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Aldrin
CASRN 309-00-2
Contents
0130
Aldrin; CASRN 309-00-2
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Aldrin
File On-Line 03/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 03/01/1988
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 07/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Aldrin
CASRN -- 309-00-2
Last Revised -- 03/01/1988
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Liver toxicity NOAEL: none 1000 1 3E-5
mg/kg/day
Rat Chronic Feeding LOAEL: 0.5 ppm diet
Study (0.025 mg/kg/day)
Fitzhugh et al., 1964
*Conversion Factors: 1 ppm = 0.05 mg/kg/day (assumed rat food consumption)
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Fitzhugh, O.G., A.A. Nelson, and M.L. Quaife. 1964. Chronic oral toxicity of
aldrin and dieldrin in rats and dogs. Food Cosmet. Toxicol. 2: 551-562.
Groups of 24 rats (12/sex) were fed aldrin in the diet at levels of 0, 0.5, 2,
10, 50, 100, or 150 ppm for 2 years. Liver lesions characteristic of
chlorinated insecticide poisoning were observed at dose levels of 0.5 ppm and
greater. These lesions were characterized by enlarged centrilobular hepatic
cells, with increased cytoplasmic oxyphilia, and peripheral migration of
basophilic granules. A statistically significant increase in liver-to-body
weight ratio was observed at all dose levels. Kidney lesions occurred at the
highest dose levels. Survival was markedly decreased at dose levels of 50 ppm
and greater.
Additional data are fairly supportive. Effect and no-effect levels are
similar (to those found for rats) for liver effects in dogs after 15 months'
exposure to aldrin in the diet. Liver effects were observed at slightly
higher doses in several other subchronic-to-chronic rat and dog studies.
Short-term exposure to higher doses resulted in mortality for a number of
species.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- The composite UF of 1000 encompasses the uncertainty of extrapolation
from animals to humans, the uncertainty in the range of human sensitivities,
and an additional uncertainty because the RfD is based on a LOAEL rather than
a NOAEL.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
None.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
The principal study, designed as a carcinogenesis bioassay, is strong in
histopathologic analysis but lacks other toxicologic parameters, and is
therefore rated medium. The data base is fairly extensive, and generally
supportive, but is rated medium because of the lack of NOELs for some studies.
Also, no chronic data exist for the dog, which may be a more sensitive species
than the rat. Medium confidence in the RfD follows.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
U.S. EPA. 1982. Toxicity-Based Protective Ambient Water Levels for Various
Carcinogens. Environmental Criteria and Assessment Office, Cincinnati, OH.
ECAO-CIN-431. Internal review draft.
The RfD has been reviewed internally by ECAO-Cin.
Agency Work Group Review -- 12/18/1985
Verification Date -- 12/18/1985
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Aldrin
CASRN -- 309-00-2
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Aldrin
CASRN -- 309-00-2
Last Revised -- 07/01/1993
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B2; probable human carcinogen
Basis -- Orally administered aldrin produced significant increases in tumor
responses in three different strains of mice in both males and females. Tumor
induction has been observed for structurally related chemicals, including
dieldrin, a metabolite.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Two studies of workers exposed to aldrin and dieldrin (a
metabolite of aldrin) did not find these workers to have an excess risk of
cancer. Both studies, however, were limited in their ability to detect an
excess of deaths from cancer. Van Raalte (1977) observed two cases of cancer
(gastric and lymphosarcoma) among 166 pesticide manufacturing workers exposed
4 to 19 years and followed from 15 to 20 years. Exposure was not quantified,
and workers were also exposed to other organochlorine pesticides (endrin and
telodrin). A small number of workers was studied, the mean age of the cohort
(47.7 years) was low, the number of expected deaths was not calculated, and
the duration of exposure and of latency was relatively short.
