UNITED STATES EPA/600/8-Si/i31
ENVIRONMENTAL PROTECTION JUNE 1988
AGENCY FINAL
RESEARCH AND
DEVELOPMENT
EVALUATION OF THE POTENTIAL CARCINQGENICITY OF
ETHYLENE OXIDE
<75-ZI»8)
IN SUPPORT OF REPORTABLE OUAHTITY 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, E).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,
LI
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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 CHEMLINE (National Library
of Medicine [NLM]), RTECS (NLM), Toxicology Data Bank (NLM), TOXLINE (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Unpublished data were not used in this evaluation.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/600/8-89/053). This document revises the previous methodology document
of 1986 according to the public comments received on the March 16, 1987 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, 1985, and is also
summarized in Volume 2, August, 1986, and Volume 3, December, 1986, The EPA's
Office of Emergency and Remedial Response (OERR) 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
iii
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effort to produce this document, Environmental Monitoring & Services, Inc.,
under EPA Contract No. 68-03-31S2, 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 thig effort.
IV
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ABSTRACT
Ethylene oxide is a probable human carcinogen, classified as weight-of-evidence
Group Bl 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 "Limited,"
The potency factor for ethylene oxide is estimated to be 1.34 (mg/kg/day) ,
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, ethylene oxide
is assigned a "MEDIUM" hazard ranking for the purposes of RQ adjustment., (When
the weight-of-evidence is expressed as a range, i.e., Bl, the hazard ranking
is based on the higher weight-of-evidence group).
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TABLE OF CONTENTS
Page
1.0 WEIGHT OF EVIDENCE ..... 1-1
1.1 ANIMAL STUDIES ....... 1-1
1.2 HUMAN STUDIES , 1-3
1.3 WEIGHT-OF-EVIDENCE ASSESSMENT 1-4
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 .P
VI
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1.0 WEIGHT OF EVIDENCE
1,1 ANIMAL STUDIES
Weekly subcutaneous injections of 0.1-1.0 mg ethylene oxide for 95 weeks
induced dose-related local sarcomas in female NMRI mice (Dunkelberg, 1979,
1981), but the incidence of tumors at distant sites was not significantly
greater in the treated mice than in controls, Walpole (1958) reported that
subcutaneous injections of ethylene oxide over a period of 94 days did not
induce local sarcomas in 12 rats (species not stated). The maximum total dose
(MTD) was 1 g/kg and the animals were observed for their lifetimes, but the
dosing schedule was not specified. Thrice weekly dermal applications of
ethylene oxide for life (approximately 10 mg per application) did not cause
skin papillomas or carcinomas in Swiss-Millerton mice (Van Duuren et al.,
1965).
Reyniers et al. (1964) observed that tumors developed at various sites (e.g.,
ovaries, lymphatic system, lungs) in 63 of 86 female germ-free Swiss-Webster
mice that were accidentally exposed to ethylene oxide- treated ground-corncob
bedding for their lifespan (maximal, 900 days). No tumors were reported in 83
female mice (100-600 days old) that were not exposed to treated bedding. It
should be emphasized that this study was not designed to test the
carcinogenicity of ethylene oxide, and that the causative agent was not
identified since chemical analysis of the bedding was not performed.
A chronic inhalation study was performed by the Bushy Run Research Center
(Snellings et al., 1984). Fischer 344 rats were exposed to 100, 33 and 10 ppra
ethylene oxide vapor for 6 hours/day, 5 days/week for 24.5 months (females) or
25 months (males). Two untreated air groups were exposed under similar
conditions. Initially, 120 rats/sex/group were exposed, but interim sacrifices
were conducted at 6, 12, and 18 months (10, 10 and 20 rats, respectively). At
terminal sacrifice, histopathologic examinations were performed on
approximately 15 major organs and tissues of rats in the 100 ppm and both
control groups, and on potential target tissues, selected tissues, and tissues
1-1
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with gross lesions in the 10 and 33 ppm groups. The results showed that there
was a dose-related increase in the incidence of mononuclear cell leukemia in
the female rats at terminal sacrifice (15/26, 14/48, 11/54 and 11/115 in the
100, 33, 10 ppm and combined controls, respectively). In male rats,
statistically significant increases in subcutis fibroma at 100 ppm (15/58 vs.
4/137 in combined controls) and pancreas islet cell adenoma at 100 ppm (10/59
vs. 10/129 in combined controls) were found. The exposure of both the male and
female rats was temporarily terminated during exposure weeks 65 and 66, due to
a Sialodacryoadenitis virus infection, but no evidence was presented that the
infection increased tumor incidence.
The chronic inhalation toxicity and carcinogenicity of ethylene oxide was
evaluated in a 2-year inhalation bioassay (Lynch et al., 1984). Five groups of
male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (paired
control; filtered air), 50 ppra, or 100 ppra (7 hr/day, 5 days/week) for 104
weeks, statistically significant increase in mortality was observed in all
groups of exposed rats compared to controls. Statistically significant
associations between ethylene oxide exposure and an increased incidence of the
following rat neoplasms were observed: peritoneal mesothelioma, and mixed cell
brain glioma. A statistically significant increase in mononuclear cell
leukemias was seen at the low dose (50 ppm) but not at the high dose (100 ppm) .
