79 

Propylene oxide (PO) 

by Paul A. Schulte PhD, Kari Hemminki PhD, and Nancy B. Hopf PhD 

Citation for most recent IARC review 

IARC Monographs 60, 1994 

Current evaluation: 

Conclusion from the previous Monograph 

Propylene oxide is possibly carcinogenic to humans (Group 2B). 

There is inadequate evidence in humans for the carcinogenicity of propylene oxide. 

There is sufficient evidence in experimental animals for the carcinogenicity of propylene 

oxide. 

Exposure and biomonitoring 

Biomarkers of exposure or effect

There are three biomarkers of effect currently being applied to measure PO exposure in 

humans: DNA adducts, hemoglobin adducts, and sister chromatid exchanges (SCE). These 

effect biomarkers integrate exposure for different time intervals, and correlation between all 

three end points is not expected.

DNA adducts of propylene oxide are formed in various organs of mice, rats and dogs. PO 

binding in mouse liver DNA was about one-twentieth that of ethylene oxide (EO). The major 

adduct formed in DNA after in vitro reaction of PO is 7-HP-guanine, followed by the adducts 

3-HP-, 1-HP-adenine, and 3-HP-cytosine. These adducts are chemically unstable: 7-HPguanine and 3-HP-adenine will depurinate, forming apurinic sites, and 1-HP-adenine and 3-

HPcytosine will spontaneously convert to N6-HP-adenine and 3-HP-uracil, respectively. The 

level of 1-HP-adenine corresponded to 2% of 7-HP-guanine. 1-HP-adenine is chemically 

more stable (t1/2 = 9.2 days for rearrangement to an N6 adduct compared with t1/2 = 5 days for 

depurination of 7-HP-guanine). Therefore, this minor adduct could be an alternative for 

monitoring PO exposures (Czene et al., 2002 and references therein). DNA adducts are 

subject to DNA repair and necrosis of the cell, which will alter the cumulative dose estimate 

depending if the exposure is intermittent (allowing for DNA repair time) or constant (no DNA 

repair time). 

PO forms adducts with albumin and hemoglobin (Hb) in man, dog, rat and mouse. Adducts to 

Hb are especially suitable because small molecules such as PO form chemically stable 

adducts with the N-terminal valine of Hb, N-(3-hydroxypropyl)valine (HOPrVal). 

Concentration of HOPrVal (Hb) is linearly related to air concentrations of PO (see below 

Boogaard et al., 1999). These adducts do not appear to affect the average life span of the 

erythrocytes. The exposure dose as measured by determination of Hb-adduct concentrations is 

integrated over the average life span of human erythrocytes, which is approximately 120 days. 
80 

Hb-adducts are not subject to repairs and therefore a cumulative dose over the past 120 days 

is achieved. 

PO may cause SCE, which is a nonmutational genotoxic event (do not alter genetic 

information); however, when they arise in vivo, they do indicate that a putative 

mutagen/carcinogen has reached the critical cellular target for direct genotoxicity. SCE is not 

specific to PO exposures, and may be caused by other chemicals. 

For dose estimates, monitoring Hb adducts is preferred to DNA adducts for several reasons: 

availability of large amounts (erythrocytes in whole blood), availability of methods for 

chemical identification (specific and sensitive), and the well-defined life span due to absence 

of DNA repair (Ogawa et al., 2006). Also, the hemoglobin adduct is strongly correlated with 

measured concentrations of PO (8h TWA) (Boogaard et al., 1999). Limitation of Hb adducts 

is that they cannot be used for monitoring of acute or short term exposures. 

Polymorphisms: 

Hypoxanthine phosphoribosyl transferase (HPRT) gene has been used for studies of the 

mutagenic effect of EO but not for PO. High exposures to EO in workers showed a 

significant increase in HPRT mutant frequency compared to controls, while at low exposures 

no such association was found. 

