See Occupational Exposure Standards
Human Health Effects:
Evidence for Carcinogenicity:
A2; Suspected human carcinogen.
Evaluation: There is limited evidence in humans for the carcinogenicity of
ethylene oxide. There is sufficient
evidence in experimental animals for the carcinogenicity of ethylene oxide. In making the overall
evaluation, the Working Group took into consideration the following supporting
evidence. Ethylene oxide is a directly
acting alkylating agent that: (1) induces a sensitive, persistent dose-related
increase in the frequency of chromosomal aberrations and sister chromatid
exchange in peripheral lymphocytes and micronuclei in bone marrow cells of
exposed workers; (2) has been associated with malignancies of the lymphatic and
hematopoietic system in both humans and experimental animals; (3) induces a dose
related increase in the frequency of hemoglobin adducts in exposed humans and
dose related increases in the numbers of adducts in DNA and hemoglobin in
exposed rodents; (4) induces gene mutations and heritable translocations in germ
cells of exposed rodents; and (5) is a powerful mutagen and clastogen at all
phylogenetic levels. Overall evaluation: Ethylene oxide
is carcinogenic to humans (Group 1).
Human Toxicity Excerpts:
INHALATION CAUSES NAUSEA, VOMITING, NEUROLOGICAL DISORDERS, & EVEN DEATH.
TRACES OF GAS IN GLOVES OR CLOTHING MAY CAUSE BURNS. ... RESIDUES IN VASCULAR
CATHETERS CAN CAUSE THROMBOPHLEBITIS; IN ENDOTRACHEAL TUBES, TRACHEITIS.
... A pulmonary irritant if inhaled
... MAY BE DESCRIBED AS A CENTRAL DEPRESSANT, AN IRRITANT ... CONTACT WITH
... DILUTE SOLN MAY CAUSE IRRITATION & NECROSIS OF EYES ... BLISTERING ...
& NECROSIS OF SKIN. EXCESSIVE EXPOSURE MAY CAUSE IRRITATION OF ... LUNGS,
& CENTRAL DEPRESSION.
Conjunctivitis, dyspnea, cough, vertigo, nausea and vomiting, abdominal pain,
parasystole, arrhythmia, pulmonary edema, and paralysis.
The incidence of spontaneous abortions among hospital staff who used ethylene oxide, glutaral (glutaraldehyde) and
formaldehyde for the chemical sterilization of instruments was studied using
data from a questionnaire and a hospital discharge register. Results showed that
the frequency of spontaneous abortions was 11.3% for the sterilizing staff and
10.6% for the nursing auxiliaries (controls). When the staff were concerned in
sterilizing during their pregnancy the frequency was 16.7% compared with 5.6%
for the nonexposed pregnancies. The incr frequency ... correlated with exposure
to ethylene oxide but not with exposure
to glutaral or formaldehyde.
Accidental exposure of a person to an estimated concn of 500 ppm in air for
2-3 min was enough to cause temporary unconsciousness and seizures, but
apparently did not produce ocular symptoms.
A report of 1st to 3rd degree burns occurring postoperatively or postpartum
in 19 women. The gowns and sheets used were found to contain 16-50 times the
safe residual concn of ethylene oxide.
Workers who had been employed for more than one year by a company producing
ethylene oxide had been studied from
1960-1961. No significant differences had been found between workers permanently
working in the ethylene oxide
manufacturing area, those who had previously worked in this
area, those working there intermittently and a further group who had never
worked in ethylene oxide production.
However, a subgroup of individuals with high exposure had decreased hemoglobin
concn and signficant lymphocytosis. When workers were followed up from
1961-1977, those who had been exposed full-time to ethylene oxide production showed a
considerably excess mortality, this being mainly due to an increased incidence
of leukemia, stomach cancer and diseases of the circulatory system. Although
malignancies could not be linked to any particular chemical associated with
ethylene oxide production it was
considered that ethylene oxide and
ethylene dichloride, possibly together with ethylene chlorohydrin or ethylene,
were the causative agents.
The permeation of ethylene oxide
through human skin was determined in vitro. Permeation studies
were performed with excised skin in diffusion cells. Ethylene oxide shows that it permeated
quickly. The health hazard involved in the use of ethylene oxide in sterilization of medical
goods is discussed.
Chronic ethylene oxide poisoning
occurred collectively in four sterilizing workers of a factory manufacturing
medical appliances in Izumo, Japan. All the patients presented with symptoms of
multiple neuropathy, of which the chief complaints were sensory disturbance of
the lower limbs and gait disturbance. One of the patients presented with
delirium and visual hallucinations. ... Clinical observations of the poisoning
/were analyzed/ and the causal factors from the standpoint of industrial
epidemiology and safety measures for the future /were discussed/.
Chromosome aberration frequencies in 61 employees potentially exposed to
ethylene oxide were compared with those
in unexposed control groups. Three worksites /were studied/ with differing
historical ambient levels of ethylene oxide.
Within worksites, groups were classified as high potential
exposed, low potential exposed, or controls. Further control groups including an
off-site community control group were added to give a total of 304 control
individuals. Blood samples were drawn several times over a 24-month period.
Aberrations were analyzed in 100 cells per sample after culture for 48-51 hours.
Worksites I, II, and III respectively represented increasing levels of potential
ethylene oxide exposure. At worksites I
and II, no consistent differences in aberration frequencies were found among
groups. At worksite III aberration frequencies in potentially exposed
individuals were significantly increased compared with controls. The frequencies
of cells with aberrations were 5.6% for the 2 individuals in the high potential
exposure category and 2.6% for 23 persons in the low potential exposure group.
The overall frequency of cells with aberrations in the matched control
individuals was 1.4%. In the total control group of 304 individuals, ...
significant increases in aberrations associated with smoking and increasing age
/were found/.
A retrospective cohort study was performed on a group of 664 male workers
employed for at least one month during the period 1942-1979 in a chemical
factory. Both established and suspected carcinogens had been handled in the
plant, primarily piperazine, but also urethane, ethylene
oxide, formaldehyde, and organic solvents. A significantly
increased mortality, compared with the regional death rate, was observed in the
cohort. The increase was mainly due to violent deaths and cardiovascular
diseases. A statistically significant increase in cancer morbidity was observed
for malignant lymphoma/myelomatosis when an induction latency time /minimum/ of
10 years was used. Furthermore, an increase in bronchial cancer was noted, but
it was statistically significant only when an induction-latency time /minimum
of/ 15 years was used.
Samples of blood were collected from a group of plant workers engaged in the
manufacture of ethylene oxide for
periods of up to 14 yr, and also from a group of control personnel matched by
age and smoking habits. Peripheral blood lymphocytes were cultured for
cytogenetic analysis. Selected immune and hematological parameters were also
investigated. The results of these studies showed no statistically significant
difference between the group of plant workers and the control group in respect
to any of the biological parameters investigated in this study. Nevertheless,
duration of employment in ethylene oxide
manufacturing was positively correlated (p< 0.05) with the
frequency of chromosome breaks and with the percentage of neutrophils in a
differential white blood cell count, and negatively correlated (p< 0.05) with
the percentage of lymphocytes. As the values of these parameters remained within
the normal limits of control populations, the correlations were considered to
have no significance for health. The amount of alkylation (2-hydroxyethyl
groups) of the Nt atom of histidinyl residues in hemoglobin was also measured in
an attempt to gauge recent individual exposures to ethylene oxide. Variable but, in most
instances, readily measurable amounts of Nt- (2'-hydroxyethyl)-L-histidine (Nt
represents the N3 atom of histidine) were found in the hemoglobin of plant
workers and in the control group who had not knowingly been exposed to an
exogenous source of ethylene oxide.
There was no statistically significant difference between the
results obtained in the control group and in the group of plant workers.
A study was made of the effects of ethylene oxide
on the health of sterilizer workers and other personnel exposed
while using ethylene oxide for
sterilization of disposable medical devices. The only significant findings were
obtained by chromosomal analysis of cultured lymphocytes harvested from the
workers. There were significant differences in the numbers and types of
chromosomal aberrations between the exposed workers and the nonexposed controls.
Quadriradial and triradial chromosomal forms, which were rarely found in
nonexposed populations, were increased in exposed workers. Increased numbers of
sister chromatid exchanges was found in the cultured lymphocytes of some, but
not all, exposed persons during the 2 yr of study. Workers (13) were removed
from exposure in 1979 because of increased numbers of aberrant cells. Follow-up
over 4 yr did not show a significant improvement, except for a moderate
reduction in sister chromatid exchanges. Recommendations were given for a
surveillance of persons working with or exposed to ethylene oxide.
... Dialyzer hypersensitivity syndrome presents as an acute anaphylactoid
reaction, the symptoms of which may range from mild to life threatening in
severity. The cause of this syndrome is unknown, but affected patients appear to
have a high incidence of positive radioallergosorbent tests to a conjugate of
human serum albumin and ethylene oxide,
suggesting that ethylene oxide,
a substance used to dry sterilize artificial kidneys, may be an
offending allergen.
Samples of peripheral blood were collected from 33 men who were employed in
the manufacture of ethylene oxide for
between 1 and 14 yr, and from 32 men from other parts of the same plant who were
used as controls. Their lymphocytes were analyzed for chromosome damage. There
were low frequencies of polyploidy, chromatid aberrations and chromosome breaks
in the cells of the 65 men. A slightly higher frequency of chromatid aberrations
was observed in the cells of the ethylene oxide
workers than in those of the controls. There was a positive
correlation between length of employment in the ethylene
oxide group and the numbers of aberrations in the cultures of
each individual. This trend was not solely attributable to the age of the men.
The levels of chromatid and chromosome damage observed in this study are
consistent with those in humans who were not recently exposed to known
chromosome-breaking agents.
EXPOSURE TO LOW VAPOR CONCN OFTEN RESULTS IN DELAYED NAUSEA AND VOMITING.
HIGHER CONCN PRODUCE IRRITATION OF EYES, NOSE, AND THROAT; HIGH CONCN MAY CAUSE
EDEMA OF LUNGS. CONTACT WITH SKIN CAUSES BLISTERING AND BURNS.
Concern about the possible adverse influence of the workplace environemnt on
reproduction now extends to women health professionals. ... A postal survey of
all women who graduated from US veterinary schools during the period 1970-1980
(n = 2,997; response rate = 90.2%) /was conducted/. Occupational and
reproductive histories were obtained, and spontaneous abortion risks were
estimated with respect to self-reported exposure to radiation, ethylene oxide, halothane and other anesthetic
gases, and pesticides. Of the 2,174 pregnancies among cohort members who had one
veterinary job at the time of conception, 83.3% of the conceptions occurred
while the veterinarian held a job that involved exposure to pesticides, 63.2%
involved exposure to radiation, 61.9% to anesthetic gases other than halothane,
50.7% to halothane, and 14.0% to ethylene oxide.