In the Carman et al. (1985) study, groups of F344 rats of each sex were exposed
to either ethylene oxide vapor (concentrations of 100, 33 or 10 ppm) or to room
air for 6 hours daily, 5 days/week, for up to 2 years. Three representative
sections of the brain from each rat were evaluated. Twenty-three primary brain
tumors were found, two of which were in control animals. Increased numbers of
brain tumors were seen in 100 ppm and 33 ppm ethylene oxide exposed male and
female rats. Significant trend analyses were found for both males and females,
indicating that, under the conditions of this study, ethylene oxide exposure
above 10 ppm was related to the development of these brain tumors.
The National Toxicology Program conducted toxicological and carcinogenesis
studies of ethylene oxide by exposing groups of 50 B6C3F1 mice of each sex to
air containing 0, 50 or 100 ppm ethylene oxide for 6 hours/ day, 5 days/week
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for 102 weeks (NTP, 1986). This study has been peer-reviewed and the data is
reproduced In Appendix A, and suraarized below.
In male B6C3F1 mice, alveolar/bronchial adenomas or carcinomas and harderian
gland cystadenomas were produced with a positive trend. Both the life table
and the incidental tumor tests showed a significant difference between controls
and experimentals exposed at 100 ppra. At 50 ppm, the above two tests were also
significant for harderian gland tumors but not for alveolar/bronchial adenomas
or carcinomas.
In female B6C3F1 mice, alveolar/bronchial adenomas or carcinomas and harderian
gland cystadenomas, malignant lyraphomas and uterine adenocarcinoraas occurred
with positive trends. Both life table and incidental tumor tests showed a
significant difference between controls and experimentals exposed at 100 ppm
for lung tumors, harderian gland tumors and malignant lymphomas, but not for
uterine adenocarcinomas.
The NTP staff and peer review group concluded that there was "clear evidence of
carcinogenic activity for B6C3F1 mice" as indicated by dose-response increases
in the incidence of benign and malignant neoplasms of the lung and benign
neoplasms of the harderian gland in both male and female mice. The NTP also
concluded that "in female mice, ethylene oxide caused additional malignant
neoplasms of the uterus, mammary gland and hemopoietic system (lymphoma)," but
of these tumors, only lymphomas were significantly different from concurrent
controls. The incidence of lyraphoraas in these ethylene oxide exposed mice was
not significantly different from historical controls for this strain of mice
(NTP, 1986).
1.2 HUMAN STUDIES
Three studies conducted in Sweden reported an increased risk of leukemia
following occupational exposure to ethylene oxide. In the first study
(Hogstedt et al., 1979a), which also showed increased rates of gastric cancer,
a small number of Swedish ethylene oxide production workers were also
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concurrently exposed to chemicals other than ethylene oxide and the increased
rates cannot confidently be attributed to ethylene oxide alone.
In the second study (Hogstedt et al., 1979b), three cases of leukemia occurred
in a small group (230) of Swedish workers who were exposed to fugitive ethylene
oxide emissions that originated from sterilized hospital equipment. The
exposure to ethylene oxide in this study (20 ± 10 ppm) was fairly well
characterized. In 1984, Hogstedt et al. reported the first follow-up on their
original studies reported in 1979. In this report, the reported cases of
leukemia increased from three cases to five cases. These were in women who had
been exposed to from two to 70 ppra ethylene oxide (8 hr/day, time-weighted
average calculated to be 20 + 10 ppm).
Hogstedt et al. (1986) reported eight cases of leukemia and six cases of
stomach cancer in workers exposed to ethylene oxide as compared to 0.8 and 0.65
cases expected as indicated in a similar industrial cohort. This study was a
follow-up on their investigations reported previously in 1979 and 1984.
In another mortality study (Morgan et al. , 1981), no significant excess of
deaths from leukemia or other malignant neoplasms was reported in a group of
767 males who were potentially exposed to ethylene oxide for 5 to 18 years at a
U.S. production facility. Although the size of the cohort was small and the
workers appeared to have only minimal exposure (<10 ppm), exposure was
associated with increased incidences of pancreatic cancer and Hodgkin's disease
(U.S. EPA, 1985).
1.3 WEIGHT-OF-EVIDENCE ASSESSMENT
There are sufficient data to indicate that ethylene oxide is a carcinogen in
rats and mice when administered via inhalation. Weekly subcutaneous injections
of ethylene oxide for 95 weeks produced a dose-related increase in the
incidence of local tumors in mice. The results of an inadequately reported
subcutaneous injection study with rats were negative, and the results of a
lifetime skin application bioassay with mice were also negative. An increased
incidence of tumors was observed in a group of mice that were accidentally
1-4
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exposed. to ethylene oxide-treated bedding, but the exposure was not
characterized and this observation does not allow an evaluation of
careinogenieity.
