UNITED STATES
ENVIRONMENTAL PROTECTION JUNE 1988
AGENCY FINAL
RESEARCH AND
DEVELOPMENT
EVALUATION OF THE POTENTIAL CARCINOGENICITY OF
ODD
(72-54-8)
IN SUPPORT OF REPORTABLE QUANTITY ADJUSTMENTS
PURSUANT TO CERCLA SECTION 102
PREPARED FOR
OFFICE OF EMERGENCY AND REMEDIAL RESPONSE
OFFICE OF SOLID WASTE AND EMERGENCY RESPONSE
PREPARED BY
CARCINOGEN ASSESSMENT GROUP
OFFICE OF HEALTH AND
ENVIRONMENTAL ASSESSMENT
WASHINGTON, D.C. 20460
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation for
use.
ii
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PREFACE
This report summarizes and evaluates information on the potential
carcinogenicity of a substance designated as hazardous under Section 101 (14)
of the Comprehensive Environmental Response, Compensation and Liability Act of
1980 (CERCLA). Pertinent epidemiologic and toxicologic data were obtained
through on-line searches and - from hard-copy sources. On-line searches were
.-extended as far back as the data bases would allow. -Retrieval of historical
data was accomplished through searches of hard-copy sources and bibliographies
of relevant publications. Every attempt has been made to rely upon primary
publications as opposed to data summaries or abstracts contained in secondary
sources such as monographs, surveys, review articles, criteria documents, etc.
The on-line data bases that were searched included CHSMLINE (National Library
of Medicine [NLM]), RTECS (NLM), Toxicology Data Bank (NLM), TQXLINE .(NLM),
CANCERLINE (NLM), and Chemical Abstracts (DIALOG Information Services).
Unpublished data were not used in this evaluation.
The Agency's Methodology for obtaining, evaluating, and ranking CERCLA
potential carcinogens is described in the Technical Background Document to
Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, April 26, 1988
(EPA/600/8-B9/053). This document revises the previous methodology document
of 1986 according to the public comments received on the March 16, 1981 Notice
of Proposed Rulemaking (52 FR 8140). -The Methodology for Adjusting reportable
quantities is described in the Technical Background Document to Support
Rulemaking Pursuant to CERCLA Section 102, Volume 1, March, 198S, and is also
summarized in Volume 2, August, 1986, and Volume 3, December, 1986. The EPA'3
Office of Emergency and Remedial Response (OERK) has considered this
evaluation in adjusting reportable quantities pursuant to CERCLA Section 102.
This report is consistent with the revised methodology. It draws largely on
information supplied by the Syracuse Research Corporation in 1984 under EPA
Contract No. 68-03-3112. Due to the amount of time elapsed between the
original work performed by Syracuse Research Corporation and the present
111
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effort to produce this document, Environmental Monitoring & Services, Inc.,
under EPA Contract No. 68-03-3182, has been involved in an extensive review of
all the Syracuse documents. In some cases, this review involved updating the
information provided but it was primarily a quality assurance effort. The
present document is a result of this effort.
IV
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ABSTRACT
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethane (DDD) is a probable human
carcinogen, classified as weight-of-evidence Group B2 under the EPA Guidelines
for Carcinogen Risk Assessment (U.S. EPA, 1986a). Evidence on potential
carcinogenicity from animal studies is "Sufficient," and the evidence from
human studies is "Inadequate."
The potency factor (F) for DDD is estimated to be 1.30 (mg/kg/day) , placing
it in potency group 2 according to the CAG's nethodology for evaluating
potential carcinogens (U.S. EPA, 1986b).
Combining the weight-of-evidence group and the potency group, DDD is assigned a
"MEDIUM" hazard ranking for the purposes of RQ adjustment.