Agent-specific spontaneous abortion risks were estimated for the
exposed/unexposed pregnancies, and risk ratios adjusted for gravidity, history
of spontaneous abortion, age and alcohol and tobacco use were derived by means
of logistic regression. Estimated risk ratios were close to 1.0, and no effect
was seen for hours worked per week, a measure of exposure intensity. Despite no
apparent influence of the exposures on spontaneous abortion risk, caution must
be exercised in interpretation of these results because of potential exposure
misclassification. Importantly, the results emphasize the extent to which women
veterinarians may be exposed to reproductive hazards while pregnant.
Eight hospital workers with chronic ethylene oxide
exposure were age-sex matched with eight nonexposed controls
with no significant differences in educational backgrounds and vocabulary
scores. The exposed group performed more poorly on all eight measures of
cognition, memory, attention, and coordination, with 71.3% less accuracy on the
Hand-Eye Coordination Test. There was a dose-response relationship between
exposure and the following: Continuous Performance Test and sural velocity.
These findings suggest that neurologic dysfunction may result from long-term
low-dose exposure to ethylene oxide, and
that these effects may occur at exposure levels common in hosptial sterilizer
operations.
Ethylene oxide is an alkylating agent
and a model direct-acting mutagen and carcinogen. This study has evaluated a
panel of biologic markers including ethylene
oxide-hemoglobin adducts, sister-chromatid exchanges,
micronuclei, chromosomal aberrations, DNA single-strand breaks and an index of
DNA repair (ratio of unscheduled DNA synthesis to NA-AF-DNA binding) in the
peripheral blood cells of 34 workers at a sterilization unit of a large
university hospital and 23 controls working in the univer library. Comprehensive
environmental histories were obtained on each subject including detailed
occupational and smoking histories. Industrial hygiene data obtained prior to
the study and personal monitoring during the 8 years preceding the study showed
that workers were subject to low level exposure near or below the current
Occupational Safety and Health Administration (OSHA) standard of 1 ppm (TWA).
Personal monitoring data obtained during 2 weeks prior to blood sampling were
uniformly less than 0.3 ppm (TWA). After adjusting for smoking, ethylene oxide workplace exposure was
significantly (p< 0.001) associated with ethylene
oxide hemoglobin (a carcinogen protein adduct) and 2 measures of
sister chromatid (the average number of sister chromatid exchanges/cell (SCE50)
and the number of high frequency cells (SCEHFC). There was an apparent
suppression of DNA repair capacity in ethylene oxide
exposed individuals as measured by the DNA repair index; ie, the
ratio of unscheduled DNA synthesis and NA-AAF-DNA binding (p< 0.01). No
association of DNA repair index with smoking was found. Another important
finding of this study is the highly significant correlation between ethylene oxide-hemoglobin adduct levels and
SCEHFC (p< 0.01) and sister-chromatid exchanges (p< 0.02) which provides
evidence of a direct link between a marker of biologically effective dose and
markers of genotoxic response. In contrast, micronuclei, chromosomal aberrations
and single-strand breaks were not significantly elevated in the workers. The
activity of the u-isoenzyme of glutathione-S-transferase was measured as a
possible genetic marker of susceptibility and a modulator of biomarker
formation. However, possibly because of confounding by age, no significant
relationships were found between glutathione-S-transferase and any of the
exposure-related markers by ANOVA or among other independent variables by
regression.
A multicenter cohort study was carried out to study the possible association
between exposure to ethylene oxide and
cancer mortality. The cohort consisted of 2658 men from eight chemical plants of
six chemical companies in the Federal Republic of Germany who had been exposed
to ethylene oxide for at least one year
between 1928 and 1981. The number of subjects in the separate plants varied from
98 to 604. By the closing date of the study (31 December 1982) 268 had died, 68
from malignant neoplasms. For 63 employees who had left the plant (2.4%) the
vital status remained unknown. The standardized mortality ratio for all causes
of death was 0.87 and for all malignancies 0.97 compared with national rates.
When local state rates were used the standardized mortality ratio were slightly
lower. Two deaths from leukemia were observed compared with 2.35 expected
standardized = 0.85). Standardized mortality ratios for carcinoma of the
esophagus (2.0) and carcinoma of the stomach (1.38) were raised but not
significantly. In one plant an internal "control group" was selected matched for
age, sex, and date of entry into the factory and compared with the exposed
group. In both groups a "healthy worker effect" was observed. The total
mortality and mortality from malignant neoplasms was higher in the exposed than
in the control group; the differences were not statistically significant. There
were no deaths from leukemia in the exposed group and one in the control group.
We have applied the micronucleus assay to exfoliated cells of buccal and
nasal cavities to monitor the genotoxic risk in a group of workers exposed to
chromic acid and in another group exposed to ethylene
oxide. The first group comprised 16 subjects working in a hard
type chrome plating factory showing increased chromium absorption and chromium
induced rhinopathy. The second group comprised 9 subjects working in a
sterilization unit, exposed to ethylene oxide
concentrations lower than 0.38 ppm as timed weighted average for
a working shift; 3 of them were involved in a acute exposure too. The frequency
of micronucleus in buccal mucosa was within the norm for exposure both to
chromium and to ethylene oxide. The
micronucleus frequency in nasal mucosa was not altered in chromium platers,
whereas a significant increase (p less than 0.01) in micronucleus was found in 2
out of 3 subjects involved in the accidental ethylene
oxide leakage and a non-significant increase in micronucleus was
found in the group chronically exposed to ethylene
oxide.
Work practices as well as personal and environmental exposure levels were
reported among ethylene oxide sterilizer
operators in health care facilities in the province of Alberta, Canada. A survey
was undertaken between October of 1985 and September of 1986 concerning the use
of and exposure to ethylene oxide in 174
hospitals. The first part of the survey considered all hospitals with ethylene oxide sterilizers, inquiring about
their use at the facility. The second part of the survey queries workers (14 men
and 151 women) concerning their work history and health status. While no
detectable levels of ethylene oxide were
found in environmental samples, over half of the respondents stated they could
smell ethylene oxide at work. While
sampling results never indicated concentrations above the provincial 15 minute
time weighted average short term exposure limit of 50 ppm, personal exposure
concentrations and the use of portable sterilizers were positively associated
with short term symptoms such as irritations of the mucous membranes and skin.
Life style behavior and exposure to other chemical irritants were not considered
in the course of this study.
A retrospective cohort study was conducted to examine the mortality
experience of 2174 men employed between 1940 and 1978 by a large chemical
company and who had been assigned to a chemical production department that used
or produced ethylene oxide. Comparisons
were made with the general United States population, the regional population,
and with a group of 26,965 unexposed men from the same plants. Comparisons with
general United States death rates showed fewer deaths than expected in the ethylene oxide group due to all causes and for
total cancers. There was no statistically significant excess of deaths due to
any cause. Seven deaths each due to leukemia and pancreatic cancer were observed
with 3.0 and 4.1 deaths expected. Among the subcohort of men who worked where
both average and peak exposure levels were probably highest, however, one death
due to pancreatic cancer (0.9 expected) and no deaths due to leukemia were
observed. Four of the seven who died from leukemia and six of the seven died
from pancreatic cancer had been assigned to the chlorohydrin department where
the potential for exposure to ethylene oxide
is judged to have been low. The relative risk of death due to
each disease was strongly related to duration of assignments to that department.
When men who worked in the chlorohydrin department were excluded, there was no
evidence for an association of exposure to ethylene
oxide with pancreatic cancer or leukemia. Together with the
failure to show independent ethylene oxide
associations, the chlorohydrin department results suggest that
leukemia and pancreatic cancer may have been associated primarily with
production of ethylene chlorohydrin or propylene chlorohydrin, or both. These
results emphasize the importance of examing additional concurrent asynchronous
exposures among human populations exposed to ethylene
oxide.
An epidemiological study was conducted in 55 subjects (mean age: 41) in
hospitals to determine the prevalence of lens opacities and cataracts in workers
exposed to ethylene oxide in six
sterilization units. The relation between occupational exposure to ethylene oxide and white blood cell
concentrations was also investigated. Lens opacities were observed in 19 of the
55 exposed. No link was found between the characteristics of the lens opacities
and the characteristics of exposure. For cataracts, their prevalence differed
significantly between the exposed (six of 21) and the non-exposed (0 of 16);
there was no relation between their existence and overexposures. The risk of
lens opacifications by ethylene oxide
could also exist during chronic exposure to low concentrations.
Linear relations were found between the logarithm of the cumulative exposure
index and the logarithms of blood concentrations of polymorphoneutrophils.
A cohort study was carried out of mortality among 2876 men and women exposed
to ethylene oxide during its manufacture
and use in England and Wales. The study cohort included employees from three
companies producing ethylene oxide and
derivative compounds such as polyethylene glycols and ethoxylates, from one
company that manufactured alkoxides from ethylene oxide
and from eight hospitals with ethylene
oxide sterilizing units. While industrial hygiene data were not
available before 1977, since then the time weighted average exposures have been
less than 5 ppm in almost all jobs and less than 1 ppm in many. Past exposures
were probably somewhat higher. In contrast to other studies, no clear excess of
leukemia was noted (three deaths occurred versus 2.09 expected), and no increase
in the incidence of stomach cancer (five deaths occurred versus 5.95 expected)
was observed. This lack of consistency with the results of earlier studies may
be due to differences in exposure levels. Total cancer mortality was similar to
that expected from national and local death rates from this disease. Small
excesses were noted in some specific cancers, but their relevance to ethylene oxide exposure was doubtful. No
excess of cardiovascular disease was found. While the results of this study did
not exclude the possibility that ethylene oxide
is a human carcinogen, they suggested that any risk of cancer
from currently permitted occupational exposures is small.
Ethylene oxide is widely used to
sterilize heat-sensitive materials. Acute and chronic neurogenic effects to the
central and peripheral nervous system in man and animals have been described. A
cross-sectional study of 25 hospital central supply workers exposed to low
levels of ethylene oxide and 24
unexposed control workers was conducted. Subjects were tested with a
neuropsychological screening battery by examiners blinded to exposure status.
Results were reviewed independently by 2 neuropsychologists without knowledge of
exposure. Subject status was categorized as normal, impaired, or disagreement
(between the two neuropsychologists). There were more subjects concordantly
judged as impaired in the exposed group than in the control group. Although
limited by the cross-sectional study design and the global categorization, these
findings suggest that central nervous system dysfunction and cognitive
impairment may result from chronic ethylene oxide
exposure in hospital central supply units.
