Ontario Air Standards for Ethylene Oxide · 2007-11-15 · Ontario Air Standards for Ethylene Oxide iii ethylene oxide-exposed workers from sterilization plants across the USA. The

Ontario Air Standards

For

Ethylene Oxide

June 2007

Standards Development Branch Ontario Ministry of the Environment

Ontario

Ontario Air Standards for Ethylene Oxide

Executive Summary

The Ontario Ministry of the Environment (MOE) has identified the need to develop and/or update air quality standards for priority contaminants. The Ministry’s Standards Plan, which was released in October, 1996 and revised in November, 1999, identified candidate substances for which current air quality standards will be reviewed or new standards developed. Ethylene oxide was identified as a priority for review based on both its pattern of use in Ontario and toxicological information that has been published subsequent to the development of the existing standard in 1986. Once a decision is made on the air standards, they will be incorporated into Ontario Regulation 419: Air Pollution – Local Air Quality (O. Reg. 419/05). The Ambient Air Quality Criterion (AAQC) will be incorporated into Schedule 3 of the regulation and the half hour standards will be incorporated into Schedule 2. An ‘Information Document’ containing a review of scientific and technical information relevant to setting an air quality standard for ethylene oxide was previously posted on the Environmental Bill of Rights Registry for public comments. This was followed more recently by the posting of a document providing the rationale (‘Rationale Document’) for recommending an Ambient Air Quality Criterion (AAQC) and a half hour standard for ethylene oxide. This document, referred to as the ‘Decision Document’, summarizes the comments received from stakeholders on the proposed standards and the Ministry responses to these comments. This document also provides the rationale for the decision on the air quality standards for ethylene oxide.

Ethylene oxide (CAS# 75-21-8) is a colourless, extremely flammable gas with a somewhat sweet odour. The primary use of ethylene oxide in Canada is as a chemical intermediate for the production of various chemicals. Ethylene oxide is also used as a disinfectant, sterilizing agent, fumigant and insecticide. However, these uses account for only a small proportion of production.

The majority of airborne, gaseous ethylene oxide is from industrial emissions. The half-life of ethylene oxide in air has been estimated to range from 38 to 382 days. Ethylene oxide is lost from the airshed by several processes, including photodecomposition, photocatalysis, and precipitation scavenging. Breakdown products can include methane, ethane, hydrogen, carbon dioxide, and simple aldehydes such as acetaldehyde, and carbon dioxide.

Data from the National Pollutant Release Inventory indicate that there were no significant changes in the release of ethylene oxide within Canada over the period of 1995-2005. Ontario has contributed to approximately 50% of the total annual air

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releases of ethylene oxide in Canada. For the year 2005, Ontario reported releases of 13.5 tonnes of ethylene oxide to the air.

Ethylene oxide is readily and rapidly absorbed following inhalation exposure. It has been found to widely distribute following absorption, with the majority found in the lungs, kidney, bladder, blood and adrenal glands. Absorbed ethylene oxide is metabolized via hydrolysis, detoxicated through glutathione conjugation and rapidly excreted from the body.

Acute inhalation exposure to high concentrations of ethylene oxide has been found to result in CNS depression and irritation of the eyes and mucous membranes. Lethal concentrations of ethylene oxide in experimental animals were found to be in the range of 1500 to 7200 mg/m3. The study of the National Toxicology Program found that no mortality in mice with exposure to 720 mg/m3 for a period of 14 days. Subchronic and chronic exposure to ethylene oxide results in effects similar to those from acute exposure. In addition, haematological effects and development of cataracts have also been noted with chronic occupational exposure.

There is only limited evidence that acute and chronic inhalation exposure results in developmental effects. Human studies have suggested that there may be a link between ethylene oxide exposure and increased risk of miscarriage, however exposure data is lacking and a mechanistic explanation for such effects requires further study.