 

Occupational exposure 

Occupational exposure occurs during the production of propylene oxide and its derivatives 

and during production of hydroxypropyl starch ethers. (IARC, 1994). Since the IARC review, 

three new occupational biomonitoring studies have been conducted: one in a chemical plant 

manufacturing glycols and glycol ethers from PO and two in PO producing plants. Included 

also is an exposure to polyethylene (PE) study because PE metabolizes to PO. 

An occupational exposure study was performed to establish a relationship between ambient 

exposure to EO and PO in air and the formation of their respective adducts to Hb (Boogaard 

et al., 1999*). The personal air monitoring (PAM) data were measured by gas-diffusion 

monitors in the breathing zone in three groups of workers: (1) In 1990: male operators (N=20) 

and controls (N=36 operators from a different division of the same plant with no exposure to 

EO or PO) in a chemical plant manufacturing glycols and glycol ethers from EO and PO; (2) 

In 1997 follow-up: male operators (N=18) from the same plant maintaining and inspecting a 

shutdown of the plant; (3) In 1997: male workers (N=28) maintaining a styrene-PO plant 

during shutdown. No correlations between random PAMs and Hb-adducts were found in the 

1990 survey of male operators and controls, but correlations were found between PO air 

concentrations spanning four months (the life span of the human erythrocyte) and the Hbadducts of male operators in the 1997 follow-up. However, in the follow-up study, 89 of 112 

PAMs (79.5%) were below the limit of detection (0.2 mg m−3 = 0.08 ppm 8-h TWA), but did 

allow calculations of increments for the 4-mo interval from which daily (8-h) increments and 

steady-state concentrations were derived. Background levels of HOPrVal were found in some 

controls; however, the publication does not reveal how many nor what level of HOPrVal 
81 

levels were found in controls and exposed operators. In the 1997 study of maintenance 

workers the median HOPrVal concentrations increased 21.3 pmol/g globin, a 2-fold increase 

from pre-maintenance activities (24.4 pmol/g globin) to end of shutdown period (45.7 pmol/g 

globin). A PO air concentration of 10 mg m-3 is equal to 5.3 nmol/g globin, and the 

operators’ blood levels were measured to 0.005 to 0.161 nmol/g globin in 1997. 

Hemoglobin adducts were assessed as a measure of PO exposure in a chemical plant using PO, 

EO, acrylamide and acrylonitrile in the production of surfactants for the textile industry in 

exposed (N=62) and controls selected from the laboratory (N=10) (Schettgen 2002). In 

addition to PO globin adduct (HOPrVal), other globin adducts (N-2-carbamoylethylvaline, N2-cyanoethylvaline, HOEtVal) were also measured for workers at this plant. HOPrVal were 

not found in either exposed workers or controls. The authors contribute this fact to either the 

limit of the analytical detection (LOD, 80 pmol/g globin), or due to the low adduct formation 

of PO, which is five times lower than for EO. This study does not report PO air concentrations 

or describe what type of jobs the workers were performing. 

A small study in China was conducted to determine DNA adducts (1-hydroxypropyl-adenine 

or 1HPAdenine), hemoglobin adducts (HOPrVal), and SCE in blood of workers (N=8) 

occupationally exposed to PO at a PO-producing plant and control subjects (N=8) at an 

institute of occupational health (Czene et al., 2002). PO concentrations were determined 

based on area air samples collected in areas workers occupied the day before blood samples 

were drawn. PO concentrations ranged from 0.9 to 6.9 ppm, and workers were reported to be 

present in the areas of highest PO concentration for 1 to 1.5 h per day. HOPrVal adduct 

concentrations in the exposed workers ranged from 0.13 to 4.92 pmol mg−1 globin for a mean 

of 2.69 ± 1.52 pmol mg−1 globin, which is in the same range as found in the glycol and 

glycol ether from PO producing plants (Boogard et al., 1999). For comparison, values for 

controls ranged from 0.005 to 0.008 pmol mg−1 globin. The mean difference between 

exposed and controls was highly significant. In this study, Hb- and DNA-adducts were 

measured in the same worker (Czene et al., 2002). DNA adducts were detected in 7 of the 8 

exposed workers with a mean value of 0.66 ± 0.34 mol per 109 mol normal nucleotides. DNA 

adducts were not detected in controls. The LOD was 0.1 mol per 109 mol normal nucleotides. 