In a retrospective mortality study, Ditraglia et al. (1981) reported no
increased incidence of deaths from cancer among 1155 organochlorine pesticide
manufacturing workers (31 observed vs. 37.8 expected, SMR=82). This result
was not statistically significant. Workers were employed for 6 or more months
and followed for 13 or more years (24,939 person-years). Workers with no
exposure (for example, office workers) were included in the cohort. Vital
status was not known for 112 (10%) of the workers, and these workers were
assumed to be alive; therefore, additional deaths may have occurred but were
not observed. Exposure was not quantified and workers were also exposed to
other chemicals and pesticides (including endrin). An increased incidence of
deaths from cancer was seen at several specific sites: esophagus (2 deaths
observed, SMR=235), rectum (3, SMR=242); liver (2, SMR=225), and lymphatic and
hematopoietic system (6, SMR=147); but these site-specific incidences were not
statistically significant.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Davis and Fitzhugh (1962) fed a group of 215 male and female
C3HeB/Fe mice a dietary mixture containing 10 ppm aldrin for up to 2 years.
The control group consisted of 217 mice. The aldrin-treated mice died 2
months earlier than controls. Intercurrent disease, pneumonia, and intestinal
parasitism may have influenced the long-term survival rate. A statistically
significant increase of hepatomas was reported in the treated animals as
compared with controls. An independent reevaluation of the liver lesions
showed most of the hepatomas to be liver carcinomas (Epstein, 1975). In a
follow-up study, Davis (1965) administered aldrin at 0 or 10 ppm in the diet
to 100 male and 100 female C3H mice for 2 years. The incidence of hepatic
hyperplasia and benign hepatomas in the aldrin group was approximately double
that of controls, whereas the number of hepatic carcinomas was about the same.
Neither study provided a detailed pathologic examination or data separated by
sex.
Aldrin (95% pure) was administered in the diet to 50 male and 50 female
B6C3FI mice at TWA doses of 4 and 8 ppm or 3 and 6 ppm. Treatment was for
80 weeks, and animals were observed for an additional 10 to 13 weeks (NCI,
1978). In male mice, there was a significant dose-related increase in
hepatocellular carcinomas when compared with matched or pooled controls.
Treon and Cleveland (1955) administered aldrin in the diet to 40 Carworth
rats/sex at concentrations of 2.5, 12.5, or 25 ppm for a period of 2 years.
Forty animals/sex served as controls. Mortality of the treated rats was
greater than controls, with 50% surviving in the 2.5 and 12.5 ppm groups and
40% surviving in the 25 ppm group at the end of the experiment. Cleveland
(1966) reported that no apparent treatment-related tumors were present in the
above study. Deichmann et al. (1970) fed 50 male and 50 female Osborne-Mendel
rats aldrin (95% pure) at final concentrations of 20, 30, or 50 ppm for 31
months. Controls consisted of 100 rats/sex. There was no evidence of
carcinogenic response in male or female rats fed aldrin. The NCI (1978) fed
50 Osborne-Mendel rats/sex aldrin (95% pure) at 30 or 60 ppm. Male rats were
treated 111 to 113 weeks and followed for 37 to 38 weeks of observation, and
female rats were treated for 80 weeks and followed for 32 to 33 weeks of
observation. Aldrin produced no significant effect on the mortality of the
rats of either sex. The tumors observed awere randomly distributed, with no
apparent relationship to aldrin treatment. Four additional bioassays observed
no carcinogenic effect of aldrin in rats, but were considered inadequate for
carcinogenicity assessment.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Aldrin causes chromosomal aberrations in mouse, rat, and human cells
(Georgian, 1974) and unscheduled DNA synthesis in rats (Probst et al., 1981)
and humans (Rocchi et al., 1980) cells. Aldrin does not cause reverse
mutations in S. typhimurium, E. coli, or S. marcesans, or mitotic gene
conversion in S. cerevisiae (Fahrig, 1974).