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TABLE OP CONTENTS
Page
1.0 WEIGHT OF EVIDENCE 1-1
1.1 ANIMAL STUDIES 1-1
1.2 HUMAN STUDIES .1-2
1.3 WEIGHT-OF-EVIDSNCE ASSESSMENT 1-2
2.0 POTENCY 2-1
3.0 HAZARD RANKING 3-1
4.0 REFERENCES-. 4-1
APPENDIX: SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
TABLES
Table 2-1. DERIVATION OF POTENCY FACTOR (F) 2-2
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1.0 WEIGHT OF EVIDENCE
1.1 ANIMAL STUDIES
An NCI report on a 2-year study in which 50 male and 50 female Osborne-Mendel
rats were fed 1,l-dichloro-2,2-bis(p-chlorophertyl)ethane (DDD) indicated no
significant excess liver tumors in either sex'at doses of 850 to 3,294 ppm
(NCI, 1978). These rats did, however, respond with some thyroid adenomas and
carcinomas in the follicular cells and C-cells at these high doses. The C-cell
response was only marginal, and neither of the thyroid responses-showed a trend
with DDD dose. The past wide variation in rat history controls for these tumor
types (especially in older animals) confounds the interpretation of these
results.
In the same NCI study, 50 male and 50 female B6C3F1 mice were'.dosed with DDD at
411 and 822 ppm. No significant excess tumors were observed, except for
hepatocellular carcinomas [controls 2/11 (18%), low-dose 12/44 (27%), and
high-dose 14/50 (28%)]. This liver response was also judged by the NCI to be
insignificant, since controls had responded with excess tumors of up to 20% in
the past.
In another study of CF-1 mice were administered DDD at 0 and 250 ppm in the
diet. It was found that lung tumors, as well as liver tumors, were induced by
DDD (Tomatis et al., 1974). Lung tumors in male mice increased from, 53/98
(54%) in controls to 51/59 (86%) at 250 ppm; and in female CF-1 mice, lung
adenomas increased from 37/90 (41%) to 43/59 (73%). Liver tumors in male CF-1
mice were increased from 33/98 (34%) to 31/59 (52%), whereas female CF-1 livers
were unaffected. DDD caused only a slightly accelerated increase in the
mortality of mice with hepatomas (author's terminology), whereas DDE caused
markedly early deaths of CF-1 mice with hepatomas, and DDD + DDE (same total
level, 250 ppm) caused an intermediate acceleration in the mortality of mice
with hepatomas. DDD did not cause an increase in the total number of
tumor-bearing animals, nor did it cause an increase in the multiplicity of
tumors.
1-1
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In other studies, mice were exposed to diets containing ODD. In the study
reported by Innes et al. (1969) and Biometics (1973), male and female mice of
two strains [(C57BL/6 x C3H/Anf) Fl and (C57BL/6 x AKR) Fl] were initially
exposed by gavage to 100 mg/kg/day of DDD from day 7 to 28 of life. Following
the initial exposure, the animals were exposed to diets containing 300 ppm of
DDD for an additional 18 months. This is approximately 45 mg/kg/day. Using the
combined data from all treated animals, there was a significant increase in the
' incidence of all tumors (P=Q,Q5) and pulmonary adenoma (P-0.01).
In the NCI study and the Innes study mice of the same strain (B6C3F~^) were
administered DDD via the sane route (diet). In the NCI study administration of
the DDD started at 8 weeks of age, while in the Innes study 7 day old mice were
given DDD by gavage at 100 mg/kg/day until the 28th day of life. The highest
dose level given by NCI was 822 ppm while the dose level given by Innes was 300
ppm. Innes dosed the animals at this rate for 18 months while NCI dosed their
animals at the higher rate for 24 months. The Innes study also utilized
another strain as well (C57B1/6 x AKR Fl), The NCI study was not considered
positive by the authors. The Innes study was considered positive by the
authors, but to achieve significance between controls and experimentals it was
necessary for them to combine the controls of both strains and strain-specific
responses were observed for several other substances tested in the study. In
addition, pulmonary adenomas are quite variable even in control animals and
total tumors are not generally utilized in evaluating carcinogenesis in
animals. The only site-specific increase in tumors in the Innes study was the
lung adenoma.
Thus, on the whole, the best evidence available for the carcinogenicity of DDD
is that of Thomatis, et al. (1974). This data is used in table 2-1 to
calculate potency.
1.2 HUMAN STUDIES
Pertinent data regarding the carcinogenic effects of long-term human exposure
to DDD were not located in the available literature.