Ethylene oxide is used to chemically
sterilize heat-sensitive materials in hospitals. Neurotoxic effects of ethylene oxide have been described in animals
and humans; cognitive deficits may be associated with chronic low level ethylene oxide exposure. In this study,
hospital workers with chronic ethylene oxide
exposure were compared with a non-exposed control group to
detect neurological and neuropsychological abnormalities. Ethylene oxide breathing zone levels of up to
250 ppm in exposed subjects were reported. The exposed group had lower P300
amplitude in electroencephalographic (EEG) tests, bilaterally hypoactive distal
deep tendon reflexes and poorer performance on neuropsychological tests
involving psychomotor speed. Exposed subjects acknowledge more symptoms and
higher levels of depression and anxiety. Nerve conduction velocities and EEG
spectral analysis were simialr in both exposed and control groups as were scores
on most psychological tests.
A 43 yr old female licensed practical nurse, while sterilizing heat sensitive
medical items, accidentally dropped and broke an ampule containing 17 gm epoxyethane. While disposing of the broken
ampule, she began to experience nausea and stomach spasms. The exposure was
estimated to have been of 2-3 min duration and not to have exceeded 500 ppm.
Upon leaving the contaminated room, she became pale, lightheaded, and passed out
for approximately 3-4 min. Convulsive movements of her arms and legs were noted
during a 1-min period of apnea. She was given oxygen, began breathing, and awoke
instantly without confusion or nausea. Approximately 3 min later she again felt
nausea, stomach spasms, and lightheadedness and became apneic and passed out.
Twitching of the extremities occurred and she was given oxygen again. Arterial
blood gases, chest X rays, and routine laboratory measurements performed at that
time were normal. During the 24 hr following discharge she continued to complain
of random muscle twitches, nausea, and malaise.
The presence of ethylene oxide in
dialysis tubing has been suggested as a possible cause of allergic reactions in
some patients. Ethylene oxide also is a
pulmonary irritant when inhaled. It is too toxic to be applied topically as an
antiseptic.
Three cases of hematopoietic cancer that had occurred been 1972 and 1977
/were reported/ in workers at a Swedish factory where 50% ethylene oxide and 50% methyl formate had been
used since 1968 to sterilize hospital equipment. Attention had been drawn to the
case cluster by the factory safety committee. One woman with chronic myeloid
leukaemia and another with acute myelogenous leukaemia had worked in a storage
hall where they were exposed for 8 hr per day to an estimated 20 plus or minus
10 (SD) ppm (36 plus or minus 18 mg/cu m) ethylene
oxide. The third case was that of a man with primary
macroglobulinemia (morbus Waldenstrom) who had been manager of the plant since
1965 and had been exposed to ethylene oxide
for an estimated 3 hr per week. (The Working Group noted that
Waldenstrom's macroglobulinemia is classified in ICD /International
Classification of Diseases codes/ 10 as a malignant immunoproliferative
disease.)
Two hundred and three workers employed for at least one year at /a Swedish
factory where 50% ethylene oxide and 50%
methyl formate had been used since 1968 to sterilize hospital equipment/ were
subsequently followed up for mortality. During 1978-82, five deaths occurred
(4.9 expected), of which four were from cancer (1.6 expected). Two of the deaths
were from lymphatic and hematopoietic cancer (0.13 expected), but one of these
decedents had been part of the original case cluster that had prompted the
study.
A retrospective cohort study /was reported/ of 767 men employed at a chemical
plant in eastern Texas, USA, between 1955 and 1977 where ethylene oxide was produced. All of the men
had worked at the factory for at least five years and were potentially exposed
to the compound. Potential exposure to ethylene oxide
was determined by personnel at the company on the basis of work
histories. In an industrial hygiene survey in all samples taken in the ethylene oxide production area contained less
than 10 ppm (18 mg/cu m). Vital status was ascertained for more than 95% of
cohort members from a combination of plant records, personal knowledge and
telephone follow-up. Altogether, 46 deaths were recorded, whereas 80 were
expected on the basis of US vital statistics. Death certificates were obtained
for 42 of the 46 deceased subjects. Eleven deaths were from cancer (15.2
expected), and nonsignificant excesses were seen of cancers of the pancreas
(3/0.8) and brain and central nervous system (2/0.7) and of Hodgkin's disease
(2/0.4); no death from leukaemia was found.
18,254 employees at 14 US industrial plants where ethylene oxide had been used to sterilize
medical supplies or spices or in the testing sterilizing equipment /were
followed/. The plants were selected because they held adequate records on
personnel and exposure and their workers had accumulated at least 400
person-years at risk before 1978. Only workers with at least three months of
exposure to ethylene oxide were included
in the cohort. Forty five percent of the cohort were male, 79% were white, 1,222
were sterilizer operators and 15,750 were employed before 1978. Analysis of 627
8 hr personal samples indicated that average exposure during 1976-85 was 4.3 ppm
(7.7 mg/cu m) for sterilizer operators; the average level for other exposed
workers, on the basis of 1,888 personal samples, was 2.0 ppm (3.6 mg/cu m). Many
companies began to install engineering controls in 1978, and exposures before
that year were thought to have been higher. There was no evidence of confounding
exposure to other occupational carcinogens. The cohort was followed to 1987
through the national death index and records of the Social Security
Administration, the Internal Revenue Service and the US Postal Service, and
95.5% were traced successfully. The expected numbers of deaths were calculated
from rates in the US population, stratified according to age, race, sex and
calendar year. In total, 1,177 cohort members had died (1,454.3 expected),
including 40 for whom no death certificate was available. There were 343 deaths
from cancer (380.3 expected). The observed and expect numbers of deaths were
36/33.8 from all lymphatic and hematopoietic cancer, including 8/5.3 from
lymphosarcoma-reticulosarcoma (ICD9 200), 4/3.5 from Hodgkin's disease, 13/13.5
from leukaemia, 8/6.7 from non-Hodgkin's lymphoma (ICD9 202) and 3/5.1 from
myeloma; 6/11.6 from cancer of the brain and nervous system; 11/11.6 from cancer
of the stomach; 16/16-9 from cancer of the pancreas; 8/7.7 from cancer of the
oesophagus; and 13/7.2 from cancer of the kidney. Mortality ratios for subjects
first exposed before 1978 were virtually identical to those for the full cohort.
No significant trend in mortality was observed in relation to duration of
exposure, but the mortality ratios for leukaemia (1.79 based on five deaths) and
non-Hodgkin's Lymphoma (1.92 based on five deaths) were higher after allowance
for a latency of more than 20 years. Among the sterilizer operators, mortality
ratios (and observed numbers of deaths) were 2.78 (two) for leukaemia and 6.68
(two) for lymphosarcoma/reticulosarcoma; no death from stomach cancer was seen.
Repeat plasma donors were studied to determine whether there was a
relationship between allergic-type reactions during plasmapheresis and
IgE-dependent sensitization to ethylene oxide
gas used for sterilization of disposable fluid administration
sets. Serums from 32 donors with allergic-type reactions and 84 donors who had
no reactions but were exposed to the same materials and served as controls were
tested for IgE antibodies to ethylene oxide.
The results, expressed as an IgE ethylene oxide index, were greater than 2 in
78% of serums from donors with allergic and 12% of serums from controls. This
association was significant (p< 0.0001). Reactivity of the antibodies was
directed against an ethylene oxide-human
serum albumin conjugate and not against human serum albumin carrier protein. IgG
antibodies with ethylene oxide
specificity also were present in the serums of repeat
plasmapheresis donors. Each of seven rabbits immunized with an ethylene oxide-protein conjugate responded
with a high serum level of antibody with ethylene oxide
specificity. It was concluded that the residual ethylene oxide in fluid administration sets is
immunogenic and may cause allergic reactions in plasma donors.
Chromosomal aberrations and micronuclei in lymphocytes were measured in
workers exposed to propylene oxide in a factory producing alkylated starch, and
in workers exposed to ethylene oxide in
connection with sterilization of medical equipment. Adduct levels in hemoglobin
were determined as a measure of in vivo doses of the two compounds. The levels
of hydroxypropylvaline in propylene oxide exposed workers were correlated in
estimated exposure doses. The levels of this adduct in the unexposed group were
close to the detection limit of the method. The levels of hydroxyethylvaline,
recorded in the propylene oxide-exposed group were consistent with earlier data
on hemoglobin alkylation in occupationally unexposed subjects. The adduct
measurements revealed increased levels of hydroxyethylvaline in the two
subgroups of ethylene oxide-exposed
workers, ie, assemblers with a low and sterilizers with a high exposure.
According to expectation the subgroups differed in adduct levels. The results of
the cytogenetic study showed that the clastogenic potency of propylene oxide was
lower than that of ethylene oxide, since
the propylene oxide-exposed individuals had lower frequencies of micronuclei and
chromosomal breaks compared to the assemblers despite a lower adduct level in
the last group.
Cases of human ethylene oxide (EtO)
neuropathy were reviewed and the clinical features characterized. ... The 12
patients with EtO toxicity selected for review were each engaged ln sterilizing
work with EtO in the factory or hospital. Sensorimotor neuropathy developed in
two patients within 3 and 5 months of exposure. They had been repeatedly exposed
to EtO for up to several hundred ppm. Complaints included muscle weakness
hypesthesia and a tingling sensation in distal lower limbs although distal upper
limbs were also sometimes involved. Ten of the 12 demonstrated muscle weakness
in neurological examinations. Needle EMG revealed neurogenic changes in eight.
Histological studies of the sural nerve biopsied in three patients demonstrated
mild abnormalities. Cerebrospinal fluid studies showed elevated protein in two
of six patients. ...
Mortality from cancer among workers exposed to ethylene oxide (EtO) has been studied in 10
distinct cohorts that include about 29800 workers and 2540 deaths. This paper
presents a review and meta-analysis of these studies, primarily for leukemia,
nonHodgkin's lymphoma, stomach cancer, pancreatic cancer, and cancer of the
brain and nervous system. The magnitude and consistency of the standardized
mortality ratios (SMRs) were evaluated for the individual and combined studies,
as well as trends by intensity or frequency of exposure, by duration of
exposure, and by latency (time since first exposure). Exposures to other
workplace chemicals were examined as possible confounder variables. Three small
studies ... initially suggested an association between EtO and leukemia, but ln
seven subsequent studies the SMRs for leukemia have been much lower. For the
combined studies the SMR = 1.06 (95% confidence interval (95% CI) 0.73-1.48).
There was a slight suggestion of a trend by duration of exposure (p = 0-19) and
a suggested incr with longer latency (p = 0.07), but there was no overall trend
in risk of leukemia by intensity or frequency of exposure; nor did a cumulative
exposure analysis in the largest study indicate a quantitative association.
There was also an indication that ln two studies with Increased risks the
workers had been exposed to other potential carcinogens. For non-Hodgkin's
lymphoma there was a suggestive risk overall (SMR = 1.35, 95% CI 0.93-1.90).