1HPAadenine rather than the N7HPG adducts were measured in this study because they are 

more stable. The group mean difference for DNA adduct concentrations between exposed 

workers and controls was highly significant, as was the correlation between the individual 

OHPrVal hemoglobin and 1HPAdenine DNA adduct concentrations when all subjects were 

included in the analysis (including the controls with no detectable adducts) (r = 0.887, P 

<0.0001). However, limiting the correlation to only the exposed workers resulted in a 

correlation with marginal statistical significance (r= 0.713, p = .047). For the third biomarker, 

the difference in mean SCE frequency was significant (p ≥ 0.011) with mean SCE frequency 

was 3.7 ± 2.11% for the exposed workers and 2.0 ±0.52% for the control group (Czene et al., 

2002). Strong and significant correlations were found between levels of N7HPG and SCE 

frequencies (r =0.792; p = 0.00026) and between OHPrVal and SCEs (r =0.766; p = 0.0014). 

Excluding smokers gave significant associations between SCE frequency and 1HPAdenine 

adducts r = 0.851 (p = .00044), and between SCE and OHPrVal r=0.757 (p = 0.011). 
82 

Exposures to PO at three manufacturing sites in France and the Netherlands were assessed by 

determining Hb-adducts (n>800 samples) over a 2-year period from operators, maintenance 

fitters and office staff (Jones et al., 2005***). The geometric means range from the three 

plants was 2.9-12.6 pmol g-1 globin, which is four to 16 times lower than the other two plants 

mentioned previously (Boogard et al., 1999, Czene et al., 2002). To evaluate smoking as a 

confounder, workers at one of the plants were separated into smokers (N=51) and nonsmokers (N=177) and their GMs were 3.8 and 3.0 pmol g-1 globin, respectively. Smoking 

does not seem to be a major confounder when measuring Hb-adduct in blood of very low 

exposed workers. 

Polyethylene (PE) is metabolized to PO. PO concentrations in blood from healthy male nonsmoking volunteers (N=4) resulting from inhalation of PE (mean concentrations of 9.82 and 

23.4 ppm for 180 min) was measured to 0.44 and 0.92 nmol/l for the two PE air levels (Filser 

et al., 2008**). The authors found a distinct species difference between rats and human in the 

activities of PO metabolizing enzymes of liver and lung cell fractions. Human microsomal 

epoxide hydrolase activities toward PO 2-4x (liver) and 6-8x (lung) higher in humans than 

those of rats. 

Environmental exposures 

Household and industrial detergents, paints, adhesives, textiles, defoamers, oil field chemicals, 

cosmetics, functional fluids and lubricants, heat transfer fluids, and automotive brake fluids 

contain PO. PO is also an additive in food. Levels of PO exposures from using these articles 

have not been measured (or reported). 

PO is also found in tobacco smoke and is an environmental pollutant. 

In a 2-year cancer bio-assay study in rats, the authors compared the results obtained from rats 

being exposed to a constant PO concentration with an unexposed human. The unexposed 

human level of PO Hb-adduct level was 0.006 pmol/mg globin (compared to Boogaard et al., 

1999 for occupational exposure of 5.32 pmol/mg globin) (Rios-Blanco et al., 2002*****). 

Human carcinogenicity: 

From the last Monograph (vol. 60, 1994): One case-control study provides information about 

cancer risk in relation to exposure to propylene oxide specifically but does not allow any firm 

conclusion regarding carcinogenicity. Since then only one epidemiological study has been 

conducted. 