1-2
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1.3 tfEIGHT-OF-EVIDENCE ASSESSMENT
DDD has been administered to both rats and mice by incorporation of the
compound into the diets. In rats, chronic exposure to DDD resulted in an
increase In thyroid adenomas/carcinomas, and in mice DDD has been reported to
increase tumors of the Lung and liver. At present, epidemiologic data are
inadequate concerning the carcinogenic effects of DDD on man. Thus, using the
EFA Guidelines for Carcinogen Risk Assessment (U.S. EFA, 1986a) for evaluating
the overall weight of evidence to humans, DDD is most appropriately classified
as a Group B2 chemical. The appendix contains summaries of the significant
human and/or animal studies cited in this review.
1-3
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2,0 POTENCY
The potency factor (F) for DDD is estimated to be 1.30 (mg/kg/day)-l, placing
it in potency group 2 under the CAG's methodology for evaluating potential
carcinogens (U.S. EPA, 1986b). Table 2-1 contains data from the selected study
used to derive the potency factor (F) for DDD.
The U.S. EPA (1986c) used a geometric mean of similar potencies from several
studies of DDT, DDE, DDD, and dicofol to estimate the potency of DDD for risk
assessment purposes. For this ranking of carcinogens, however, it is
considered important that all substances be ranked by the same methodology as
much as possible. Therefore, the study judged most appropriate for each
substance individually has been used in ranking these' substances.
2-1
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Table 2-1. Derivation of Potency Factor(F)
Agent: ODD
REFERENCE:
EXPOSURE ROUTE:
SPECIES:
STRAIN:
SEX:
VEHICLE OR PHYSICAL STATE:
BODY WEIGHT:8
DURATION OF TREATMENT:
DURATION OF STUDY:
LIFESPAN OF ANIMAL:
TARGET ORGAN:
TUMOR TYPE:
EXPERIMENTAL DOSES/
EXPOSURE:
TRANSFORMED DOSES :b
(ng/kg/day)
TUMOR INCIDENCE:
ANIMAL POTENCY:
(ng/kg/day)'1
HUMAN POTENCY:0
(mg/kg/day)'1
Tomans et al., 1974
oral
mice
CF-1
M
diet
0.03 kg
861 days
861 days
861 days
liver
hepatoma
0.0 ppm 250 ppm
0.0 32.5 ;
33/98 31/59
0.10
1.30
* Estimated
food per day) x duration of treatment (days)/ duration of study (days).
c Human potency = animal potency x (70 kg/0.03 kg)1^
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3.0 HAZARD RANKING
Based on the weight-of-evidence Group B2 for DDD, and the potency factor (F) of
1.30 (nig/kg/day) , DDD receives a hazard ranking of "MEDIUM."
3-1
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4.0 REFERENCES
Blonetlcs Research Laboratories, 1973. Evaluation of Carcinogenic,
Teratogenic, and Mutagenic Activities of Selected Pesticides and Industrial
Chemicals. Vol. 1: Carcinogenic Study Available from: Nation Technical
Information Service, Springfield, VA (NTIS PB-223-159).
Innes, J.R., B.M. Dlland, M.G. Valerio et al., 1969. Bioaasay of Pesticides
and Industrial Chemicals for Tumorigenlcity in Mice: A Preliminary Note. J.
Natl. Cancer Inst. 42: 1101-1114.
NCI (National Cancer Institute). 1978. Bioassays of DDT, TDE, and p,p'-DDE for
Possible Carcinogenicity. Publ, No. KCI-CG-TR-131. U.S. DHEtf, PHS, NIH. p.
117.
Tooatis, L., V. Turusov, R.T. Charles and K, Boiocchi, 1974. The Effect of
Long-Tertn Exposure to l,l-Dichloro-2,2-Bia(p-Chlorophenyl)Ethylene (p.p'-DDE),
l,l-Dichloro-2,2-Bls(p-Chlorophenyl)Ethane (p,p'-DDD) and to the Two Chemicals
Combined, on CF-1 mice. J. Natl. Cancer Inst. 52: 883.
U.S. EPA (Environmental Protection Agency), 1986a. Guidelines for Carcinogen
Risk Assessment, 51 ?R 33992-34003, September 24, 1986.
U.S. EPA (Environmental Protection Agency), 1986b. Methodology for Evaluating
Potential Carcinogenicity in Support of Reportable Quantity Adjustments
Pursuant to CERCLA Section 102, OHEA-C-073, December 1986. Available from
CERCLA Docket 102RQ-273C. The public docket for RQ rulemaking is located in
room M2427, U.S. Environmental Protection Agency, 401 K Street, SW, Washington,
DC 20460. It is available for inspection Monday through Friday excluding
Federal holidays, between the hours of 9:00 a.m. and 4:00 p.m.