Five compounds structurally related to aldrin--dieldrin, chlordane,
heptachlor, heptachlor epoxide, and chlorendic acid--have induced malignant
liver tumors in mice. Chlorendic acid has also induced liver tumors in rats.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 1.7E+1 per (mg/kg)/day
Drinking Water Unit Risk -- 4.9E-4 per (ug/L)
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 2E-1 ug/L
E-5 (1 in 100,000) 2E-2 ug/L
E-6 (1 in 1,000,000) 2E-3 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- liver carcinoma
Test Animals -- mouse/C3H (Davis); mouse/B6C3F1, male (NCI)
Route -- diet
Reference -- Davis, 1965 (see table); NCI, 1978
Administered Human Equivalent Tumor Reference
Dose (ppm) Dose (mg/kg-day) Incidence
------------ ---------------- --------- ------------
females
0 0 2/53 Davis, 1965
10 0.104 72/85 reevaluated
males by Reuber
0 0 22/73 (cited in
10 0.104 75/91 Epstein, 1975)
0 0 3/20 NCI, 1978
4 0.04 16/49
8 0.08 25/45
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Body weights for mice were assumed to be 0.03 kg for purposes of dose
conversion. The above data sets were used for calculation of the following
slope factors: 2.3E+1 per (mg/kg)/day for female C3H mice, 1.8E+1 per
(mg/kg)/day for male C3H mice, and 1.2E+1 per (mg/kg)/day for male B6C3F1
mice. No strain or sex specificity was noted in the studies, since aldrin
treatment induced liver tumors in all mouse strains tested. A geometric mean
of 1.7E+1 per (mg/kg)/day was thus chosen for the quantitative estimate, since
all three slope factors were very similar.
The unit risk should not be used if the water concentration exceeds 20
ug/L, since above this concentration the unit risk may not be appropriate.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Adequate numbers of animals were treated for a large proportion of their
lifetime. The route of treatment was appropriate. Slope factors calculated
from three data sets from two independent assays were within a factor of 2. A
slope factor for dieldrin, a major metabolite of aldrin, was determined to be
1.6E+1, essentially identical to that of aldrin.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 4.9E-3 per (ug/cu.m)
Extrapolation Method -- Linearized multistage procedure, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- ---------------
E-4 (1 in 10,000) 2E-2 ug/cu.m
E-5 (1 in 100,000) 2E-3 ug/cu.m
E-6 (1 in 1,000,000) 2E-4 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
The unit risk was calculated from the oral data presented in II.B.2.
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The unit risk should not be used if the air concentration exceeds
2 ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
See II.B.4.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986
The values in the 1986 Carcinogenicity Assessment for Aldrin/Dieldrin have
been reviewed by the Carcinogen Assessment Group.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 03/22/1987
Verification Date -- 03/22/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Aldrin
CASRN -- 309-00-2
Last Revised -- 09/01/1989
__VI.A. ORAL RfD REFERENCES
Fitzhugh, O.G., A.A. Nelson, and M.L. Quaife. 1964. Chronic oral toxicity
of aldrin and dieldrin in rats and dogs. Food Cosmet. Toxicol. 2: 551-562.
U.S. EPA. 1982. Toxicity-Based Protective Ambient Water Levels for Various
Carcinogens. Environmental Criteria and Assessment Office, Cincinnati, OH.
ECAO-CIN-431. Internal review draft.
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Cleveland, F.P. 1966. A summary of work on aldrin and dieldrin toxicity at
the Kettering Laboratory. Arch. Environ. Health. 13: 195.
Davis, K.J. 1965. Pathology report on mice fed dieldrin, aldrin, heptachlor,
or heptachlor epoxide for two years. Internal FDA memorandum to Dr. A.J.
Lehrman, July 19.
Davis, K.J. and O.G. Fitzhugh. 1962. Tumorigenic potential of aldrin and
dieldrin for mice. Toxicol. Appl. Pharmacol. 4: 187-189.
Deichmann, W.B., W.E. McDonald, E. Blum, et al. 1970. Tumorigenicity of
aldrin, dieldrin and endrin in the albino rat. Ind. Med. 39(10): 426-434.
Ditraglia, D., D.P. Brown, T. Namekata and N. Iverson. 1981. Mortality study
of workers employed at organochlorine pesticide manufacturing plants. Scand.
J. Environ. Health. 7(suppl 4): 140-146.
Epstein, S.S. 1975. The carcinogenicity of dieldrin. Part 1. Sci. Total
Environ. 4: 1-52.
Fahrig, R. 1974. Comparative mutagenicity with pesticides. IARC Publ.
(U.N.) 10: 161-181.
Georgian, L. 1975. The comparative cytogenic effects of aldrin and
phosphamidon. Mutat. Res. 31: 103-108.
NCI (National Cancer Institute). 1978. Bioassays of aldrin and dieldrin
for possible carcinogenicity. DHEW Publication No. (NIH) 78-821. NCI
Carcinogenesis Tech. Rep. Ser. No. 21. NCI-C6-TR-21.
Probst, G.S., R.E. McMahon, L.W. Hill, D.Z. Thompson, J.K. Epp and S.B. Neal.
1981. Chemically-induced unscheduled DNA synthesis in primary rat hepatocyte
cultures: A comparison with bacterial mutagenicity using 218 chemicals.
Environ. Mutagen. 3: 11-32.
Rocchi, P., P. Perocco, W. Alberghini, A. Fini and G. Prodi. 1980. Effect of
pesticides on scheduled and unscheduled DNA synthesis of rat thymocytes and
human lymphocytes. Arch. Toxicol. 45: 101-108.
Treon, J.F. and F.P. Cleveland. 1955. Toxicity of certain chlorinated
hydrocarbon insecticides for laboratory animals, with special reference to
aldrin and dieldrin. Agric. Food Chem. 3: 402-408.
U.S. EPA. 1986. Carcinogenicity Assessment of Aldrin and Dieldrin. Prepared
by the Office of Health and Environmental Assessment, Carcinogen Assessment
Group, Washington, DC, for the Hazard Evaluation Division, Office of Pesticides
and Toxic Substances, Office of Pesticide Programs, Washington, DC.
Van Raalte, H.G.S. 1977. Human experience with dieldrin in perspective.
Ecotoxicol. Environ. Safety. 1: 203-210.
_VII. REVISION HISTORY
Substance Name -- Aldrin
CASRN -- 309-00-2
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/30/1987 II. Carcinogenicity section added
03/01/1988 II.B.4. Confidence statement revised
12/01/1988 II.B.4. Corrected slope factor in text
09/01/1989 II.A.2. Ditraglia reference changed to Ditraglia et al.
09/01/1989 II.A.3. Deichmann reference changed to Deichmann et al.
09/01/1989 II.B.3. Body weight for mice corrected to kg
09/01/1989 VI. Bibliography on-line
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
01/01/1992 I.A.7. Secondary contact changed
01/01/1992 IV. Regulatory actions updated
07/01/1993 II.D.3. Secondary contact's phone number changed
VIII. SYNONYMS
Substance Name -- Aldrin
CASRN -- 309-00-2
Last Revised -- 03/31/1987
309-00-2
Aldrex
Aldrin
Aldrite
Aldrosol
1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-
Hexahydro-, (1 alpha, 4 alpha, 4a beta, 5 alpha, 8 alpha, 8a beta)-
1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-Hexahydro-
Drinox
ENT 15,949
1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-Hexahydro-1,4,5,8-Dimethanonaphthalene
1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-Hexahydro-1,4-endo-exo-5,8-
Dimethanonaphthalene
1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-Hexahydro-exo-1,4-endo-5,8-
Dimethanonaphthalene
Hexachlorohexahydro-endo-exo-Dimethanonaphthalene
HHDN
NCI-C00044
Octalene
Seedrin
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0130.HTM
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