In a. two-year inhalation study, a dose-related increased incidence of
mononuclear cell leukemia was found in female rats. Significantly increased
incidences of subcutis fibromas and pancreatic adenomas were found in males.
Gliomas were also significantly increased in both males and females.
Thus in B6C3F1 mice, there was clear evidence of carcinogenic activity as
indicated by a dose-related increased incidence of benign and malignant
neoplasms of the lung as well as benign neoplasms of the harderian gland. The
incidences were significantly elevated above control animals in both sexes.
The evidence indicating a carcinogenic effect in humans due to ethylene oxide
exposure is limited because human exposure has been difficult to quantitate.
Three studies of human populations exposed occupationally to ethylene oxide
have shown increased rates of stomach cancer and leukemia, but the exposure
associated with these increases in cancer has been difficult to quantitate,
making human potency estimates tenuous. The results of a fourth mortality
study did not report increased leukemia or sto r.ach cancer, but significant
increases in pancreatic cancer and Hodgkin's disease were noted.
The findings of leukemia in rats exposed to ethylene oxide via chronic
inhalation, however, were consistent with the epidemiologic data. Thus, using
the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a) for
evaluating the overall weight of evidence to humans, ethylene oxide is most
appropriately classified as a Group Bl chemical. The appendix contains
summaries of the significant human and/or animal studies cited in this review.
1-5
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2.0 POTENCY
The potency factor (F) for ethylene oxide is estimated to be 1.34
(mg/kg/day)-1, placing it in potency group 2 under the CAG's 2-1 contains data
from the selected study used to derive the potency factor (F) for ethylene
oxide.
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Table 2-1. Derivation of Potency Factor(F)
Agent: Ethylene oxide
REFERENCE:
EXPOSURE ROUTE:
SPECIES:
STRAIN:
SEX:
VEHICLE OR PHYSICAL STATE:
BODY WEIGHT:
DURATION OF TREATMENT:
DURATION OF STUDY:
LIFESPAN OF ANIHAL:
TARGET ORGAN(S):
TUMOR TYPE:
EXPERIMENTAL DOSES/EXPOSURE:8
TRANSFORMED DOSES:b
(mg/kg/day)
TUMOR INCIDENCE:6
ANIMAL POTENCY:
(mg/kg/day)
HUMAN POTENCY :f
(mg/kg/day)
•1
NTP, 1986
inhalation
mice
B6C3F1
M
inhalation
0.035 kg
730 days (6 hrs/day, 5 days/week)
730 days
730 days
lung
adenomas and carcinomas
100 ppm 50 ppm
39.90 19.95
26/50d
0.106
1.34
19/50e
0 ppm
0
11/50
Exposure was via inhalation for 6 hours/day, 5 days/week, for approximately 2 years.
b To derive the transformed dose from the experimental dose data: experimental dose (ppm) x 0.041 x M.U. of ethylene oxide (44.05 g/mol) x 0.0432
mg/day (rat's breathing rate)/ 0.035 kg (animal weight) x 5 (treatment days/week)/? (days/week) x 6 (treatment hours/day)/24 (hours/day).
c Total tumor count ratios based on number of rats alive at 24 months.
One animal developed both an adenoma and a carcinoma.
e Two animals developed both an adenoma and a carcinoma.
' Human potency = animal potency x (70 kg/0.035 kg)^'
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3.0 HAZARD RANKING
Based on the weight-of-evidence Group Bl for ethylene oxide, and the potency
factor (F) of 1,34 (mg/kg/day)"^-, ethylene oxide receives a hazard ranking of
"MEDIUM."
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4.0 REFERENCES
Dunkelberg, H., 1979. On the Oncogenic Activity of Ethylene Oxide and
Propylene Oxide in Mice. Br. J. Cancer, 39(4); 588-589,
Dunkelberg, H. , 1981. Carcinogenic Activity of Ethylene Oxide and Its Reaction
Products 2-Chloroethanol, 2-Bromoethanol, Ethylene Glycol, and Diethylene
Glycol. I. Carcinogenicity of Ethylene Oxide in Comparison with 1,2-Propylene
Oxide After Subcutaneous Administration in Mice. Zentrabl, Bakteriol.,
Mikrobiol. Hyg. 174(5): 383-404.
Carman, R.H., W.M. Snellings, and R.R. Maronpot, 1985. Brain Tumors in F344
Rats Associated with Chronic Inhalation Exposure to Ethylene Oxide,
Neurotoxicology 6(1): 117-138.
Hogstedt, C,, D. Rohlen, B.S. Berndtsson, 0. Axelson and L. Ehrenberg, 1979a.
A Cohort Study of Mortality and Cancer Incidence in Ethylene Oxide Production
Workers. Br. J. Ind. Med. 36(4): 276-280.
Hogstedt, C., N. Malmgrist and B. Wadraan, 1979b. Leukemia in Workers Exposed
to Ethylene Oxide. J. Araer. Med. Assoc. 241(11): 1132-1133.