U.S. EPA (Environmental Protection Agency), 1986c. The Assessment of
Carcinogenicity of Dicofol (Kelthane), DDT, DDE, and ODD (TDE), O ^~- 1 ,~^ £"
EPA-600/6-86-001, February 1986. AIT**
4-1
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U.S. EPA (Environmental Protection Agency), 1988, Technical Background
Document to Support Ruleaaklng Pursuant to CERCLA Section 102, Volxime 3, Draft,
Appendix A, April 26, 1988.
4-2
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APPENDIX
SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
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Table A. Animal
Agent: p,p'-DDD
Reference: Innes et al., 1969, and Bionetics Research Laboratories, 1973
Exposure
Route
oral
oral
Species/
Strain
mouse/
B6C3F1
and
B6AKF,
mouse/
B6C3F1
and
B6AKF,
Dose
or
Sex Exposure
H,F 100 tng/kg
initial dose
fol lowed by
300 ppm
H,F negative8
control
group
Duration Duration
of of
Treatment Study
14 days 18. 5 months
initial dose
followed by
18 months
14 days 18.5 months
initial dose
followed by
18 months
Purity Vehicle or
of Physical Target
Compound State Organ Tumor Type
NR 0.5% gelatin all NA
for initial tumors
dose fol lowed
by incorporation
into diet
NR O.SX gelatin all NA
for initial tumors
dose followed
by incorporation
into diet
Tumor
IriL idence
(P value)
20/72
(P=0.024)
53/320b
QUALITY OF EVIDENCE
Strengths of Study: Animals were exposed from the 7th day after birth.
Weaknesses of Study: The only data analysis available combined both strains of mice as well as male and female animals.
Although data for site specific tumors was given, only total tumor incidence was significantly increased.
Overall Adequacy: The authors considered that ODD required additional evaluation. This was only a preliminary study, used
to test many compounds at maximal doses.
* Thirty-two animals received gelatine as a control vehicle; 288 controls untreated.
k The tumor incidence front pooled negative controls
NR = Not reported
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Table A. Animal
Agent: TDE (Tctrachlorodiphenylethane)
(same compound as ODD)
Reference: NCI, 1978
Exposure
Route
o
o
o
Dose i Duration Duration Purity Vehicle or
Species/ or of of of Physical Target
Strain Sex Exposure Treatment Study Compound State Organ
rat/ H 0.0 ppn NA 111 wks NA NA thyroid
Osborne -
Hendel
rat/ H 1647 ppma 78 wks 112 wks 60Xb diet thyroid
Osborne-
Hendel
rat/ N 3294 ppm8 78 wks 112 wks 60Xb diet thyroid
Osborne
Hendel
Tumor Type
follicular cell
adenomas and
carcinomas
follicular cell
adenomas and
carcinomas
follicular cell
adenomas and
carcinomas
Tumor
Incidence
(P value)
1/19
16/49
(p=0.016)
11/49
(p=0.089)
rat/ F 0.0 ppm
Osborne -
Mendel
rat/
Osborne-
Hendel
rat/
Osborne-
Mendel
NA
111 wks
F 850 ppm 78 wks 113 wks
NA NA
any organ any tumor
60X diet any organ any tumor
F 1700 ppm 78 wks 113 wks 60Xb diet any organ any tumor
NA
NS
NS
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Table A. Animal
Reference: NCI, 1978 (cont.)
Exposure
Route
o
o
o
o
o
Dose Duration Duration Purity Vehicle or
Species/ or of of of Physical Target
Strain Sex Exposure Treatment Study Compound State Organ Tumor Type
mouse/ N 0.0 ppm NA 90 uks NA NA any organ any tumor
B6C3F1
mouse/ N 411 ppn8 78 wks 91 wks 60Xb diet any organ any tumor
B6C3F1
mouse/ N 822 ppma 78 wks 91 wks 60Xb diet any organ any tumor
B6C3F1
mouse/ F 0.0 ppm NA 90 wks NA NA any organ any tumor
B6C3F1
mouse/ F 411 ppm" 78 wks 91 wks 60Xb diet any organ any tumor
B6C3F1
Tumor
Incidence
(P value)
NA
NS
NS
NA
NS
o mouse/ F 822 ppoa 78 wks
B6C3F1
91 wks 60XD diet any organ any tumor
NS
QUALITY OF EVIDEUCE
Strengths of Study: Complete histologic examinations were performed on all major organs. The first thyroid tumors appeared at
60, 99. and 103 weeks in the high, low. and control groups, respectively.