 

Mortality study of workers formerly employed in a ethylene chlorohydrin and propylene 

chlorohydrin process plant (Olsen et al., 1997 ). The objective was to compare the SMRs 

at this plant with previous excess mortality from pancreatic cancer and lymphopoietic and 

hematopoietic cancer found among workers in another chlorohydrin unit. All male workers 

(N=1361) who had worked in the ethylene or propylene production area for a month and 

worked at either manufacturing site for a year were included in the study. These workers were 

identified using work histories. Vital status was determined from 1940 to 1992. SMR was 

non-significantly elevated for lymphopoietic and hematopoietic cancers (SMR=129; 95%CI 

62-238, observed 10 cases, expected 7.7), and not elevated for malignant neoplasms 
83 

(SMR=94) and pancreatic cancer (SMR=25),. Including a latency of 25 years gave increased 

the SMR to 144 for lymphopoietic and hematopoietic cancers, but did not reach statistical 

significance (95%CI 52-312). Comparing the SMRs across plants gave similar results except 

for lymphopoietic and hematopoietic cancer deaths at one plant SMR=181 (95%CI 66-393, 

observed 6 cases and expected 3.3). Comparing SMRs across process gave similar nonsignificant results; however, including a latency of 25 years gave a SMR= 194 (95%CI 71-

423, 6 observed, 3.1 expected,) for lymphopoietic and hematopoietic cancer among those 

employees with exposure only to the ethylene chlorohydrin process. At 10-20 years of 

employment in the chlorohydrin plants, there was a significant Mantel-Haenszel RR (RR 3.56, 

95% CI 1.23-10.29) for lymphopoietic and hematopoietic cancer based on three observed 

deaths. This effect disappeared with different categories were used in a Poisson regression. 

Limitation of this study is that following exposures are not considered: cigarette smoking, the 

ratio of exposure to chlorohydrin versus oxide, exposure in enclosed versus outdoor 

production facility, earlier versus later exposure periods (usually industrial hygiene improves 

over the years). The mean follow-up time was 25 years and additional follow-up time might 

change the outcome. 

Animal cancer data (excluding mechanisms): 

From the last Monograph (vol. 60, 1994): Propylene oxide was tested by oral gavage in one 

study in rats, by inhalation in one study in mice and in three adequate studies in rats and by 

subcutaneous administration in one study in mice and in one study in rats. 

Propylene oxide administered by oral gavage to rats produced tumours of the forestomach, 

which were mainly squamous-cell carcinomas. In mice exposed by inhalation, propylene 

oxide produced hemangiomas and hemangiosarcomas of the nasal cavity and a few malignant 

nasal epithelial tumours. In a study in rats of each sex exposed by inhalation, papillary 

adenomas of the nasal cavity were observed in males and females and thyroid adenomas and 

carcinomas were found in females; in the second study, in males, papillary adenomas of the 

nasal cavity and an increased incidence of adrenal phaeochromocytomas were observed; in 

the third study, in females, increased incidences of mammary fibroadenomas and 

adenocarcinomas were observed. Subcutaneous administration of propylene oxide to mice 

produced local sarcomas; the study in rats was inadequate for evaluation. 

Male Fischer 344/N rats in closed exposure chambers were exposed to constant PE 

concentrations, between 20.1 and 3000 ppm (7 h at least) and the PO concentrations were 

measured in the blood of these rats (Filser et al., 2008** ). The PO blood concentrations 

ranged from 53 nmol/l at 20.1 ppm PE to 1750 nmol/l at 3000 ppm PE. The PO blood 

concentrations measured in this study are too low for resulting in PO treatment–related tumors 

seen in a long-term study (Renne et al., 1986; U.S. National Toxicology Program, 1985b). 

Mechanisms of carcinogenicity: 

From the last Monograph (vol 60, 1994): In rats exposed by inhalation, there is strong uptake 

of propylene oxide, which is then metabolized extensively and eliminated rapidly. 

Metabolism occurs predominantly by conjugation with glutathione. Propylene oxide can also 
84 

be hydrolyzed by epoxide hydrolase to 1,2-propanediol, which is subsequently metabolized to 

lactic and pyruvic acids. 