Breakdowns by exposure intensity or frequency, exposure duration, or latency did
not indicate an association, but a positive trend by cumulative exposure (p =
0.05) was seen In the largest study. There was a suggested incr ln the overall
SMR for stomach cancer (SMR = 1.28, 95% CI 0.98-1.65 (CI 0.73-2.26 when
heterogeneity among the risk estimates was taken Into account)), but analyses by
intensity or duration of exposure or cumulative exposure did not support a
causal association for stomach cancer. The overall SMRs and exposure-response
analyses did not indicate a risk from EtO for pancreatic cancer (SMR = 0.98),
brain and nervous system cancer (SMR = 0.89), or total cancer (SMR = 0.94).
Although the current data do not provide consistent and convincing evidence that
EtO causes leukemia or non-Hodgkin's lymphoma, the issues are not resolved and
await further studies of exposed populations.
Ethylene oxide (EtO) induced
mutations in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene were
characterized in 28 independently derived 6-thioguanine resistant human diploid
fibroblast clones using polymerase chain reaction based techniques and Southern
blot analysis. Sequence analysis revealed one single base pair deletion and 13
base substitutions nine of which were transversions: five AT-TA three GC-TA and
one GC-CG. Four mutants were found to have GC-AT transitions. Seven of the point
mutations caused splicing errors. Six occurred in splice site sequences and one
created a new splice acceptor site 16 bp upstream of exon 9. Three splice
mutations were localized at the same site in the splice donor sequence of intron
8. Fourteen mutants had large HPRT gene deletions. In seven mutants the entire
HPRT gene was deleted. The remaining deletion mutants had a truncated HPRT gene
where one or several exons were lost. These results show that EtO induces many
different kinds of HPRT mutations, among which as many as 50% are large
deletions.
A cohort of 1971 chemical workers licensed to handle ethylene oxide was followed up retrospectively
from 1940 to 1984 and the vital status of each subject was ascertained. No
quantitative information on exposure was available and therefore cohort members
were considered as presumably exposed to ethylene oxide.
The cohort comprised 637 subjects allowed to handle only ethylene oxide and 1334 subjects who obtained
a license valid for ethylene oxide as
well as other toxic gases. Potential confounding arising from the exposure to
these other chemical agents was taken into consideration. Causes of death were
found from death certificates and comparisons of mortality were made with the
general population of the region where cohort members were resident. Seventy six
deaths were reported whereas 98.8 were expected; the difference was
statistically significant. The number of malignancies for any site exceeded the
expected number (standardized mortality ratio (SMR) = 130; 43 observed deaths;
95% confidence interval (95% CI) 94-175) and approached statistical
significance. For all considered cancer sites the SMRs were higher than 100 but
the excess was only significant p < 0.05, two sided test for lymphosarcoma
and reticulosarcoma ICD-9 = 200; SMR = 682; four observed deaths; (95% CI
186-1745) The excess of cases for all cancers of hematopoietic tissue (ICD-9)=
200-208) also approached statistical significance (SMR = 250; six observed
deaths; 95% CI 91-544).
Human Toxicity Values:
No effect level: 5-10 ppm, during 10 yr; severe toxic effects: 60 min 250
ppm= 450 mg/cu m; symptoms of illness: 100 ppm= 180 mg/cu m; unsatisfactory
>10 ppm= 18 mg/cu m
Skin, Eye and Respiratory Irritations:
Ethylene oxide is irritating to the
eyes, respiratory tract, and skin.
Aqueous solutions of ethylene oxide
or solutions formed when the anhydrous cmpd comes in contact
with moist skin are irritating and may lead to a severe dermatitis with
blisters, blebs and burns. It is also absorbed by leather and rubber and may
produce burns or irritation. Allergic eczematous dermatitis has also been
reported. Exposure to the vapor in high concn leads to irritation of the eyes.
Severe eye damage may result if the liquid is splashed in the eyes. Large
amounts of ethylene oxide evaporating
from the skin may cause frostbite.
Medical Surveillance:
Biological monitoring of ethylene oxide
exposure by analysis of alveolar air and blood was studied in 10
workers employed in a hospital sterilizer unit. Environmemtal air, alveolar air,
and venous blood were sampled during and at the end of an 8 hr workshift. The
mean environmental concentration of ethylene oxide
was 5.4 mg/cu m air and the mean alveolar ethylene oxide concentration was 1.2 mg/cu m
alveolar air. Regression analysis showed that blood ethylene oxide concentrations were higher than
environmental ethylene oxide
concentrations by a mean ratio of 3 and higher than alveolar
ethylene oxide concentrations by a mean
ratio of 12.
PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in
particular when exposure to a carcinogen has occurred, ad hoc decisions should
be taken concerning ... /cytogenetic and/or other/ tests that might become
useful or mandatory. /Chemical Carcinogens/
The 1984 OSHA standard for ethylene oxide
(EtO) mandates medical surveillance under various circumstances.
When performed medical surveillance for EtO must include a complete blood count
(CBC) with differential leukocyte count. This requirement is based on reports of
EtO associated absolute lymphocytosis and other hematologic effects. This paper
describes experiences in providing EtO medical surveillance for a 300 bed
hospital over a 6 year period. An apparent relative lymphocytosis which
persisted over 3-4 years in sterilization workers with documented TWA personal
EtO exposures averaging 0.07 ppm /was observed/. In addition three workers had a
history of acutely toxic overexposure to EtO as a result of a sterilizer
malfunction. These workers became symptomatic following the high accidental
overexposure but did not show absolute lymphocytosis or altered patterns in the
relative lymphocytosis. Finally a cross-sectional comparison of the CBC data
from the EtO exposed workers to data from non-EtO exposed hospital workers
showed no significant differences ruling out an association of the relative
lymphocytosis with EtO exposure. These observations led us to review the basis
for the inclusion of the CBC in routine EtO medical surveillance. /Such/
experience, review of the literature on EtO associated lymphocytosis and anemia,
and review of the literature on the use of the CBC with differential as
screening test suggest that the leukocyte differential may not be useful in
routine medical surveillance for EtO exposure.
In a study on workers in a chemical plant where ethylene oxide (EtO) is manufactured and
partly used for ethylene glycol production, exposure to EtO was monitored during
annual periodic health assessments In January 1988, December 1988, and March
1990 by the determination of the level of 2-hydroxyethylvaline in hemoglobin.
The 2-hydroxyethylvaline levels in workers corresponded with the potential EtO
exposures. The highest level was found in December 1988, in blood samples
collected 1-2 months after a shut down, maintenance, and start up program. The
range of adduct levels found in the three examinations indicated that average
EtO exposures during the 4 months preceding blood sampling were below 0.5 ppm.
It was demonstrated that the method allows for the accurate monitoring of low
levels of EtO exposure and provides personalized time integrated exposure data
with great discriminative power. In addition, the method may serve to identify
unexpected personal exposures, which may lead to targeted exposure control
measures.
Populations at Special Risk:
Ethylene oxide is a suspected
occupational toxicant of the male reproductive system indigenous to the
occupation of hospital sterilizers. /From table/
Industrial and occupational exposure is generally the result of inhalation of
ethylene oxide vapor released from
leaking or faulty equipment, valves, or fittings.
/Hospital workers/ operating a defective ethylene
oxide sterilizer.
Probable Routes of Human Exposure:
Exposure to ethylene oxide is
primarily occupational via inhalation. (SRC)
OSHA estimates that approximately 80,000 and 144,000 workers are directly and
indirectly exposed to ethylene oxide in
ethylene oxide production, chemical
synthesis by ethoxylation, health care facilities (sterilization), medical
products (sterilization) and miscellaneous manufacturers (e.g., spice
sterilization)(1). The number of workers exposed directly (indirectly) in the
various industries are: production and synthesis 3676; sterilization - health
care facilities 62,370 (25,000); sterilization - medical products manufacture
14,000 (116,900); sterilization - spice manufacturers 160(1). Typical exposures
are usually high during short periods in which sterilizer doors are opened,
typically 5-10 ppm for 20 minutes(1). Some typical survey results are: Medical
products manufactures 0.1.1-2.0 ppm 8 hr TWA; Hospital sterilizer chamber
operators 2.5 ppm TWA; 121 use sites in Southern California <5 ppm (TWA) in
114/121 sites; 2 hospitals 3-6 ppm and <5 ppm resp; survey of 27 hospitals
TWA exposures less than or equal to 1, <4 and >10 ppm in 9/27, 16/27 and
5/27, respectively(1). Union Carbide production plant in Texas City 5-33 ppm and
7.25 and 10.25 ppm avg in 2 control rooms and 0-56 ppm, 11.6 ppm avg throughout
plant(2). In-depth survey of 2 Union Carbide production facilities in West
Virginia- 2 of 48 and 4 of 41 samples positive, TWA exposure of positive samples
1.5-82 ppm(4,5). Production and maintenance workers in the 1960's avg exposure
levels 0.6-60 ppm(3).
NIOSH (NOES Survey 1981-1983) has statistically estimated that 50,132 workers
are exposed to ethylene oxide in the
USA(2). The personal 8-hr TWA exposure in 12 hospitals ranged from ND to 6.3 ppm
for sterilizer operators and ND to 6.7 ppm for folders and packers. Short term
(2 to 30 min) exposure levels for sterilizer operators ranged from ND to 103
ppm(1). Lower exposure levels were correlated with effective engineering
controls and good work practices, rather than with the size of the hospital, or
number or location of sterilizers.
Emergency Medical Treatment:
Emergency Medical Treatment:
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The following Overview, *** ETHYLENE OXIDE ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted. |
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o Early signs and symptoms of exposure to ethylene oxide
(ETO) may include eye, nose, and throat irritation and
noticing a sweet or peculiar taste in the mouth.
o Delayed effects may include headache, nausea, vomiting,
diarrhea, abdominal pain, dyspnea, cough, weakness,
lethargy, numbness, incoordination and vertigo. Acute
effects such as pneumonia, pulmonary edema, respiratory
failure, asthma, cardiac arrhythmias, seizures,
allergic reaction, paralysis and coma may also be seen.
o Direct contact with the eye can cause severe ocular
damage. Direct dermal contact with the gas or liquid
ethylene oxide can cause blistering, severe chemical
burns and tissue necrosis. Evaporation of the liquid
from the skin may cause frostbite.
o Occupational exposure to ethylene oxide may be linked
with spontaneous abortions and other adverse
reproductive effects. ETO is known to cause cancer in
laboratory animals and is a probable human carcinogen.
Leukemia and non-Hodgkin's lymphoma have been primarily
associated with ETO. Cases of Hodgkin's disease,
stomach, breast and pancreatic cancer, lymphosarcoma
and reticulosarcoma have also been reported.
o CNS and musculoskeletal abnormalities have been
reported in the offspring of laboratory animals.
VITAL SIGNS
0.2.3.1 ACUTE EXPOSURE
o Pulmonary irritation is likely after inhalation;
dyspnea may occur.
HEENT
0.2.4.1 ACUTE EXPOSURE
o Ocular irritation and conjunctivitis may be seen on
splash contact with the eyes. ETO has been implicated
as a causal agent for the formation of cataracts.
o Irritation of eyes, nose and throat, as well as a
peculiar taste, are the early symptoms of ethylene
oxide exposure.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Ethylene oxide has no appreciable effect on the
cardiovascular system until respiratory compromise is
serious enough to cause anoxia.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Pulmonary irritation is a common symptom after
inhalation. Pulmonary edema may be seen with acute
exposures. Pneumonia may be a complication of ethylene
oxide exposure. A rare report of asthma has also been
reported.
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Convulsive movements, twitching, malaise, lethargy,
headache, seizures, and dizziness have been reported.
Serious exposure may result in coma. Chronic exposure
may result in peripheral and central nervous system
effects, including neuropsychiatric symptoms, cognitive
dysfunction, and polyneuropathies.
0.2.7.2 CHRONIC EXPOSURE
o Various polyneuropathies, memory impairment, and mood
changes have been reported after chronic exposure.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Nausea, vomiting, and diarrhea may occur.
GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
o Severe cases of ethylene oxide exposure may result in
renal damage.
HEMATOLOGIC
0.2.13.1 ACUTE EXPOSURE
o Severe cases of ethylene oxide exposure may result in
cyanosis.
o Anemia developed in rats after chronic exposure.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Pure anhydrous ETO does not injure dry skin, but
solutions have a vesicant action. Exposure to the
liquid or gas may cause irritation or burns to moist
skin. ETO may also cause contact dermatitis, allergic
contact dermatitis, thermal burns, frostbite, edema,
erythema, vesiculation, blebs, and desquamation.
REPRODUCTIVE HAZARDS
o Ethylene oxide has been fetotoxic and teratogenic in
experimental animals.
CARCINOGENICITY
0.2.21.1 IARC CATEGORY
o IARC has classified ethylene oxide as Group 1
(carcinogenic to humans), based on limited evidence in
humans and sufficient evidence in experimental animals
(IARC, 2001).
0.2.21.2 HUMAN OVERVIEW
o Ethylene oxide has been linked with leukemia, stomach,
brain and pancreatic cancer, lymphatic cancer,
hematopoietic cancer, non-Hodgkin lymphoma, and
Hodgkin disease.
o The evidence for human and animal carcinogenicity and
for genotoxicity has been extensively reviewed (Their
& Bolt, 2000).
GENOTOXICITY
o MUTAGENIC effects due to ethylene oxide exposure have
been shown in non-mammalian animals. Many of the
observed mutagenic effects are a result of high
dose/short term exposure (Sheikh, 1984). Case studies
indicate ethylene oxide is fetotoxic (Sheikh, 1984).
In man, cytogenetic studies have shown increases in
sister chromatid exchanges, ethylene oxide-hemoglobin
adducts, micronuclei, chromosomal aberrations and DNA
strand breaks in those exposed to ethylene oxide (ACGIH,
1991; Baselt, 2000; Mayer et al, 1991; Schulte, 1995;
Landrigan et al, 1984). |
| Laboratory: |
o Chest film should be considered to evaluate the extent of
pulmonary involvement after inhalation. |
| Treatment Overview: |
ORAL EXPOSURE
o EMESIS - Oral exposure to ethylene oxide is unusual.
Because of the volatility of the liquid, and the extreme
reactivity of ethylene oxide, it is questionable whether
emesis would be of value. Activated charcoal may be of
more benefit.
o ACTIVATED CHARCOAL: Administer charcoal as a slurry
(240 mL water/30 g charcoal). Usual dose: 25 to 100 g
in adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
o CATHARTIC - Ethylene oxide is irritating and probably
serves as its own cathartic.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
o Clothing should be removed and washed thoroughly.
o TREATMENT - If significant amounts of ethylene oxide
have been inhaled, immediate hospitalization and
observation for 72 hours are recommended. There may be
delayed onset of pulmonary edema.
o ACUTE LUNG INJURY: Maintain ventilation and oxygenation
and evaluate with frequent arterial blood gas or pulse
oximetry monitoring. Early use of PEEP and mechanical
ventilation may be needed.
EYE EXPOSURE
o DECONTAMINATION: Irrigate exposed eyes with copious
amounts of tepid water for at least 15 minutes. If
irritation, pain, swelling, lacrimation, or photophobia
persist, the patient should be seen in a health care
facility.
DERMAL EXPOSURE
o DECONTAMINATION - If liquid is spilled on the skin,
allow ethylene oxide to vaporize before washing with
water. Dermal exposure should be washed with water,
from a hose or shower. A physician should examine the
exposed area if irritation or pain persists after the
area is washed. |
| Range of Toxicity: |
o 30 mg/kg caused nausea, vomiting, and diarrhea for 2 hours
in animals. The permissible exposure limit in air is 1
ppm as an eight hour TWA. The OSHA action level is 0.5
ppm. |
Antidote and Emergency Treatment:
Treatment consists of general supportive care.
Animal Toxicity Studies:
Evidence for Carcinogenicity:
A2; Suspected human carcinogen.
Evaluation: There is limited evidence in humans for the carcinogenicity of
ethylene oxide. There is sufficient
evidence in experimental animals for the carcinogenicity of ethylene oxide. In making the overall
evaluation, the Working Group took into consideration the following supporting
evidence. Ethylene oxide is a directly
acting alkylating agent that: (1) induces a sensitive, persistent dose-related
increase in the frequency of chromosomal aberrations and sister chromatid
exchange in peripheral lymphocytes and micronuclei in bone marrow cells of
exposed workers; (2) has been associated with malignancies of the lymphatic and
hematopoietic system in both humans and experimental animals; (3) induces a dose
related increase in the frequency of hemoglobin adducts in exposed humans and
dose related increases in the numbers of adducts in DNA and hemoglobin in
exposed rodents; (4) induces gene mutations and heritable translocations in germ
cells of exposed rodents; and (5) is a powerful mutagen and clastogen at all
phylogenetic levels. Overall evaluation: Ethylene oxide
is carcinogenic to humans (Group 1).
Non-Human Toxicity Excerpts:
Perturbations in bone marrow and peripherial blood elements of mice exposed
to ethylene oxide were evaluated. Mice
exposed to 225 ppm ethylene oxide for 6
hr/day were removed for analysis 1, 2, 4, 8, and 14 days and 4, 6, 8, and 10 wk
(5 day/week). Blood analysis included blood cell counts, hemoglobin
determination, and hematocrit. Bone marrow evaluation included stem-cell assay
(CFU-S) or flow cytometry analysis, cell cycle and B-cell analysis.
Perturbations of peripheral leukocytes occurred after one exposure. After
multiple exposures, hematocrit, red cell number, and hemoglobin were generally
depressed, with transient compensatory bursts, and bone marrow cellularity and
CFU-S were below normal. White cell numbers fluctuated dramatically during the
exposure period. There was a shift in the numbers of granulocytes in the bone
marrow followed by replacement and relative lymphocyte deficit, especially
pronounced at 10 wk.
Female mice of hybrid stocks (C3H x C57BL)F1 and (SEC x C57BL)F1 were exposed
to 300, 1200, or 1800 ppm of ethylene oxide
for various exposure periods. Exposed females were either mated
before or after treatment to male mice (C3H x C57BL)F1 and killed on the 17th
day after observation of a vaginal plug. Fetal abnormalities and mortality were
observed in both treatment groups. Early developmental stages of the zygote
appears to be more sensitive to the action of ethylene
oxide than later stages.
... REPEATED EXPOSURES OF RATS @ 400 PPM CAUSED RESP IRRITATION, WT LOSS,
WEAKNESS & DEATH. ... REPEATED EXPOSURES OF DOGS, RATS & MICE @ 100 PPM
FOR SIX MONTHS CAUSED NO SIGNIFICANT EFFECTS; HOWEVER, THERE WAS A SLIGHT ANEMIA
IN DOGS.
... THERE WAS IRRITATION OF RESP PASSAGES, INCLUDING THE LUNGS, IN ANIMALS
REPEATEDLY EXPOSED TO 204, 357 & 841 PPM ... IN ADDITION THERE WERE GROWTH
DEPRESSIONS, ORGAN WT CHANGES & ORGANIC INJURY TO THE LIVERS, KIDNEYS,
ADRENALS, & TESTES OF RATS & GUINEA PIGS.
Exposure of animals to high concn of the gas has caused lacrimation in cats,
and inflammation of the conjunctiva and clouding of the cornea in dogs, cats,
rabbits, and especially guinea pigs.
30 8-WK OLD FEMALE ICR/HA SWISS MICE WERE PAINTED THRICE WEEKLY ON CLIPPED
DORSAL SKIN WITH APPROX 0.1 ML OF 10% SOLN ... IN ACETONE FOR LIFE. MEDIAN
SURVIVAL TIME WAS 493 DAYS; NO SKIN TUMORS WERE OBSERVED.
12 RATS RECEIVED MAX TOTAL DOSES OF 1 G/KG BODY WT ... IN ARACHIS OIL BY SC
INJECTION ... PERIOD OF TREATMENT WAS 94 DAYS. ANIMALS WERE OBSERVED FOR
LIFETIME; NO LOCAL SARCOMAS WERE OBSERVED.
... 86 FEMALE SWISS-WEBSTER MICE, GERM-FREE & INBRED, WERE EXPOSED TO ...
ETHYLENE OXIDE TREATED GROUND-CORNCOB
BEDDING FOR 150 DAYS & THEN TO UNTREATED BEDDING FOR LIFESPAN (MAXIMAL, 900
DAYS); 63 MICE DEVELOPED TUMORS @ VARIOUS SITES. NO TUMORS WERE REPORTED IN 83
FEMALE MICE, 100-600 DAYS OLD, WHICH WERE NOT EXPOSED TO TREATED BEDDING ...
(THIS OBSERVATION DOES NOT ALLOW AN EVALUATION OF THE CARCINOGENICITY OF ETHYLENE OXIDE).
EXPOSURE OF MALE LONG-EVANS RATS FOR 4 HR TO 1.83 G/CU M (1000 PPM) ETHYLENE OXIDE PRODUCED DOMINANT LETHAL
MUTATIONS; CHROMOSOME ABERRATIONS WERE OBSERVED IN BONE-MARROW CELLS OF MALE
LONG-EVANS RATS EXPOSED TO 0.45 G/CU M (250 PPM) ETHYLENE OXIDE FOR 7 HR PER DAY FOR 3 DAYS.
TERATOGENIC POTENTIAL OF IV ADMIN WAS ASSESSED IN CD-1 MOUSE @ DOSE 0, 75,
& 150 MG/KG @ 4 PERIODS DURING GESTATION. RESULTS INDICATE TERATOGENICITY @
LEVELS 500-5000 TIMES ABOVE EXPOSURE LIMITS CURRENTLY PROPOSED BY FDA FOR ETO
RESIDUES IN MEDICAL DEVICES.
Ethylene oxide was reported positive
for mutagenicity test performed on bacteria, Neurospora, Drosophila, mammalian
cells.
Statistically significant increases in mononuclear cell leukemia in female
Fischer rats increased linearly with dose. Among male Fischer 344 rats in the
same experiment, ethylene oxide induced
peritoneal mesothelioma which originated in the testicular mesothelium.
Rats and mice exposed to ethylene oxide
had significantly increased numbers of polychromatic
erythrocytes containing micronuclei.
/Ethylene oxide/ was injected iv on
several days during organogenesis in the mouse. Skeletal malformations occurred
in fetuses whose mother received 150 mg/kg which produced maternal toxicity.
Doses of 75 mg/kg caused no defects. Rats /were/ exposed on days 6-15 of
gestation for 6 hr daily to 10-100 ppm. At the highest dose, fetal growth
retardation occurred but there was no increase in congenital defects.
Ethylene oxide was administered
intragastrically by gavage at 2 dosages, 30 and 7.5 mg/kg body weight to groups
of 50 female Sprague-Dawley rats twice weekly for a period of nearly 3 years
using salad oil as the solvent. It induced local tumors, mainly squamous cell
carcinomas of the forestomach, dependent on the dosage. The first tumor occurred
in the 79th week. The following tumor rates resulted 62 and 16%. In addition
carcinomata in situ, papillomas and reactive changes of the squamous epithelium
of the forestomach were observed in other animals, but ethylene oxide did not induce tumors at sites
away from the point of administration.
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 6 hr daily, 5 days/wk, for up to 2 yr. Three
representative sections of the brain from each rat were evaluated. Of 23 primary
brain tumors which were found, 2 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 ethylene exposure > 10
ppm was related to the development of these brain tumors.
In a dose-response study, male mice were exposed to inhalation of ethylene oxide for 4 consecutive days. Mice
were exposed for 6 hr per day to 300 ppm, 400 ppm, or 500 ppm ethylene oxide for a daily total of 1,800,
2,400, or 3,000 ppm per hr, respectively. In the dose-rate study, mice were
given a total exposure of 1,800 ppm per hr per day delivered either at 300 ppm
in 6 hr, 600 ppm in 3 hr, or 1,200 ppm in 1.5 hr. Quantitation of
dominant-lethal responses was made on matings involving sperm exposed as late
spermatids and early spermatozoa, the most sensitive stages to ethylene oxide. In the dose-response study, a
dose related increase in dominant-lethal mutations were observed, the
dose-response curve proved to be nonlinear. In the dose-rate study, increasing
the exposure concentrations resulted in increased dominant-lethal responses.
The offspring of DBA/2J male mice exposed to ethylene
oxide (ETO) by inhalation had an increased incidence of both
dominant visible and electrophoretically detected mutations over that found in
control populations. The progeny at risk were obtained from matings during the
exposure period and were the products of germ cells that were exposed throughout
the entire spermatogenic process. Apparently, male germ cells repeatedly exposed
to ethylene oxide during spermatogenesis
are susceptible to ethylene oxide
induced transmissible damage.
Ethylene oxide at 357 ppm 35 hr/week
for 12 weeks produced a sensorimotor neuropathy in rats, rabbits, and monkeys,
but not guinea pigs or mice. Continued exposure resulted in paralysis and muscle
atrophy of the hindlimbs. At 204 ppm, 35 hr/wk for 32 weeks, rabbits and
monkeys, but not guinea pigs, rats, or mice, developed a clinical neuropathy.
The monkeys had decreased tendon reflexes, loss of withdrawal from superficial
pain over the hindquarters, partial paralysis, and muscle atrophy indicative of
toxic axonopathy. A positive Babinski reflex in these monkeys indicated that
upper motor neurons or their axons were also affected. Dogs showed occasional
tremors, transient weakness, atrophy and fatty replacement of skeletal muscle
following ethylene oxide exposures of
292 ppm, 30 hr/week for 6 weeks. Levels of about 100 ppm repeatedly were without
neurotoxicity in rats, rabbits, guinea pigs, mice, dogs, and monkeys.
The results of efforts to identify and quantify macromolecular adducts of
ethylene oxide, to determine the source
and significance of background levels of these adducts, and to generate
molecular dosimetry data on these adducts are reviewed. A time-course study was
conducted to investigated the formation and persistence of 7-(2-hydroxyethyl)
guanine in various tissues of rats exposed to ethylene
oxide by inhalation, providing information necessary for
designing investigations on the molecular dosimetry of adducts of ethylene oxide. Male F344 rats were exposed 6
hr/day for up to 4 weeks (5 days/wk) to 300 ppm ethylene
oxide by inhalation. Another set of rats was exposed for 4 weeks
to 300 ppm ethylene oxide, and then
killed 1-10 days cessation of exposures. DNA samples from control and treated
rats were analyzed for 7-(2-hydroxyethyl)guanine using neutral thermal
hydrolysis, HPLC separation, and fluorescence detection. The adduct was
detectable in all tissues of treated rats following 1 day of ethylene oxide exposure and increased
approximately linearly for 3-5 days before the rate of increase began to level
off. Concentrations of 7-(2-hydroxyethyl)guanine was greatest in brain, but the
extent of formation was similar in all tissues studied. The adduct disappeared
slowly from DNA, with an apparent half-life of approx 7 days. The shape of the
formation curve and the in vivo half-life indicate that
7-(2-hydroxyethyl)guanine will approach steady-state concentrations in rat DNA
by 28 days of ethylene oxide exposure.
The similarity in 7-(2-hydroxyethyl)guanine formation in target and nontarget
tissues indicates that the tissue specificity for tumor induction is due to
factors in addition to DNA-adduct.
The utility of hemoglobin as a DNA monitor in cases of exposure to ethylene oxide was investigated in rats via
use of an inhalation system with dynamically generated test atmospheres. Animals
were exposed to atmospheres containing 1, 10, or 33 ppm radiolabeled ethylene oxide for 6 hours. After exposure,
the animals were sacrificed and the organs removed for isolation of DNA. DNA
hydrolysates and adducts were further analyzed by high pressure liquid
chromatography. Globin was isolated from pooled erythrocytes. The relationship
between inhalation doses of ethylene oxide
and alkylation DNA and globin was described in terms of moles of
adduct per gram of DNA or globin. Linear relationships were observed between
formation of hydroxyethyl adducts in both DNA and hemoglobin and the exposure
concentration of radiolabeled ethylene oxide.
Alkylation frequencies of DNA were similar in all tissues
studied with exception of testis; corresponding alkylation in hemoglobin was not
significantly different. Results indicate that the results support the
suggestion that, in the case of ethylene oxide
exposure, determination of the hemoglobin dose in vivo is a
valid indicator of the dose delivered to DNA.
Exposure of female mice to ethylene oxide
by inhalation 1 or 6 hr after mating produced not only
multitemporal death of conceptuses but also high rates of abnormalities among
surviving fetuses. In contrast, only marginal effects were observed when females
were exposed 9 or 25 hr after mating. The abnormalities found among 17 day
gestation live fetuses were predominated by hydrops and eye defects, which,
together, constitute 54% of all anomalies. Most of the remaining anomalies were
distributed among 5 other types: small size, cleft palate, and cardiac,
abdominal wall, or extremity and/or tail defects. In a follow-up study the
fetuses of females treated 6 hr postmating were examined at 11-15 days gestation
and the progression of fetal death and of malformations was studied. Results
indicate that the expression of most fetal anomalies does not become apparent
until late in gestation. Several of these induced anomalies are similar to
common human sporadic birth defects. This new class of experimentally induced
fetal anomalies provides a new avenue for investigating zygotic biology and a
system for studying the progression of aberrant development.
Wistar male and female rats were exposed to ethylene
oxide at a concentration of 250 ppm, 6 hours a day, 5 days a
week for 17 weeks simultaneously, and the sex difference of anemia induced by
ethylene oxide was investigated.
Hemoglobin concentrations of both the male and female exposed groups were
decreased when compared with each control group, and the anemia in the female
exposed group was more severe than that in the male exposed group. Absolute
spleen weight increased only in the female exposed group. We have already
reported that a decrease of the glutathione reductase activity in the
erythrocyte plays an important role in the ethylene
oxide induced anemia. In the present study, the activity in both
male and female exposed groups decreased when compared with each control group,
and there was no sex difference in the degree of the decrease. From these
observations, /it was/ concluded that there was a sex difference in the ethylene oxide induced anemia.
The effect of chronic inhalation of ethylene oxide
on urinary coproporphyrin and delta- aminolevulinic acid were
studies. When Wistar male rats were exposed to 500 ppm ethylene oxide three times a week, daily urine
volume was increased by 200-300% from the first week to the fifth week of the
experimental period. After exposure, daily coproprorphyrin excretion and urinary
coproporphyrin per mg of creatinine increased by 250% and 141%, respectively. On
the other hand, daily excretion of delta-aminolevulinic acid in urine tended to
increase but did not increase significantly by creatinine correction. This /may
be/ the first report of ethylene oxide
induced experimental porphyria.
Male Wistar rats were exposed to ethylene oxide
at concentrations of 50, 100, or 250 ppm for six hours a day, on
five days a week for 13 weeks. Dose effect relations of inhaled ethylene oxide on spermatogenesis were
evaluated from testicular and epididymal weights, histopathological changes and
lactate dehydrogenase X (LDH X) activity in the testis, and sperm counts and
sperm head abnormalities in the epididymis. At 250 ppm, a decrease in epididymal
weights, slight degenerations in the seminiferous tubules, decreased sperm
counts, and increased numbers of abnormal sperm heads in the tail of the
epididymis were found; these were not seen at lower doses. When the abnormal
sperm heads were classified into immature types and teratic types, the number of
immature heads increased only at 250 ppm. On the other hand, the teratic type
had increased at doses of 50 and 100 ppm ethylene oxide
when compared with the control group. Hence, subchronic
inhalation of ethylene oxide at low
concentrations affects spermatogenesis in rats.
The effects of systemic toxicity including reproductive toxicity of ethylene oxide on female rats were studied.
When Wistar female rats were exposed to 250 ppm of ethylene oxide for six hours a day, five days
a week for ten weeks, they showed inhibition of body weight gain and paralysis
of the hindlegs. Hematogological examination revealed macrocytic and
normochromic anemia with high reticulocyte counts. The estrus cycle of the
exposed group was prolonged and the percentage of the diestrus stage increased.
There was no atrophy in the ovary or the uterus. However, the activity of
glutathione reductase in the ovary decreased by 18% and that of
glutathione-S-transferase increased by 30%. These results indicate that ethylene oxide has a similar effect on both
female and male rats and that the female reproductive system is also affected.