Weaknesses of Study: This study was designed to test the carcinogenic*ty of technical grade, rather than pure ODD.
Overall Adequacy: Adequate
The dose was altered during the study and this is the time-weighted average dose for the expousre period.
b Technical grade TDE was used and at least 19 impurities were detected by gas liquid chromatography.
NA = Not applicable; NS = Hot significant
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Table A. Animal
Agent: DDD
Reference: Tomatis et al., 1974
Exposure Species/
Route Strain
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
Dose
or
Sex Exposure
H 250 ppm
F 250 ppm
H 0.0 ppm
F 0.0 ppm
Duration Duration
of of
Treatment Study
123 ueeks 123 weeks
123 weeks 123 ueeks
HA 123 ueeks
NA 123 ueeks
Puri ty
of
Compound
NR
MR
NA
NA
Vehicle or
Physical
State
diet
diet
NA
NA
Target
Organ
liver
lung
I iver
lung
1 iver
lung
I iver
lung
Tumor Type
hepatoma
NR
hepatoma
NR
hepatoma
NR
hepatoma
NR
Tumor
Incidence
(P value)
31/59 (p=0.015)
51/59 (ptO.0001)
1/59 (NS)
43/59 (p=0.0001)
33/98
53/98
1/90
37/90
QUALITY OF EVIDENCE
Strengths of Study: Survival was not affected by treatment. Lung tumors increased in both sexes.
Weaknesses of Study: Only one dose level was used. Liver tumors did not increase in females.
Overall Adequacy: Adequate
HA « Mot applicable; NR = Not reported
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fPter
TECHNICAL REPORT DATA
' -fore compieif
1. REPORT NO.
EPA/600/8-91/099
PS93-185205
4, TITLE ANDSUiTITLE
Evaluation of the
ODD (72-54-8)
Potential Carcinogenicity of
S, REPORT DATE
. June 1QRR
6. PERFORMING ORGANIZATION CODE
Inr.
7, AUTHOR(S!
Syracuse Research Corporation
Environmental Monitoring &'Services, ^__^
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Syracuse Research Corporation, Syracuse, NY
Environmental Monitoring & Services, Inc. (now ABB
Environmental Services, Inc.}, Washington, DC
8. PERFORMING ORGANIZATION REPORT NO
QHEA-r.-073-rm
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
68-03-3112
68-03-3182
12. SPONSORING AGENCY NAME AND AOOR6SS
Office of Health and Environmental Assessment
Carcinogen Assessment Group (RD-689)
U.S.'Environmental Protection Agency
Washington,' DC 20460
13. TYPE Of REPORT AND PiRlOO COVIREO
14. SPONSORING AGENCY CODE
. EPA/600/021
15. SUPPLEMENTARY NOTiS
16. ABSTRACT
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethane (ODD) is a probable human carcinogen,
classified as weight-of-evidence Group B2 under the EPA Guidelines for Carcinogen Risk
. Assessment (U.S. EPA, 1986a). Evidence on potential carcinogenicity from animal studies is
"Sufficient," and the evidence from human studies is "Inadequate."
The potency factor (F) for ODD is estimated to be 1.30 (mg/kg/day)"1, placing it in
potency group 2 according to the CAG's methodology for evaluating potential carcinogens
(U.S. EPA, 1986b).
Combining the weight-of-evidence group and the potency group, ODD is assigned a
"MEDIUM" hazard ranking for the purposes of RQ adjustment.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TIRMS
COSATi Field; Group
18. DISTRIBUTION STATEMENT
Release to Public
19. SECURITY CLASS i.Tliis Ritpart)
Unclassified
21. NO. of PAGES
19
20. SECURITY CLASS f
- Unclassified
22. PRICE
EPA Form 2220-1 (««. 4-771 PREVIOUS EDITION is OBSOLETE
T
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