Dominant lethal mutations were not induced in rats or mice, and sperm abnormalities were 

not observed in mice exposed to propylene oxide in vivo. Micronuclei and, in single studies, 

chromosomal aberrations and sister chromatid exchange were induced in mouse bone marrow 

after intraperitoneal injection of propylene oxide. Neither sister chromatid exchange nor 

chromosomal aberrations were induced in monkeys exposed by inhalation to 300 ppm. 

Propylene oxide induced chromosomal aberrations and sister chromatid exchange in human 

lymphocytes and DNA damage, gene mutation, chromosomal aberrations and sister chromatid 

exchange in mammalian cells in vitro. It caused dominant lethal mutation in Drosophila and 

was mutagenic to yeast, fungi and bacteria. 

PO binds covalently to the cyclic ring nitrogens in DNA producing hydroxypropyl (HP) 

adducts. HP adducts can be non-promutagenic lesions being eliminated spontaneously, 

leaving behind the depurinated sites that can result in mutations only if not repaired before 

DNA replication occurs, or the adduct may be at the coding site resulting in potentially 

promutagenic lesions (Albertini et al., 2007). These adducts may cause mutation by 

transversions. PO can also react with the phosphate groups in the DNA backbone. 

PO is a less potent mutagen than the week EO mutagen. 

In a 2-year cancer bioassay with rats exposed to constant PO concentration the pattern for 

DNA and Hb-adduct accumulation did not correlate with the incidence curve for nasal tumors 

(Rios-Blanco et al., 2002*****). Tumor formation was only seen at >300 ppm exposure 

(highest levels tested 300 and 500 ppm). Neither adduct accumulation in tissues can explain 

the threshold in nasal tumor formation. The authors suggest an increased cell proliferation in 

the nose occurs at high PO concentration to be a critical factor for tumorigenesis in this tissue. 

Research needs and recommendations: 

The animal data consist of oral, inhalation and subcutaneous studies in three strains of rats 

and two strains of mice. Propylene oxide caused tumors at or near the site of administration in 

rodents, causing nasal tumors after inhalation exposure (NTP, 1985). 

One of the major limitations in cancer epidemiological studies is that records of exposure are 

often incomplete or lacking (Kolman et al., 2002). Measuring hemoglobin adducts, an 

extremely sensitive effect biomarker, which does not undergo repair as DNA-adducts, may 

overcome this problem. In addition, low background level of OHPrVal shows that 

contributions from non-occupational sources are minor. The levels of OHPrVal of the 

smokers were similar to those of the nonsmokers, indicating that tobacco smoking is not the 

major contributing factor to the found background levels. Therefore, a future prospective 

study exploring cytogenetic effect would be feasible even though PO exposures are low 

because: 

1) the great difference in means between exposed and controls seen in the pilot study will 

require few participants in the two groups (exposed and unexposed workers) and 
85 

2) the OHPrVal is a sensitive and specific biomarker to PO exposures (even detected in 

controls with unknown exposures). 

The OHPrVal adduct represents cumulative exposures over a 3-month time period. The 

number of workers recruited to such a study would only be about 11 assuming equal variances 

in the two groups; however, other possible confounders should be included in the study such 

as gender, age, ethnicity, years of education, smoking, and possibly polymorphisms in the 

GST metabolizing pathway of PO. In addition, loss of follow-up and errors in power 

calculations would benefit from a larger study (~ 100 exposed and 100 controls in a balanced 

design). Various exposure-selective cross sectional epidemiological studies that look at 

OHPrVal adducts and cytogenetic effects would be useful.

Possible sources of future cohorts for such a study might be the already established cohorts in 

PO manufacturing workers (USA) (Olsen et al., 1997), which did not show an increased 

mortality rate due to cancer by duration with or without latency or cancer risk by process (PO 

versus EO); or the manufacturing cohorts in France and the Netherlands (Jones et al., 2005), 

and China (Czene et al., 2008). PO production is being expanded, and workers at these new 

PO manufacturing sites should be recruited for a future study. Other possible cohorts for 

propylene oxide biomarker epidemiological studies are: processing workers where PO is used 

as a starting material in polyurethane polyols (NTP 11th RoC), surfactants for textiles 

(Schettgen et al., 2002) and glycol/glycol ether manufacturing (Boogaard et al., 1999), and 

manufacturing of polyethylene (PE), which metabolizes to PO. Women should be included in 

the study as PO might be mammary carcinogen (Rudel et al., 2007). Workers’ exposures to 

PO in paint and automotive fluids have not been adequately characterized. If these workers 

have exposures to PO then these could potentially be included in a future biomarker 

epidemiological study. Therefore recruiting sufficient workers to a future prospective study 

should be feasible. 