Hogstedt, C., L. Aringer, A. Gustavsson, 1984, Ethylene Oxide and Cancer:
Review of the Literature and Follow-up of 2 Studies. Arb. Halsa 49:1-32.
Hogstedt, G., L. Aringer, A. Gustavsson, 1986. Epidemiologic Support for
Ethylene Oxide as a Cancer-causing Agent. J. Am. Med. Assoc. 255:1575-1578.
Lynch, D.W., T.R. Lewis, W.J. Moorman, J.R. Burg, D.H. Groth, A. Khan, L,J.
Ackerman, and B.Y. Cockrell, 1984. Carcinogenic and Toxicologic Effects of
Inhaled Ethylene Oxide and Propylene Oxide in F344 Rats. Toxicol. Appl.
Pharraacol. 76: 69-84.
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Morgan, R.W., K.W. Claxton, B.J. Divine, S.D. Kaplan and V,B, Harris, 1981,
Mortality Among Ethylene Oxide Workers. J. Occup, Med. 23(11): 767-770.
National Toxicology Program (NTP), 1986 (Final Draft). Toxicology and
Carcinogenesis Studies of Ethylene Oxide in B6C3F1 Mice. NTP TR 326. National
Institute of Health, Research Triangle Park, NC.
Reyniers, V., M. Sachsteder and L, Ashburn, 1964. Multiple Tumors in Female
Germ-Free Inbred Albino Mice Exposed to Bedding Treated with Ethylene Oxide.
J. Natl. Cancer Inst. 32; 1045-1057.
Inhalation Study of the Carcinogenic Potential of Ethylene Oxide in Fischer 344
Rats, Toxicology and Applied Pharmacology 75: 105-117.
U.S. EPA (Environmental Protection Agency), 1985. Health Assessment Document
for Ethylene Oxide, Final Report. EPA/600/8-84/009F, Office of Health and
Environmental Assessment, Washington, D.C., June, 1985. NTIS PB86-102597.
U.S. EPA (Environmental Protection Agency), 1986a. Guidelines for Carcinogen
Risk Assessment, 51 FR 33992-34003, September 24, 1986.
U.S. EPA (Environmental Protection Agency), 1986b. Methodology for Evaluating
Potential Careinogenieity in Support of Reportable Quantity Adjustments
Pursuant to CERCLA Section 102, OHEA-C-073, December 1986. Available from
CERCLA Docket 102RQ-273C. The public document for RQ rulemaking is located in
room M2427, U.S. Environmental Protection Agency, 401 M 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), 1988. Technical Background
Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, Draft,
Appendix A, April 26, 1988.
Van Duuren, B., L, Orris and N. Nelson, 1965. Carcinogenicity of Epoxides,
Lactones, and Peroxy Compounds. II. J. Natl. Cancer Inst. 35: 707-717.
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Walpole, A., 1958. Carcinogenic Action of Alkylating Agents. Ann NY Acad.
Sci, 68: 750-761.
4-3
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APPENDIX
SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
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Table A. Animal
Agent: Ethylene Oxide
Reference: Dunkelberg, 1979; 1981
Exposure Species/
Route Strain Sex
subcu- mice/NMRI F
taneous
subcu- mice/NMRI F
taneous
subcu- mice/NMRI F
taneous
subcu- mice/NMRI F
taneous
Dose
or
Exposure
1 .0 mg/in-
jection/wk
0.3 mg/in-
jection/wk
0.1 mg/in-
jection/wk
0.0 mg/in-
jection/wk
Duration Duration Purity Vehicle or
of of of Physical
Treatment Study Compound State
95 weeks 91 weeks NRb tricapry-
lin
95 weeks 91 weeks NRb tricapry-
I in
95 weeks 91 weeks NR tricapry-
lin
NA 91 weeks NA tricapry
I in
QUALITY OF EVIDENCE
Target
Organ
inject i on
site (inter-
scapular)
injection
site (inter-
scapular)
injection
site (inter-
scapular)
injection
site (inter-
scapular)
Tumor Type
total tumors
sarcoma6
lymphoma
granuloma
total tumors
sarcoma0
lymphoma
basal cell carcinoma
total tumors
sarcoma0
lymphoma
total tumors
sarcoma6
lymphoma
Tumor
Incidence
(P value)
15/100
11/100
2/100
2/100
12/100
8/100
2/100
2/100
7/100
5/100
2/100
5/100
4/100
1/100
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Comments:
Multiple dose levels of the compound were administered over a significant portion of the lifespan.
A non-natural route of administration was employed.
Limited.
The number of tumors at distant sites was not significantly greater in treated mice compared with vehicle controls.
Preliminary results up to 91st week of treatment.
Purity not reported, but impurities checked for by IR, GC, and Fluoresence methods.
c Predominately fibrosarcomas.