The toxic effects of residual ethylene oxide,
a frequently used gas-sterilant, on embryos either frozen for
long-term purposes or stored acutely for 30 min to 9 hr in a fresh condition in
0.25 ml straw containers were evaluated. In Experiment 1, fresh embryos were
frozen (using conventional technology) in straws previously aerated for 0 hr to
8 mo after ethylene oxide sterilization.
With the exception of the 8 mo group in which survival and quality ratings were
depressed, embryo viability was not affected significantly by short-term
prefreeze and post-thaw exposure to ethylene oxide
residues. Experiment 2 was conducted to analyze the influence of
prefreeze exposure to ethylene oxide
residues on embryo development in vitro for embryos temporarily
stored in previously sterilized straws aerated for different intervals. Compared
to non-ethylene oxide sterilized control
straws, the development, quality, and viability of embryos exposed to ethylene oxide-treated straws were compromised
(p less than 0.05) as the aeration interval decreased and the exposure interval
increased. The combined results of both experiments indicate that ethylene oxide-treated straws can be used to
cryopreserve gametes efficiently, but only if the aeration interval is greater
than or equal to 72 hr and the prefreeze duration of exposure is less than or
equal to 3 hr.
Thirty B6C3F1 mice of both sexes that were exposed at ethylene oxide vapor concentrations of 1, 10,
50, 100, or 250 ppm, 6 hours/day, 5 days/week for 10 to 11 weeks showed no
effects on survival, body weight, or histologic sections of various organs.
Neuromuscular toxicity was observed at the three highest exposure levels, and
both sexes in the 250 ppm exposure group had a statistically significant
increase in hunched posture, reduced locomotion, and righting reflex. These
symptoms were also observed in some animals of both sexes exposed at 50 or 100
ppm. Neuromuscular effects appeared to be the most sensitive indicator of
exposure to ethylene oxide in this
study.
When ethylene oxide/saline solutions
of varied concentrations (0.1% to > 20%) were applied repeatedly over a
6-hour period to the eyes of rabbits, a dose-dependent increase in congestion,
swelling, discharge, iritis, and corneal cloudiness was observed. These effects
were an indication of the irritating effect of ethylene
oxide on mucous membranes and corneal epithelium. The 0.1% ethylene oxide concentration was the maximum,
nondamaging concentration of this chemical for the 6 hour exposure period.
Infusion of ethylene oxide into the
aorta of rats caused a significant decrease (approximately 30%) in kidney
glomerular filtration rates, resulting in kidney dysfunction.
Pathological examination of tissues from mice, rats, and guinea pigs that
died after lethal exposure to ethylene oxide
revealed adverse effects that included lung congestion,
hyperemia of the liver and kidneys, and gray discoloration of the liver. Animals
that experienced delayed death had emphysema of the lungs, fatty degeneration of
the liver, cloudy swelling of the kidney tubules, and congestion of the spleen
and brain, all believed to be a cause or contributing to these deaths.
Mice, rats, guinea pigs, rabbits, and dogs exposed to lethal concentrations
of ethylene oxide had symptoms of mucous
membrane irritation, central nervous system (CNS) depression, lacrimation, nasal
discharge, salivation, nausea, vomiting, diarrhea, respiratory irritation,
incoordination, and convulsions. Surviving animals showed subsequent bronchitis,
pneumonia, and loss of appetite with delayed symptoms of apathy, dyspnea,
vomiting, paralysis (particularly of the hindquarters), and periodic
convulsions, followed eventually by death. Rapid deaths were usually associated
with lung edema; delayed deaths frequently resulted from secondary infections in
the lungs, although general systemic intoxication is also believed to be
associated with these delayed deaths.
... Fischer 344 rats, 120 rats/sex/group, /were exposed/ at 10, 30, or 100
ppm ethylene oxide vapor, 6 hours/day, 5
days/week for 2 years. Two groups of controls were exposed to untreated air
under similar conditions. Ten animals each at 6 and 12 months and 20 animals at
18 months were sacrificed to determine possible treatment-related effects. Both
interim and terminal evaluations included hematology, serum clinical chemistry,
urinalysis, body weight, organ weight, bone marrow cytogenicity studies, and
gross and histologic examinations. Histopathologic examinations of rat tissue
from the 100 ppm ethylene oxide exposed
animals and the control group were performed at 6, 12, and 18 month necropsy
intervals. At the 24 month sacrifice, histopathologic examination was made on
all tissues of the 100 ppm exposed rats as well as controls and on potential
target tissues, other selected tissues, and tissues with gross lesions in the 10
and 33 ppm exposed animals. The six types of tumors found in the ethylene oxide exposed rats that appear to be
treatment related are subcutaneous fibroma, peritoneal mesothelioma, pancreatic
adenoma, pituitary adenoma, brain neoplasm, and mononuclear cell leukemia. In
this 2-year study, a dose-related increased incidence of mononuclear cell
leukemia was found in both sexes. It was significant in the 100 and 33 ppm
exposed females from the 18th or 19th month onward. A trend test revealed a
treatment-related response in both sexes. An increased incidence of peritoneal
mesotheliomas originating from the testicular mesothelium was found in males
exposed at 33 and 100 ppm from the 23rd month onwards and an increased incidence
of subcutaneous fibroma in males surviving the 24-month, 100 ppm exposures.
There was no increased incidence of pituitary tumors, although they appeared
earlier in the 100 ppm exposed group.
No specific testicular damage was seen in test animals exposed at nontoxic
doses of ethylene oxide. When maternally
toxic doses of ethylene oxide were
administered intravenously in mice, embryo and fetal toxicity were found.
Pregnant rats inhaling ethylene oxide
had a reduction in fetal weight but no teratogenic effects.
Earlier studies ... revealed that ethylene oxide
or ethyl methanesulfonate induced high frequencies of
midgestation and late fetal deaths and of malformations among some of the
surviving fetuses when female mice were exposed at the time of fertilization of
their eggs or during the early pronuclear stage of the zygote. Effects of the
two mutagens are virtually identical. Thus ln investigating the mechanisms
responsible for the dramatic effects ln the early pronuclear zygotes the two
compounds were used interchangeably in the experiments. First a reciprocal
zygote-transfer study was conducted in order to determine whether the effect is
directly on the zygotes or Indirectly through maternal toxicity. And second
cytogenetic analyses of pronuclear metaphases early cleavage embryos and
midgestation fetuses were carried out. The zygote transplantation experiment
rules out maternal toxicity as a factor ln the fetal maldevelopment. Together
with the strict stage specifically observed in the earlier studies this result
points to a genetic cause for the abnormalities. However the cytogenetic studies
failed to show structural or numerical chromosome aberrations. Since intragenic
base changes and deletions may also be ruled out it appears that the lesions in
question induced In zygotes by the two mutagens are different from conventional
ones and therefore could be a novel one ln experimental mammalian mutagenesis.
A ... 2-year carcinogenic study involved male Fischer 344 rats (80 in each
group) and 12 Cynomolgus-monkeys per group exposed at either 50 or 100 ppm ethylene oxide 7 hours/day, 5 days/week for 24
months. Rats exposed at 50 ppm had a significantly increased incidence of
mononuclear cell leukemia. The absence of a dose-response relationship was
attributed to an increased mortality rate for the rats exposed at 100 ppm.
Peritoneal mesotheliomas originating from the testicular mesothelium and mixed
cell gliomas in the brain were found in a dose related increased incidence that
was statistically significant for the 100 ppm exposure group. Exposures at the
50 and 100 ppm concentrations also reduced body weight gain and had an adverse
effect upon the survival rate of the rats compared to the controls. Mortality
was dose-dependent. Peritoneal mesotheliomas and gliomas are tumor types that
can be found in humans. The 50 or 100 ppm exposed monkeys did not show any
significant changes in hematological, clinical or urine chemistry, or
ophthalmological parameters. At 100 ppm, nerve conduction velocities were
decreased, and evidence of neurotoxicity and demyelination was noted in the 50
ppm and 100 ppm exposure groups. Sperm counts and motility were also reduced,
and both exposure concentrations caused significant increases in the incidence
of sister-chromatid exchanges (SCE) and chromosomal aberrations.
... Monkeys /were exposed/ at 50 or 100 ppm ethylene
oxide for 7 hours/day, 5 days/week for 2 years. ... Data /were
collected/ in 1987 for sister chromatid exchanges (SCE) in peripheral blood
lymphocytes and compared these data with those generated immediately prior to
cessation of the 2 year exposure in 1981. Ethylene oxide
induced SCE persisted at levels significantly higher than those
of the nonexposed controls. These findings indicate that long lived lymphocytes
may not be efficient with repair of the ethylene oxide
induced lesions which produce SCE.
Male mice were exposed to ethylene oxide
for 6 hours/day on 4 consecutive days at 300, 400, or 500 ppm
for a daily total of 1800, 2400, or 3000 ppm hours (total exposures of 7200,
9600, and 12,000 ppm hours), respectively. A dose related increase in
dominant-lethal mutations was observed; the dose response curve proved to be
nonlinear. In a dose rate study, mice were given a total exposure of 1800 ppm
hours per day for 4 consecutive days. This exposure was delivered at 300 ppm for
6 hours, 600 ppm for 3 hours, or 1200 ppm for 1.5 hours. Increasing the exposure
concentrations resulted in increased dominant lethal responses even when the
total dose was the same.
When freshly prepared aqueous solutions (2 to 5 percent) were injected
intravenously into dogs, the LD50 was found to be about 125 mg/kg. A dose of 30
mg/kg or more usually caused vomiting and defecation for about 2 hr, followed by
weakness and flaccidity, usually apparent in the hind limbs first. Doses up to
100 mg/kg in dogs under barbiturate anesthesia caused no apparent changes in
blood pressure or cardiac rate. Respiration is adequate until terminal stages,
when it becomes labored and cyanosis develops. Tonic extensor spasm may precede
respiratory cessation. Since the heart usually beats after all reflexes
disappear, death is believed due to respiratory failure .
... In aqueous solution the maximum concentration that could be applied
externally to the ... /eyes of rabbits/, one drop every 10 minutes for 6 hours,
without causing damage to the conjunctiva was 0.1%, to the cornea was 1%, and to
the lens or retina was 20%. ... /Also/ if the aqueous humor was replaced once
with an aqueous solution of ethylene oxide
the maximum nondamaging concentration for the iris and lens was
0.1%, and for the cornea was 1%. At higher concentrations, damage consisted of
irreversible opacities of cornea and lens.
Ethylene oxide is a classical mutagen
and a carcinogen based on evidence from studies in experimental animals. Chinese
hamster V79 cells were treated for 2 hr with gaseous ethylene oxide, in sealed treatment chambers,
and assayed for survival and mutagenic response by analysis of induced
resistance to 6-thioguanine or ouabain. Significant numbers of mutants were
produced at both genetic markers by 1,250-7,500 ppm ethylene oxide. Similarly, primary Syrian
hamster embryo cells were treated for 2 or 20 hr with gaseous ethylene oxide in sealed treatment chambers
and subsequently assayed for survival and increased sensitivity to SA7 virus
transformation. Treatment concentrations extended from toxic to several nontoxic
concentrations. After 2 hr ethylene oxide
treatment at 625-2,500 ppm a significant enhancement of virus
transformation was observed. At 20 hr after treatment no enhancement was
observed. Treatment of hamster cells with ethylene oxide
in both bioassay systems yielded concentration-related,
quantitative results.
In mice exposed by inhalation for 5 hr/day, 5 days/week, for 10 weeks to 250,
100, 50, 10, or 0 ppm epoxyethane in
air, clinical significant pathological findings were limited to the group
exposed to 250 ppm. These findings included minimal decreases in red blood cell
count, packed cell volume, and hemoglobin; decreased testicular and spleen
weights; and increased liver weight. Abnormal pinch and righting reflexes,
posture, and locomotion were also observed in mice exposed to 250 ppm. However,
histological sections of the liver, testis, bone marrow, brain, and spleen taken
from these mice were normal.
Groups of 120 male and 120 female Fischer 344 rats, eight weeks of age, were
exposed by inhalation to ethylene oxide
(purity, > 99.9%) vapor at 10, 33 or 100 ppm (18, 59 or 180
mg/cu m) for 6 hr per day on five days per week for two years. Two control
groups, each of 120 male and 120 female rats, were exposed in inhalation
chambers to room air. All animals that died or were killed when moribund and
those killed at scheduled intervals of 6, 12, 18 an 24-25 months were examined.
During month 15 of exposure, mortality increased in both treated and control
groups due to a viral sialodacryoadenitis. Mortality was higher in the groups
inhaling 33 and 100 ppm ethylene oxide
than in the other groups and was more frequent in females than
in males near the fifteenth month. Up to 18 months of exposure, no significant
increase in tumor incidence was observed. In treated rats killed after 18
months, the incidence of tumors in the brain classified as gliomas, malignant
reticulosis and granular-cell tumors was increased for animals of each sex. The
incidences of glioma among rats killed at 18 and 24-25 months were: males: 1/181
(controls), 0/92 (10 ppm), 3/86 (33 ppm) and 6/87 (100 ppm) (p < 0.05, trend
analysis and Fisher's exact test for high dose versus control); and females:
0/187 (controls), 1/94 (10 ppm), 2/90 (33 ppm) and 2/78 (100 ppm) (p < 0.05,
trend analysis). In females killed after 24 months of exposure mononuclear-cell
leukaemia was found in 5/60 (control I), 6/56 (control II), 11/54 (10 ppm),
14/48 (33 ppm) and 15/26 (100 ppm) animals; the incidence of leukaemia was
reported ... to be significantly increased in the 100 ppm group (p < 0.001)
and in a mortality adjusted trend test (p < 0.005). In males,
mononuclear-cell leukaemia was found in 5/48 (control I), 8/49 (control II),
9/51 (10 ppm), 12/39 (33 ppm) and 9/30 (100 ppm) animal (p < 0.05 in a
mortality adjusted trend test). Peritoneal mesotheliomas originating in the
testicular serosa were found in 1/48 (control I), 1/49 (control II), 2/51 (10
ppm), 4/39 (33 ppm) and 4/30 (100 ppm) males (p < 0.005 trend test). The
incidence of subcutaneous fibromas in male rats of the high-dose group was also
significantly increased: 1/48 (control I) 2/49 (control II), 9/51 (10 ppm), 1/39
(33 ppm) and 11/30 (100 ppm) (p < 0.001).
The effects of repeated exposure to ethylene oxide
on lipid peroxidation and glutathione metabolism in both rat
liver and brain were examined. Increased levels of malondialdehyde in the liver
were observed after 6 and 13 weeks of exposure to ethylene oxide. The increased level of
malondialdehyde observed in the hepatic homogenates of the treated rats
reflected that of the microsomal fraction. On the other hand, no change in the
level of malondialdehyde was detected in the brain of rats either at a 6- or
13-week treatment. Glutathione reductase activity was found to decrease at 6 or
13 weeks in liver and brain of treated rats. Both reduced and oxidized forms of
glutathione in homogenates of liver and brain obtained from treated rats were,
however, similar to those of the control at 40 hr after the last exposure in
individual experiments. To elucidate the cause of lipid peroxidation, the time
course of glutathione content after exposure with ethylene oxide were studied in more detail.
Significant decreases in both GSH and GSSG content in these organs were detected
shortly after exposure to ethylene oxide
and their levels recovered gradually with time and reached the
control values at 40 hr in the liver, although the changes were less significant
in the brain as compared with those in the liver. These results suggest that
enhancement of lipid peroxidation in the microsomal fraction of the liver after
repeated exposure to ethylene oxide may
possibly arise from repeated depletions of glutathione to certain critical
levels and less removal of lipid peroxidation.
This paper describes a dominant neurological mutation identified among the
progeny of a male parent treated with ethylene oxide.
The defects observed in the heterozygous mutant include: head
tossing, poor limb coordination, and corneal clouding. Both the behavior and
ocular manifestations of the mutant syndrome worsen progressively as the
affected animals grow older. The mutant animals swim poorly, although they do
orient themselves in reference to the surface of the water. Breeding in general
is poor. Very small litter sizes result when heterozygous animals of either sex
are mated to normal mice. Many male carriers are functionally sterile. All
mutant animals had abnormal karyotypes. The original carrier mouse had a
translocation between chromosomes 4 and 17, which was also present in all but
one mutant animal. The exceptional animal, which showed all mutant behavior
characteristics, had 41 chromosomes, which included two normal 4 and 17 homologs
and the small 417 translocation chromosome. Karyotypes of unaffected siblings of
mutants were normal. ...
Male Fischer and B6C3Fl mice (10/species/group) were exposed to ethylene 6
hr/day, 5 days/week, for 4 weeks. The ethylene target concentrations were 0, 40,
1000, and 3000 ppm. An ethylene oxide
(EO) control group for each species was exposed under the same
conditions at a target concentration of 200 ppm. Bone marrow was collected
approximately 24 hr after the final exposure. Polychromatic erythrocyte (PCE) to
normochromatic erythrocyte (NCE) ratios were determined and 2000 PCE/animal were
scored for the presence of micronuclei. Ethylene did not produce statistically
significant, exposure-related increases in the frequency of micronucleated PCE
(MNPCE) in the bone marrow of either rats or mice when compared to air exposed
control animals. As expected, EO exposure resulted in significant increases in
the frequencies of MNPCE in both species.
... Conclusions: Under the conditions of these 2 yr inhalation studies, there
was clear evidence of carcinogenic activity for B6C3F1 mice as indicated by dose
related incr incidences of benign or malignant neoplasms of the lung and benign
neoplasms of the harderian gland in both male and female B6C3F1 mice following
exposure to ethylene oxide vapors at 50
and 100 ppm. In female mice, ethylene oxide
caused additional malignant neoplasms of the uterus, mammary
gland, and hematopoietic system (lymphoma).
National Toxicology Program Studies:
... Toxicology and carcinogenesis studies of ethylene
oxide (greater than 99% pure) were conducted by exposing groups
of 50 B6C3F1 mice of each sex to air containing 0, 50, or 100 ppm ethylene oxide, 6 hours per day, 5 days per
week for 102 wk. ... Conclusions: Under the conditions of these 2 yr inhalation
studies, there was clear evidence of carcinogenic activity for B6C3F1 mice as
indicated by dose related incr incidences of benign or malignant neoplasms of
the lung and benign neoplasms of the harderian gland in both male and female
B6C3F1 mice following exposure to ethylene oxide
vapors at 50 and 100 ppm. In female mice, ethylene oxide caused additional malignant
neoplasms of the uterus, mammary gland, and hematopoietic system (lymphoma).
Ethylene oxide (ETO) ... was
evaluated for toxic and teratogenic effects in artificially inseminated New
Zealand white (NZW) rabbits which were matched for body weight across treatment
groups on gestational day (gd) 0. Ethylene oxide
in 5% dextrose was administered daily in a volume of 1 ml/kg of
body weight on gestational day 6 through 14 at dosages of 0, 9, 18 or 36
mg/kg/day, iv, or on gestational day 6 through 9 at dosages of 0, 18 or 36
mg/kg/day, iv. ... Administration of ethylene oxide
(0, 9, 18 or 36 mg/kg/day, iv) on gestational days 6-14 resulted
in mortality rates of 0% (0/27), 8.3% (2/24), 4.2% (1/24) and 22.2% (6/27), for
the control through high-dose groups, respectively. Measures of maternal body
weight (gestational days 14 and 30), maternal weight gain (i.e., weight gain
during gestation, weight gain during treatment and absolute weight gain) and
gravid uterine weight were each decreased in a dose-related manner. Examination
of uterine contents on gestational day 30 revealed significant dose-related
increases in the percentage of resorptions, nonlive and affected fetuses per
litter. Average live litter size was decreased in a dose-related manner, as was
the percentage of males per litter. No evidence of a treatment-related
teratogenic effect observed, even at dosages which produced maternal and fetal
toxicity. Maternal toxicity related to ethylene oxide
(0, 18 or 36 mg/kg/day, iv) administered on gestational days 6-9
was limited to localized inflammation at the injection site for 1/23
confirmed-pregnant females in the high-dose group. Maternal weight gain during
treatment and during gestation were reduced in a dose-related manner, but
absolute maternal weight gain was not affected. At sacrifice on gestational day
30, examination of the uterine contents failed to reveal any evidence of a
fetotoxic or teratogenic effect. In conclusion, no evidence for a teratogenic
effect of ethylene oxide was observed
when the compound was administered intravenously to NZW rabbits on gestational
days 6-14 or gestational days 6-9 of gestation.
Non-Human Toxicity Values:
LC50 Rat 1460 ppm (Exposure: 882-2298 ppm/4 hr). Effects were ocular and
respiratory irritation, diarrhea, increased activity. /From table/
LC50 Mouse 835 ppm (Exposure: 533-1365 ppm/4 hr). Effects were ocular and
respiratory irritation, increased activity. /From table/
LD50 Rat oral 330 mg/kg
LC50 Rat inhalation 1462 ppm/4 hr
LC50 Mouse inhalation 836 ppm/4 hr
LC50 Dog inhalation 973 ppm/4 hr
LD50 Guinea pig oral 270 mg/kg
Ecotoxicity Values:
LC50 Goldfish 90 mg/l/24 hr modified ASTM D 1345
TSCA Test Submissions:
Chronic toxicity was evaluated