Selected relevant publications since IARC review: 

Albertini RJ, Sweeney LM. Propylene-oxide-Genotoxicity profile of a rodent nasal 

carcinogen. Crit Rev Toxicol 2007; 37: 489–520. 

Boogaard PJ, Rocchi PSJ, van Sittert NJ. Biomonitoring of exposure to ethylene oxide and 

propylene oxide by determination of hemoglobin adducts Correlations between airborne 

exposure and adduct levels. Int Arch Occup Environ Health 1999; 72: 142-150. 

Czene K, Osterman-Golkar S, Xiao Y, et al. Analysis of DNA and hemoglobin adducts and 

sister chromatid exchanges in a human population occupationally exposed to propylene oxide 

A pilot study. Cancer Epidemiol Biomark Prev 2002; 11: 315–318. 

Filser J, Hutzler C, Rampf F, et al. Concentrations of the propylene metabolite propylene 

oxide in blood of propylene exposed rats and humans A basis for risk assessment. Toxicol 

Sci 2008; 102: 219–231. 
86 

Jones AL, van der Woord M, Bourrillon F. Use of a whole blood competitive immunoassay 

for the assessment of worker exposed to propylene oxide at three manufacturing facilities. 

Ann Occup Hyg 2005; 49: 241–243. 

Kolman A, Chovanec M, Osterman-Golkar S. Genotoxic effects of ethylene oxide, propylene 

oxide and epichlorohydrin in humans Update review (1990-2001). Mutat Res 2002; 512: 173–

194. 

Ogawa M, Oyama T, Isse T, et al. Hemoglobin adducts as a marker of exposure to chemical 

substances, especially PRTR class I designated chemical substances. J Occup Health 2006; 

48: 314-328. 

Olsen GW, Lacy SE, Bodner KM, et al. Mortality from pancreatic and lymphopoietic cancer 

among workers in ethylene and propylene chlorohydrin production. Occup Environ Med

1997; 54: 592-598. 

Ríos-Blanco MN, Ranasinghe A, Upton P, et al. Exposure dependent accumulation of N-(2-

hydroxypropyl)valine in hemoglobin of F344 rats exposed to propylene oxide by the 

inhalation route. J Chrom B 2002; 778: 383–391. 

Rudel RA, Attfield KR, Schifano JN, Brody JG. Chemicals causing mammary gland tumors 

in animals signal new directions for epidemiology, chemicals testing, and risk assessment for 

breast cancer prevention. Cancer 2007; 109: 2635-2666. 

Schettgen T, Broding HC, Angerer J, Drexler H. Hemoglobin adducts of ethylene oxide, 

propylene oxide, acrylonitrile and acrylamide biomarkers in occupational and environmental 

medicine. Toxicol Lett 2002; 134: 65–70. 

* Authors from: Shell Research and Technology Center, Amsterdam Shell International Chemicals 

** Study paid for by CEFIC – an organization representing the European chemical industry 

*** Authors from: Lyondell Chemical Europe – a chemical manufacturing company 

  Authors from: Dow Chemical Company, Health and Environmental Sciences 

** *** Study supported in part by ACC PO/PGP and Olefin panel, CEFIC PO/PG sector group, NIH grants 

Formaldehyde 

by Bernard D. Goldstein PhD and Martyn T. Smith PhD 

Citation for most recent IARC review 

IARC Monograph 88, 2006 

Current evaluation 

Conclusion from the previous Monograph: