 1986. Record #199. Online.
0096h -23- 01/29/87
-------
IARC (International Agency for Research on Cancer). 1982. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Chemicals,
Industrial process, and Industries associated with cancer In humans. WHO,
IAHC, Lyons, France. Vol. 4, p. 112-114.
Jager, K.W. 1970. Aldrln, Dleldrln, Endrln and Telodrln: An Epldemlologl-
cal and lexicological Study of Long-term Occupational Exposure. Elsevler
Publishing Co., Amsterdam. (CHed In U.S. EPA, 1980a)
Khan, R.R. and B. Oev. 1962. Toxicology Data Sheets on Chemicals: Aldrln.
NT1S PB-82-219007.
Lu, P. and L. Metcalf. 1975. Environmental fate and blodegradablllty of
benzene derivatives as studied In a model aquatic ecosystem. Environ.
Health Perspect. 10: 269-284.
NCI (National Cancer Institute). 1977. Bloassays of aldHn and dleldrln
for possible carclnogenlclty. NCI CaMnogenesIs Tech. Rep. Ser. No. 21.
(Also published as NTIS PB-275-666)
OSHA (Occupational Safety and Health Administration). 1983. OSHA Safety
and Health Standards. 29 CFR. 1910.1000.
Ottolenghl, A.B., et al. 1974. Teratogenlc effects of aldHn, dleldrln and
endrln In hamsters and mice. Teratology. 9: 11. (Cited In U.S. EPA, 1980a)
0096h -24- 01/29/87
-------
Qualfe, J.S. and M.L. FHzhugh. 1967. Survey of quantitative relationships
between Ingestlon and storage of aldrln and dleldrln 1n animals and man.
Food Cosmet. Toxlcol. 5(1): 39-50.
Sabljlc, A. 1984. Prediction of the nature and strength of soil sorptlon
of organic pollutants by molecular topology. J. Agrlc. Food. Chem. 32:
243-246.
Sanborn, J.R., 8.M. Francis and R.L. Metcalf. 1977. The Degradation of
Selected Pesticides In Soil: A Review of the Published Literature. EPA
600/9-77-02. p. 268-286.
Treon, J. and F.D. Cleveland. 1955. Toxlclty of certain chlorinated hydro-
carbon Insecticides for laboratory animals, with special reference to aldrln
and dleldrln. Agrlc. Food Chem. 3(5): 402-408.
Trlolo, A.J. and A.J. Coon. 1966. The protective effect of aldrln against
the toxlclty of organophosphate antlchollnesterases. J. Pharmacol. Exp.
Ther. 154(3): 613-623.
Trlolo, A.J., E. Mat a and J.M. Coon. 1970. Effects of organochloMne
Insecticides on the toxlclty and \n_ vitro plasma detoxlcatlon of paraoxon.
Toxlcol. Appl. Pharmacol. 17(1): 174-180.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Aldr1n/D1e1dr1n,
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu-
lations and Standards. Washington, DC. EPA 440/5-80-018. NTIS PB 81-117301.
0096h -25- 05/06/87
-------
U.S. EPA. 1980b. Hazard Profile for AldMn. Prepared by the Office of
Health and Environmental Assessment. Environmental Criteria and Assessment
Office, Cincinnati. OH for the Office of Solid Waste, Washington, DC.
U.S. EPA. 1980c. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Carclnogenlclty Assessment of AldMn and Dleldrln.
December 1986 Review Draft. Office of Health and Environmental Assessment,
Carcinogen Assessment Group, Washington, DC.
Van Raalte, H.G.S. 1977. Human experience with dleldrln 1n perspective.
Ecotoxlcol. Environ. Saf. 1: 203. (Cited 1n U.S. EPA, 1980a)
Versteeg, J.P.J. and K.W. Jager. 1973. Long-term occupational exposure to
the Insecticides aldrln, dleldrln, endrln, and telodrln. Br. Ind. Med. 30:
201. (Cited 1n U.S. EPA, 1980a)
0096h -26- 05/06/87
-------
Vettorazl, G. 1975. State of the art of the toxlcologlcal evaluation
carried out by the Joint FAO/WHO expert committee on pesticide residues. I.
Organohalogenated pesticides used 1n public health and agriculture. Residue
Rev. 56: 107-134.
Williams, C.H., J.L. Casterllne, Jr., K.H. Jacobson and J.E. Keys. 1967.
ToxIcHy and enzyme activity resulting from Interaction between chlorinated
hydrocarbon and carbamate Insecticides. Toxlcol. Appl. Pharmacol. 11(2):
302-307.
Zoetemann, B.C.J., K. Harmsen, J.B.H.J. Lindens, C.F.H. Morra and M. Slooff.
1980. Persistent organic pollutants In river water and groundwater of The
Netherlands. Chemosphere. 9: 243.
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