NA * Not applicable; NR - Not reported
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Table A. Animal
Agent: Ethylene Oxide
Reference: Lynch et al.( 1984
Dose Duration Duration Purity Vehicle or
Exposure Species/ or of of of Physical Target
Route Strain Sex Exposure Treatment Study Compound State Organ
inhal- rats/ M 100 ppm 104 weeks 104 weeks 99. 7X filtered adrenal
ation Fischer pure air
344
brain
body
cavity
pancreas
pituitary
spleen
inhal- rats/ H 50 ppm 104 weeks 104 weeks 99.7% filtered adrenal
ation Fischer pure air
344
brain glioma (mixed
body
cavity
pancreas
pituitary
spleen
Tumor Type
pheochromocytoma
glioma (mixed cell)
peritoneal
mesothel iomas
islet cell
adenoma
adenoma
mononuclear
cell leukemia
pheochromocytoma
cell)
peritoneal
mesothel iomas
islet cell
adenoma
adenoma
mononuclear
cell leukemia
Tumor
Incidence
(P value)
13/78
(MS)
5/79
(P<0.05)
21/79
(P<0.01)
15/73
(MS)
21/67
(P<0.05)
30/76
(MS)
14/77
(MS)
2/77
(NS)
9/79
(NS)
16/73
(MS)
20/66
(P<0.05)
38/79
(P<0.05)
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Table A. Animal
Agent: Ethylene Oxide
Reference: Lynch et al., 1984 (Page 2)
Dose
Exposure Species/ or
Route Strain Sex Exposure
inhal- rats/ H 0 ppm
ation Fischer
344
Duration Duration Purity Vehicle or
of of of Physical Target
Treatment Study Compound State Organ
104 weeks 104 weeks 99.7% filtered adrenal
pure air
brain
body
cavi ty
pancreas
pi tui tary
spleen
QUALITY OF EVIDENCE
Tumor Type
pheochromocytoma
gl ioma (mixed cell)
peri toneal
mesothel iomas
islet eel I
adenoma
adenoma
mononuc lear
cell leukemia
Tumor
Incidence
(P value)
8/78
0/76
3/78
23/77
44/73
24/77
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Comments:
2-year study duration
Only one species and strain used
Adequate
Other response data was given, but is not recorded in this table.
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Table A. Animal
Agent: Ethylene Oxide
Reference: NTP, 1986-Draft (Page 1)
Dose
Exposure Species/ or
Route Strain Sex Exposure
inhal- mice/ H 0 ppm
at ion B6C3F1
inhal- mice/ H 50 ppm
at ion B6C3F1
inhal- mice/ M 100 ppm
at ion B6C3F1
Duration Duration Purity Vehicle or
of of of Physical Target
Treatment Study Compound State Organ
102 weeks 104 weeks >99X air lung
pure
lung
102 weeks 104 weeks >99X air lung
pure
lung
102 weeks 104 weeks >99X air lung
pure
lung
Tumor Type
alveolar/
bronchiolar
adenoma
alveolar/
bronchiolar
carcinoma
alveolar/
bronchiolar
adenoma
alveolar/
bronchiolar
carcinoma
alveolar/
bronchiolar
adenoma
alveolar/
bronchiolar
carcinoma
Tumor
Incidence
(P value)
5/10
6/50
11/50
(P=0.095)
10/50
(P*0.230)
11/50
(P=0.127)
16/50
(P=0.019)
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Table A. Animal
Agent: Ethylene Oxide
Reference: NTP, 1986-Draft (Page 2)
Dose
Exposure Species/ or
Route Strain Sex Exposure
inhal- mice/ F 0 ppm
ation B6C3F1
inhal- mice/ F 50 ppm
ation B6C3F1
inhal- mice/ F 100 ppm
ation B6C3F1
Duration Duration Purity Vehicle or
of of of Physical Target
Treatment Study Compound State Organ
102 weeks 104 weeks >99X air lung
pure
lung
lymph
gland
102 weeks 104 weeks >99X air lung
pure
lung
lymph
gland
102 weeks 104 weeks >99X air lung
pure
lung
lymph
gland
Tumor Type
alveolar/
bronchiolar
adenoma
alveolar/
bronchiolar
carcinoma
mal ignant
lymphoma
alveolar/
bronchiolar
adenoma
alveolar/
bronchiolar
carcinoma
malignant
lymphoma
alveolar/
bronchiolar
adenoma
alveolar/
bronchiolar
carcinoma
mal i gnant
lymphoma
Tumor
Incidence
(P value)
2/49
0/49
9/49
4/48
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Table A. Animal
Agent: Ethylene Oxide
Reference: NTP, 1986-Oraft (Page 3)
Dose
Exposure Species/ or
Route Strain Sex Exposure
inhala- mice/ F 50 ppm
ation B6C3F1
100 ppm
Duration Duration Purity Vehicle or
of of of Physical Target
Treatment Study Compound State Organ Tumor Type
102 weeks 10A weeks >99% air uterus uterine
pure adenocarci noma
mammary mammary gland
gland adenocarcinoma or
adenosquamous
carcinoma
uterus uterine
adenocarcinoma
mammary mammary gland
gland adenocarcinoma or
adenosquamous
carcinoma
QUALITY OF EVIDENCE
Tumor
Incidence
(P value)
1/A7
(P=0.383)
8/A8
(P=0.012)
5/A9
(P=0.051)
6/A9
(P=0.087)
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Comments:
Used two sexes; 2-year study duration; statistical information given.
Only one species and strain of animal used.
Adequate
Authors report benign neoplasms of the Harderian gland (not included in this table).
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Table A. Animal
Agent: Ethylene Oxide
Reference: Snelling et al., 1981
Dose Duration Duration Purity Vehicle or
Exposure Species/ or of of of Physical Target
Route Strain Sex Exposure* Treatment Study Compound State Organ Tumor Type
inhal- rat/F344 H 100 ppm 98 weeks 100 weeks NR vapor subcutis fibroma
at ion
pancreas adenoma
pituitary adenoma
peritoneum mesothel ioma
spleen leukemia
Tumor
lncidencec
(P value)
10/28e
(P<0.001)
15/78e
(P<0.001)
5/30
(NS)
11/80
(P<0.05)
12/29
(NS)
11/80
(P<0.05)
4/30
(NS)
21/80
(P<0.001)
8/30
(NS)
25/80
(NS)
-------
Table A. Animal
Reference: Snelling et al., 1981 (cont.)
Dose Duration Duration Purity Vehicle or
Exposure Species/ or of of of Physical Target
Route Strain Sex Exposure8 Treatment" Study Compound State Organ Tumor Type
inhal- rat/F344 H 33 ppm 98 weeks 100 weeks NR vapor subcutis fibroma
ation
pancreas adenoma
pituitary adenoma
peritoneum mesothel ioma
spleen leukemia
inhal- rat/F344 H 10 ppm 98 weeks 100 weeks NR vapor subcutis fibroma
at ion
pancreas adenoma
pituitary adenoma
peritoneum mesothelioma
spleen leukemia
Tumor
Incidence0
(P value)
1/34e
(NS)
3/75e
(NS)
V2f
1/43f
13/39
(NS)
16/79
(NS)
4/39
(NS)
6/80
(P<0.05)
10/39
(NS)
23/80
(NS)
8/48e
(P<0.01)
10/776
(P<0.001)
2/30
2/32f
15/51
(NS)
26/79
(NS)
2/51
(NS)
3/80
(NS)
9/51
(NS)
21/80
(NS)
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Table A. Animal
Reference: SnelUng et al., 1981 (cont.)
Dose
Exposure Species/ or
Route Strain Sex Exposure8
inhal- rat/F34A H 0 ppm
at ion
inhal- rat/F3A4 F 100 ppm
at ion
33 ppm
10 ppm
0 ppm"
Duration Duration Purity Vehicle or
of of of Physical Target
Treatment Study Compound State Organ Tumor Type
NA 100 weeks NA NA subcutis fibroma
pancreas adenoma
pituitary adenoma
peritoneum mesothelioma
spleen leukemia
96 weeks 98 weeks NR vapor spleen leukemiad
96 weeks 98 weeks NR vapor spleen leukemiad
96 weeks 98 weeks NR vapor spleen leukemiad
NA 98 weeks NA NA spleen leukemiad
Tumor
Incidence0
(P value)
3/91
4/154
7/97
7/160
19/97
43/157
2/97
3/160
13/97
38/160
15/26
(P<0.001)
27/80
(P<0.001)
K/48
(P<0.01)
24/80
(P<0.01)
11/54
(P<0.05)
H/80
(NS) .
11/115
22/156
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Table A. Animal
Reference: Smelling et al., 1981 (cont.)
Exposure
Route
Species/
Strain Sex
Dose
or
Exposure8
Duration
of
Treatment
Duration
of
Study
Purity
of
Compound
Vehicle or
Physical
State
Target
Organ Tumor Type
Tumor
Incidence0
(P value)
QUALITY OF EVIDENCE
Strengths of Study: Multiple exposure levels were administered by a natural route over a significant portion of the lifespan.
Weaknesses of Study: All rats became infected with sialodacryoadenitis virus during the 15th exposure month.
Overall Adequacy: Adequate
a Exposures were 6 hours/day, 5 days/week.
Exposures were temporarily terminated during weeks 64 and 65 to permit recovery from sialodacryoadenitis virus infection.
c Pooled control data given. Incidence of tumors In rats at final sacrifice listed first. Combined incidence of tumors in rats
at final sacrifice and rats dying spontaneously or euthanized when moribund listed second.
Hononuclear cell leukemia
e Examined only if gross lesions were present (except flank region which was routinely examined microscopically).
Data from the 33 and 10 ppm groups were not statistically analyzed because tissues wsere not examined from all rats (e.g.,
only gross lesions were examined).
9 Two untreated air groups were exposed.
-------
Table A. Animal
Agent: Ethylene Oxide
Reference: Snelling et al., 1984
Dose
Exposure Species/ or
Route Strain Sex Exposure
inhal- rats/ F 100 ppm
ation F344
33 ppm
10 ppm
0 ppm
Duration
of
Treatment
730 days
730 days
730 days
730 days
Duration
of
Study
730 days
730 days
730 days
730 days
Purity Vehicle or
of Physical
Compound State
99. 9X air
99. 9X air
99. 9X air
99. 9X air
Target
Organ
hematopoetic/
brain
hematopoetic/
brain
hematopoetic/
brain
hematopoetic/
brain
Tumor Type
leukemia/
gliomas
leukemia/
gliomas
leukemia/
gl iomas
leukemia/
gliomas
Tumor
Incidence
(P value)
32/73
27/72
15/71
23/186
QUALITY OF EVIDENCE
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Comments:
Both male and female rats were used. Two control groups were used.
Only the results which the author considereJ significant were reported.
Sufficient
Dosage was 6 hrs/day, 5 days/wk.
-------
Table A. Animal
Agent: Ethylene Oxide
Reference: Van Duuren et al., 1965
Exposure Species/
Route Strain
dermal mice/
Swiss
Hi llerton
dermal mice/
Swiss
Hi llerton
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Dose Duration Duration Purity Vehicle or
or of of of Physical Target
Sex Exposure Treatment Study Compound State Organ Tumor Type
F approx. 10 mg/ life life 99. 7X acetone skin papilloma
application carcinoma
thrice weekly*
F 0 mg/appli- NA life MA acetone skin papilloma
cation (vehicle carcinoma
control)
QUALITY OF EVIDENCE
The compound was administered over the lifespan and all gross tumors were con firmed microscopically.
Aqueous solutions are not typical for dermal exposure. All organs were not examined.
Adequate
Tumor
Incidence
(P value)
0/30
0/30
0/60
0/60
a Approximately 0.1 ml of a 10X solution/application.
b Median survival times in the treated and control rats were 493 and 447 days, respectively.
NA * Not applicable
-------
Table B. Humans
Agent: Ethylene Oxide
Reference: Hogstedt et al., 1979a
Exposure
Route
inhal-
ation
inhal-
ation
inhal •
at ion
inhal •
ation
inhal •
ation
inhal •
ation
Size of
Exposed
Populat ion
89 (1324
person
years)
NR (372
person
years)
86 (1211
person
years)
NR (736
person
years)
66 (955
person
years)
NR (603
person
years)
Size of
Control Level of Duration of
Population Sex Exposure8 Exposure
Swedish M fulltlme >.! yr exposure,
population exposure >.10 yrs latency
Swedish H fulltlme >.10 yr exposure,
population exposure >.20 yrs latency
Swedish M Intermit- >,1 yr exposure,
population tent expo- >.10 yrs latency
sure
Swedish H intermit- >.! yr e>P-osure,
population tent expo- >20 yrs latency
sure
Swedish H unexposed >,1 yr exposure,
population £10 yrs latency
Swedish H unexposed >.10 yr exposure,
population >20 yrs latency
Target
Organ
total tumors
stomach
hematopoiet ic
total tumors
stomach
hematopoiet ic
total tumors
stomach
hematopoiet ic
total tumors
stomach
hematopoiet ic
total tumors
stomach
hematopoiet ic
total tumors
stomach
hematopoiet ic
Number of
Tumor Tumors
Type Observed
NR
NR
leukemia
NR
NR
leukemia
NR
NR
leukemia
NR
NR
leukemia
NR
NR
leukemia
NR
NR
1 eukemia
9
3
2
5
1
1
3
1
1
3
1
1
1
0
0
1
0
0
Number of
Tumors
Expected15
3.4
0.4
0.14
1.1
0.13
0.04
3.4
0.4
0.13
2.6
0.3
0.1
2.0
NA
NA
1.6
NA
NA
Relative
Risk
(P value)
2.7
(P<0.01)
7.5
(P<0.01)
14.3
(P<0.01)
4.5
(P<0.01)
7.7
(NS)
25
(P<0.05)
0.9
(NS)
(NS)
7.7
(NS)
1.2
(NS)
3.3
(NS)
10
(NS)
0.5
(MS)
NA
NA
0.6
(NS)
NA
NA
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Table B. Humans
Reference: Hogstedt et al., 1979a
Exposure
Route
Size of
Exposed
Population
Size of
Control
Population Sex
Level of
Exposure8
Duration of
Exposure
Target
Organ
Tumor
Type
Number of
Tumors
Observed
Number of
Tumors
Expected15
Relative
Risk
(P value)
QUALITY OF EVIDENCE
Strengths of Study: Adequately controlled mortality study.
Weaknesses of Study:
Overall Adequacy:
Comments:
Subjects were exposed to a variety of other chemicals, some that are documented animal carcinogens (see
Footnote a). Exposure durations and concerntrat ions were uncertain. Group sizes were small in the subco-
hort with HO years employment and 20 years induction-latency.
Adequate
The observed increases cannot be attributed definitely to ethylene oxide alone.
8 Ethylene oxide production workers who were exposed to estimated ethylene oxide levels of <25 mg/m (with occasional
exposures up to the odor threshold (1300 mg/m3) during 1941-1947. The workers were also exposed to ethylene chlorohydrin (approx. 5
mg/m3), ethylene dichloride (approx. 100.05 mg/m3), bis(2-chloroethyl) ether (approx. 0.05mg/m3} and ethylene (approx. 600 mg/m3); it is
possible that up to 1000 times these concentrations may have occurred momentarily. Exposure time was estimated as a slightly
more than 1 ho.ur/shift. From 1950 to 1963, exposure to chemicals other than ethylene oxide decreased because of production
changes, and exposure to ethylene oxide increased (10-50 mg/m3 with peaks above the odor threshold). Subsequnt years were
characterized by a lower ethylene oxide exposure (approx. 1-10 1119/in with higher peaks), but also by exposure to proplene oxide
(10-25 mg/m3, occasionally 120-150 mg/m3).
The expected number of deaths due to malignanoise were calculated from the cause-, sex-, and age-specific Swedish national
death rates from respective 5-year age categories.
NR « Not reported; NS = Not significant
-------
Table B. Humans
Agent: Ethylene Oxide
Reference: Hogstedt et al., 1979b
Exposure
Route
inhal-
ation
Size of
Exposed
Population
230
Size of
Control
Population Sex
U.S. M,F
population
Level of
Exposure8
20 + 10
ppm
Duration of
Exposure
Afl-yrs
Target
Organ
hematopoiet ic
Tumor
Type
leukemia
Number of
Tumors
Observed
3
Number of
Tumors
Expected15
0.2
Relative
Risk
(P value)
15 (NS)
QUALITY OF EVIDENCE
Strengths of Study: Exposure concentrations and components were fairly well characterized.
Weaknesses of Study: The cohort was small, and the duration of exposure was short.
Overall Adequacy: Limited
Comments: One of the subjects with leukemia had "some occasional contact" with benzene in laboratory work.
8 Workers were employed in a small Swedish factory that sterilized hospital equipment. Seven people (4 males, 3 females) were
sterilizer operators, 70 (68 females, 2 males) were exposed via outgassing from treated boxes in a storage hole for 8
hours/day, and 153 other workers (101 females, 52 males) were eni^.oyed in neighboring rooms.
-------
Table B. Humans
Agent: Ethylene Oxide
Reference: Morgan et al., 1981
Exposure
Route
inhal-
ation
Size of Size of
Exposed Control Level of
Population Population Sex Exposure8
767 U.S. M <10 ppma
(13,969 population
person-
years)
Duration of Target
Exposure Organ
5-18 years All malignant
pancreas
bladder
brain/CHS
lymphatic
hematopoietic
Tumor
Type
neoplasms
cancer
cancer
cancer
Hodgkin's
disease
leukemia
Number of
Tumors
Observed
11
3
1
2
2
0
Number of
Tumors
Expected
15.24
0.80
0.31
0.70
0.35
0.70
Standard
Mortality
Ratiob
72 (NS)
375 (NS)
322 (NS)
285 (NS)
571 (NS)
0 (NS)
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
QUALITY OF EVIDENCE
The subjects were employed in a plant that is one of the largst and oldest producers of ethylene oxide in
the United States.
Cohort size was small, and exposures were poorly characterized. Additional tests of significance
demonstrated a relationship between ethylene oxide and the incidence of Hodgkins disease and
pancreatic cancer0.
Limited
a The subjects had potential exposures to ethylene oxide at a Texaco Chemical Company plant that continuously produced
ethylene oxide. A recent (1977) industrial hygiene survey indicated time-weighted average concentrations "well below" the OSHA
50 ppm limit; detectable concentrations were routinely <10 ppm.
Each of these standard mortality ratios (number of tumors observed/number of tumors expected x 100) has a lower 95X confidence limit under
100 (i.e., not significantly elevated).
0 EPA evaluation of the Morgan data, June, 1985.
-------
Table B. Humans
Agent: Ethylene Oxide
Reference: Hogstedt et al., 1986
Exposure
Route
inhal-
ation
Strengths
Weaknesses
Size of
Exposed
Population
733
(total)
of Study:
of Study:
Overall Adequacy:
Comments:
Size of
Control Level of
Population Sex Exposure8
Swedish H,F 2-300 ppm
population
Duration of Target
Exposure Organ
19-48 yrs stomach,
hematopoietic,
lung
QUALITY OF EVIDENCE
Three groups of exposed workers in various locations all demonstrated
The cohort was relatively small, and
Limited
The author noted that one group had
used in the previous two studies.
exposures were not well defined.
Tumor
Type
adenocar-
cinoma,
leukemia,
adenocar-
cinoma
Number of
Tumors
Observed
4
2
5
1
Number of
Tumors
Expected6
0.3
0.5
0.6
0.16
Relative
Risk
(P value)
13
4
8
6
increased rates of cancer.
There were no
worker cohort
controls.
an exposure to almost pure ethylene oxide compared to the cohorts
Sterilization workers from hospitals combined with production workers.
------- |