In reviewing Ontario’s air quality standards, the Ministry of the Environment is considering risk assessments, standards, and guidelines developed by environmental agencies worldwide. This report reviews the scientific basis for air quality guidelines and standards for ethylene oxide from Environment Canada and Health Canada, Alberta, Newfoundland, Quebec, U.S. EPA, California, Massachusetts, Michigan, New York, North Carolina, Texas and some other U.S. state jurisdictions as well as in the European Community.

A number of jurisdictions have concluded that ethylene oxide is probably carcinogenic to humans, based on epidemiological studies, animal bioassays and evidence of mutagenicity. Ethylene oxide has been clearly shown in a number of in vivo and in vitro studies to alkylate DNA and cause a number of mutagenic and genotoxic effects (e.g., SCE, chromosomal aberrations, etc.). However, it has been noted that these mutagenic and genotoxic effects reach significant levels only at high concentrations of ethylene oxide. Until recently, available epidemiological data in the past decade has not been consistent and a clear dose-response relationship between ethylene oxide exposure and cancer has not been demonstrated. In September 2006, the U.S. EPA posted for public comments a report of the evaluation of carcinogenicity of ethylene oxide based on epidemiological data from previous analyses on lymphohaematopoietic cancers of


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ethylene oxide-exposed workers from sterilization plants across the USA. The outcome of the cancer risk assessment and the selection of information and the method of dose-response analysis have been challenged by industry representatives.

In view of the lack of consistent and reliable human carcinogenicity information, the pending challenge to the U.S. EPA ‘s cancer risk assessment, and the fact there is sufficient data from laboratory studies to support a dose-response analysis of the carcinogenic effects of ethylene oxide, animal carcinogenicity data would appear to be the most appropriate scientific basis for the development of air standards for Ontario. In support to this consideration, many regulatory agencies have derived their respective air quality guidelines using cancer risk assessment based on animal data. Jurisdictions that have developed cancer-based guidelines include Environment Canada and Health Canada, the U.S. Environmental Protection Agency (U.S. EPA), the States of California and Michigan. These cancer-based guidelines fall within a narrow range of values of 0.01-0.04 µg/m3, based on a lifetime increased cancer risk at a risk level of one in a million for ethylene oxide. These agencies all derived their respective guidelines from a common data set of mononuclear leukaemia in female rats. The U.S. EPA proposed to adopt the unit risk factor developed by the California Environmental Protection Agency (CalEPA) as its provisional inhalation cancer unit risk factor. The CalEPA used unpublished metabolic data in converting the animal dose data to equivalent human doses in deriving their inhalation unit risk value of 8.8x10-5 (µg/m3)-1. The State of Michigan disagreed with CalEPA’s method of animal to human data extrapolation due to the fact that this method is not readily available for review. The State of Michigan derived its cancer unit risk factor from the animal data without animal to human dose conversion and developed a cancer risk guideline that is marginally higher than that of the CalEPA. Environment Canada and Health Canada have conducted dose-response analyses to derive their cancer risk estimates for ethylene oxide. These Canadian federal jurisdictions analysed different animal data sets including different animal species and types of tumours and have come to the agreement with the U.S. EPA, CalEPA and the State of Michigan that data from mononuclear leukaemia of rats is the most appropriate for the development of their Tumourigenic Concentration for cancer risk. However, Environment Canada and Health Canada also considered that interspecies metabolic conversion was not necessary, considering that the pharmacokinetic differences between animals and humans are minor.

The Ministry of the Environment is in agreement with the toxicological assessment of Environment Canada and Health Canada that ethylene oxide is likely carcinogenic to humans and the data from animal studies are the most appropriate to derive air quality standards for ethylene oxide. The Ministry also concurs with these Canadian federal jurisdictions that the metabolic difference in the breakdown of ethylene oxide between rats and humans is not significant and that ethylene oxide is likely the active toxicant for


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the carcinogenesis of this compound. Thus, metabolic conversion between species was not applied.

Based on an evaluation of the scientific rationale of air guidelines from leading agencies, an examination of current toxicological research, and comments from stakeholders, the following air quality standards are set for ethylene oxide (75-21-8):

• An annual average AAQC of 0.04 µg/m3 (micrograms per cubic of air), based on the carcinogenic effects of ethylene oxide;

• A 24-hour average AAQC of 0.2 μg/m3 (micrograms per cubic metre of air) based on the carcinogenic effects of ethylene oxide; and

• A half-hour standard of 0.6 μg/m3 (micrograms per cubic metre of air) based on the carcinogenic effects of ethylene oxide.

These effects-based standards (which include the AAQCs and the corresponding effects-based half hour standards) will be incorporated into Ontario Regulation 419/05: Air Pollution – Local Air Quality (O. Reg. 419/05). The AAQCs (except the annual AAQC) will be incorporated into Schedule 3 of O. Reg. 419/05; the half-hour standard will be incorporated into Schedule 2.

MOE generally proposes a phase-in for new standards or standards that will be more stringent than the current standard or guideline. The phase-in for ethylene oxide is set out in O. Reg. 419/05.

Among other things, O. Reg. 419/05 sets out the applicability of standards, appropriate averaging times, phase-in periods, types of air dispersion model and when various sectors are to use these models. There are 3 guidelines that support O. Reg. 419/05. These guidelines are:

• “Guideline for the Implementation of Air Standards in Ontario” (GIASO);

• “Air Dispersion Modelling Guideline for Ontario” (ADMGO); and

• “Procedure for Preparing an Emission Summary and Dispersion Modelling Report” (ESDM Procedure).

GIASO outlines a risk-based decision making process to set site specific alternative air standards to deal with implementation barriers (time, technology and economics) associated with the introduction of new/updated air standards and new models. The alternative standard setting process is set out in section 32 of O. Reg. 419/05.


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For further information on these guidelines and O. Reg. 419/05, please see the Ministry’s website http://www.ontario.ca/environment and follow the links to local air quality.

http://www.ontario.ca/environment


Table of Contents

Executive Summary ....................................................................................................... i Table of Contents......................................................................................................... vi 1.0 Introduction......................................................................................................... 1

2.0 General Information ........................................................................................... 3 2.1 Physical and Chemical Properties .....................................................................3 2.2 Production and Uses of Ethylene Oxide ............................................................4 2.3 Sources and Levels ...........................................................................................4 2.4 Environmental Fate............................................................................................5

3.0 Toxicology of Ethylene Oxide ........................................................................... 6 3.1 Acute Toxicity.....................................................................................................8 3.2 Subchronic and Chronic Toxicity........................................................................8 3.3 Developmental and Reproductive Toxicity .......................................................10 3.4 Genotoxicity and Mutagenicity .........................................................................12 3.5 Carcinogenicity ................................................................................................13 3.6 Environmental Effects ......................................................................................17

4.0 Review of Existing Air Quality Criteria ........................................................... 18 4.1 Overview..........................................................................................................18 4.2 Evaluation of Existing Criteria ..........................................................................23

5.0 Responses of Stakeholders to the Information Draft.................................... 25

6.0 Responses of Stakeholders to the Rationale Document .............................. 26

7.0 Considerations in the Development of an Ambient Air Quality Criterion for Ethylene Oxide ............................................................................................................ 30

8.0 Decision ............................................................................................................ 33

9.0 References ........................................................................................................ 36

10.0 Appendix: Agency-Specific Reviews of Air Quality Guidelines .................. 53 10.1 Agency-Specific Summary: Federal Government of Canada..........................53 10.2 Agency-Specific Summary: Federal Government of the United States...........56 10.3 Agency-Specific Summary: California.............................................................58 10.4 Agency-Specific Summary: Massachusetts ....................................................62 10.5 Agency-Specific Summary: Michigan..............................................................63 10.6 Agency-Specific Summary: North Carolina .....................................................66 10.7 Agency-Specific Summary: World Health Organization (WHO) ......................68

11.0 Acronyms, Abbreviation, and Definitions ...................................................... 69

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1.0 Introduction

Ontario regulates air emissions in order to achieve and maintain air quality which is protective of human health and the environment. The Environmental Protection Act (Section 9) requires stationary sources that emit, or have the potential to emit, a contaminant to obtain a Certificate of Approval which outlines the conditions under which the facility can operate.

The Ministry of the Environment uses a combination of regulated point of impingement (POI) standards and guidelines (MOE, 2005a) in reviewing Emission Summary and Dispersion Modelling Reports submitted to support a Certificate of Approval application or a Ministry request for a compliance assessment. Ambient Air Quality Criteria form the basis for an air standard or guideline and represent human health or environmental effects-based values, normally set at a level not expected to cause adverse effects based on continuous exposure. As such, factors such as technical feasibility and costs are not considered when establishing AAQCs or the equivalent half hour standards which are derived from the AAQCs using a mathematical scaling factor. The risk based process for alternative standards, as set out in section 32 of O. Reg. 419/05, is the mechanism created to deal with the time, technical and economic issues. The Guideline for the Implementation of Air Standards in Ontario (GIASO) is the supporting document for stakeholders who are interested in more information on alternative standards. For further information on O. Reg. 419/05 and GIASO, please see the Ministry’s website http://www.ene.gov.on.ca/envision/air/regulations/localquality.htm.

Air standards referenced in O. Reg. 419/05 are used for compliance and enforcement. Dispersion modelling, as referenced in the regulation, is used to relate emission rates from a source to resulting concentrations of a particular contaminant. Air standards specified under O.Reg. 419/05 apply to stationary sources only.

In addition to air standards established under O. Reg. 419/05, the Ministry also has a large number of guidelines (including AAQCs). Similar to standards, guidelines are used by the Ministry to assess general air quality and the potential for causing adverse effect (MOE, 2005). Like the air standards specified in O. Reg. 419/05, guidelines (and now AAQCs) are used in reviewing Emission Summary and Dispersion Modelling reports submitted in support of applications for Certificates of Approval, to approve new and modified emission sources or other requirements. Once incorporated into a legal instrument such as a Certificate of Approval, guidelines can become legally binding.

The Ontario Ministry of the Environment continues to develop and/or update air standards for priority toxic contaminants. The Ministry’s Standards Plan, which was released in October 1996 and revised in November 1999 (MOEE, 1996 & MOE, 1999), identified candidate substances for which current air standards will be reviewed. The

http://www.ene.gov.on.ca/envision/air/regulations/localquality.htm


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MOE 1999 Standards Plan outlines a multi-step process for developing air quality standards (MOE, 1999). Each standard has undergone a two step consultation process involving postings on the Environmental Registry, under the Environmental Bill of Rights (EBR):

• Information Drafts (Risk assessment/science review only)

• Rationale Documents (Proposed numerical limits)

Ethylene oxide was identified as a priority for review based on its pattern of use in Ontario, and recent toxicological information. The initial step, an Information Draft (MOE, 2005b), provided risk assessment information relevant to establishing a standard for a particular substance. This provided stakeholders with the opportunity to critically review the information and provide any additional information they felt should be considered by the Ministry in setting an air quality standard for a particular compound. The Ministry considered comments received on the Information Draft and recommended proposed standards: Ambient Air Quality Criterion (AAQC) and a half hour point of impingement (POI) standard, in a Rationale Document (MOE, 2006) and again solicited comments from stakeholders by posting on the Environmental Registry. After assessing comments on the Rationale Document the Ministry has finalized its work by making a decision on the air quality standards for ethylene oxide. This decision, which also highlights key comments from stakeholders on the proposed standards and the responses provided by the MOE, is documented by posting a Decision Notice (and supporting ‘Decision Document’, which provides the rationale for the decision on the air quality standards) onto the Environmental Registry.

In the 1999 Standards Plan, MOE made a commitment to consider time, technical, and economic issues for air standards and develop a risk management framework to address implementation issues. The risk-based framework has been developed and is part of O. Reg. 419/05. The alternative standards setting process is a risk-based process that considers time, technical and economic issues on a site specific basis. For further information on Regulation 419/05 and the process for requesting an alternative site specific air standard, please see the Ministry’s website and follow the links to local air quality.

http://www.ene.gov.on.ca/envision/air/regulations/localquality.htm


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2.0 General Information

2.1 Physical and Chemical Properties

Ethylene oxide (also known as oxirane; CAS# 75-21-8) is a colourless, extremely flammable gas with a somewhat sweet odour. At room temperature and atmospheric pressure, ethylene oxide is found in the gaseous form; however it can be condensed to a clear liquid at 10 EC (ACGIH, 2002a; ATSDR, 1990). As a liquid, ethylene oxide is relatively stable with respect to several detonating compounds however, it may polymerize violently after contact with acids, bases or heat, especially when in contact with metal chloride and oxide catalysts (Hellman and Small, 1974; Jacobson et al., 1956). The following list provides some specific chemical information on ethylene oxide and its properties (ACGIH, 2002a; Hellman and Small, 1974; PHRED, 1988; Vershueren, 1983; Weast, 1985):

Chemical Name: Ethylene Oxide

CAS # 75-21-8

UN # UN 1040

RTECS # KX2450000

Melting Point -111EC

Boiling Point 10.73EC

Flash Point < -18EC

Water Solubility soluble

Henry’s law Constant 7.56 x 10-5 atm-m3/mol

Log octanol/water -0.22

Log Koc 0.342

Formula C2H4O

Molecular Weight 44.05 g/mol

Odour Threshold 470 mg/m3 perception; 900-1260 mg/m3 recognition


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Specific Gravity (water=1) 0.6 at 0EC

Vapour Density (air = 1) 1.5

Vapour Pressure 1.095 x 103 mmHg @ 20EC

Conversion Factor 1 ppm = 1.80 mg/m3

Common Synonyms Dihydrooxirine; Dimethylene oxide;1,2-Epoxyethane; Ethene oxide; EO; ETO; EtO; Oxane; Oxirane; Alpha beta-oxidoethane

2.2 Production and Uses of Ethylene Oxide

It has been estimated that world wide production of ethylene oxide exceeds 5.5 million tonnes per year (WHO, 1985). Data available in 1991 indicated that ethylene oxide was produced worldwide from countries including the United States and Canada (Chemical Information Services Ltd, 1991).

In the U.S.A., since the 1930s ethylene oxide has been produced using the direct vapour phase oxidation process in which ethylene is oxidized to ethylene oxide with either air or oxygen in the presence of a silver catalyst (Rebsdat and Mayer, 1987; Berglund et al., 1990).

The primary use of ethylene oxide in Canada is as a chemical intermediate for the production of various other chemicals. In 1993, 89% of the total Canadian production of ethylene oxide was used in the production of ethylene glycol (CEPA, 2001). In 1996, 95% of the total production was used in producing ethylene glycol. It has been forecasted that the volume of use in ethylene glycol production will continue to increase. An estimated 4% (26,000) tonnes is used in the manufacture of surfactants (CEPA, 2001). Ethylene oxide alone or in combination with other inert gases such as carbon dioxide and nitrogen is used to sterilize instruments from the health care, publication and wood products sectors. Ethylene oxide is also use in other industries such where heat sensitive goods are sterilized (CEPA, 2001). In Canada, ethylene oxide is also used in the manufacture of choline chloride, glycol ethers and polyglycols and as the active ingredients in some pesticides. Other minor uses worldwide include use in the manufacture of rocket propellant and petroleum demulsifiers (CEPA, 2001).

2.3 Sources and Levels

Ethylene oxide is produced synthetically, the majority of which has been used to produce other chemicals under an industrial setting. Industrial emissions of ethylene oxide are a result of uncontrolled fugitive emissions or venting with other gases


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(ATSDR, 1990). In the United States, emissions of ethylene oxide during 1985 were estimated to have been approximately 5,000 tonnes per year. Of the total emissions, sterilization and fumigation sources accounted for 57%, production and captive use for 31%, medical facilities for 8%, and ethoxylation for 4% (Markwordt, 1985). Ethylene oxide emissions reported to the U.S. Environmental Protection Agency by industrial facilities in the USA were 2,900 and 835 tonnes in 1987 and 1991, respectively (U.S. National Library of Medicine, 1993).

Other sources of atmospheric ethylene oxide include combustion of hydrocarbon fuels, losses during disinfections of hospital equipment, bacterial degradation products, photochemical smog and cigarette smoke (Bogyo et al., 1980).

According to the National Pollutant Release Inventory (NPRI), the release of ethylene oxide within Canada has not significantly changed over the period from 1995-2005 (NPRI, 1995; 1996; 1997; 1998; 1999; 2000; 2001; 2002; 2003; 2004; 2005). National release amounts for 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, and 2005 were 26.2, 23, 18.4, 19.5, 22.3, 20.4, 19.3, 15.4, 11.87, 15.0, and 20.1 tonnes, respectively. There was a trend of decrease in the emissions of ethylene oxide since 1995 to 2003, followed by increases in two subsequent years. On-site releases in Ontario in past years exhibited no change in the emissions over the previous year. In the years of 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, and 2005. Ontario released 9.3, 7, 9.9, 10.5, 13, 11.2, 8.5, 7.7, 6.73, 5.96, and 13.5 tonnes of ethylene oxide, respectively. Over this time period, Ontario contributed approximately 50% of the total ethylene oxide released in Canada.

Data quantifying environment levels of ethylene oxide in the atmospheric are limited. Ethylene oxide was detected at concentrations of 3.7, 3.9 and 4.9 µg/m3 in 3 of 50 24-hr samples of air collected outside of randomly selected residences during a multimedia exposure study conducted in Canada (CEPA, 2001). The mean value was found to be 0.34 µg/m3 when a concentration equivalent to one-half the limit of detection (e.g., 0.5 x 0.19 µg/m3) was assumed for the 47 samples in which ethylene oxide was not detected. Ethylene oxide was detected at 3 (or 33%) of 9 locations in Alberta, but none of the 35 locations in Ontario or the locations in Nova Scotia during this study (CEPA, 2001).

2.4 Environmental Fate

Ethylene oxide is not readily removed from the air by washout or by adsorption into aqueous aerosols in the air (Winer et al., 1987; Cupitt, 1987). The high vapour pressure and rapid volatilization of ethylene oxide’s limit this avenue of removal (CEPA, 2001). The dominant chemical removal process is via degradation by reaction with hydroxyl radicals, with the half-life associated with this reaction estimated as 120 days (Atkinson, 1986), 99 days (Lorenz and Zellner, 1984), 151 days (Zetzsch, 1985) and 200 to 300 days (Schonfeld, 1969). Other studies have estimated the atmospheric half-life at 38 to


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3.0

382 days without accounting for other removal mechanisms (Pesetsky, 1980; Baldwin et al., 1984). Half-life which ranges from 69 to 149 days have also been reported (ATSDR, 1990). Since the concentration of hydroxyl radicals varies as a function of light duration and intensity, then the half-life can vary with latitude across Canada (CEPA, 2001).

When ethylene oxide as a liquid comes in contact with soil, much of the chemical will be lost by evaporation and the balance will infiltrate the soil into the groundwater as it does not adsorb strongly to soil and is highly soluble in water (HSDB, 2002). Downward penetration of liquid toward the groundwater table may cause environmental concerns as hydrolysis to ethylene glycol is relatively slow. However, the ethylene glycol formed from hydrolysis biodegrades rapidly (0.2 to 0.9 day half-life) (McGahey and Bouwer, 1992). The half-lives for hydrolysis in groundwater and soil are estimated to be between 10.5 and 11.9 days, increasing with increasing pH (5 to 9) (Mabey and Mill, 1978; Howard et al., 1991).

Chemical hydrolysis is a major removal process in water, with a half-life of 14 days (Hirose, 1974). The rate of hydrolysis is both pH and temperature dependent with acidic conditions having a significant positive effect on hydrolysis rates (Olson, 1977). However, water temperature will probably have a greater effect on half-life than expected pH differences in natural waters (Hirose, 1974). The hydrolysis product, ethylene glycol, is biodegraded rapidly in the aquatic environment, with a half-life of 12 to 14 days at pH 5 to 7 (Conway et al., 1983). Evaporation appears to be a significant removal process, with the reported half-life for evaporation of ethylene oxide in water of 1 hour with no wind and 0.8 hours with a 5 m/s wind (Conway et al., 1983). Volatilization is another major removal process, with half-lives for ethylene oxide removal from a model river and model lake of 5.9 hours and 3.8 days, respectively (SRC, 2003).

Ethylene oxide will biodegrade in aerobic systems such as rivers, lakes, and activated sludge units, although high concentrations may cause inhibition of bacterial respiration in activated sludge units (IC50 of 10 to100 mg/L) (Hirose, 1974). This is related to the common use of ethylene oxide as a sterilizing agent because of its bactericidal activity. The degradation rate in aerobic water was estimated to be from 1 to 6 months, whereas the anaerobic half-life was estimated at 4 to 24 months (Howard et al., 1991).

Toxicology of Ethylene Oxide

For consideration of airborne ethylene oxide, the following toxicological review is focussed primarily on the inhalation of ethylene oxide, as this is the predominant route of human exposure to ethylene oxide in air. Data on other exposure routes are included in this review where relevant or where inhalation exposure data are lacking.


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The available literature indicates that ethylene oxide is readily absorbed by the respiratory system (U.S. EPA, 1985). Approximately 75 % of inhaled ethylene oxide was retained in the alveolar region of the lungs of exposed hospital workers (Brugnone et al., 1985). Animal studies also provide evidence of rapid absorption of ethylene oxide through the lungs (Cumming et al., 1981; Ehrenberg et al., 1974; Koga et al., 1987; Matsuoka, 1988; Nakashima et al., 1987; Tardif et al., 1987). Ethylene oxide has relatively wide distribution following absorption, with the majority found in the lungs, liver, kidneys, bladder, packed blood cells and adrenal glands (Ehrenberg et al., 1974; Tyler and McKelvey, 1980). Tissue:air partition coefficients developed via physiologically based pharmacokinetic (PBPK) modelling suggest relatively broad distribution of ethylene oxide throughout the body (Krishnan et al., 1992; Fennell and Brown, 2001). The metabolic pathways for ethylene oxide have been examined in human liver cytosol and microsomes with hydrolysis to ethylene glycol, and glutathione conjugation via glutathione S-transferase being identified (Fennell and Brown, 2001). Ethylene oxide is rapidly excreted from the body following inhalation; studies have shown that the majority is eliminated within 48 hours (Ehrenberg et al., 1974), and that elimination occurs mainly via the urine or by expiration as carbon dioxide (Tyler and McKelvey, 1980).

From recent studies, biomarkers of ethylene oxide exposure include haemoglobin adducts, sister chromatid exchanges, other haematological parameters such as haematocrit and haemoglobin levels, chromosomal aberrations and micronuclei as well as hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutants (Ribeiro et al., 1994; Sarto et al., 1991; Tates et al., 1991; Schettegen et al., 2002; Schulte et al., 1995). Other biomarkers used to identify exposure to ethylene oxide can be ethylene oxide levels in blood or alveolar air (Baily et al., 1987; Brugnone et al., 1986; Farmer et al., 1986), or metabolic products such as N-(2-hydroxyethyl)histidine and/or N-(2-hydroxyethyl)valine in blood (ATSDR, 1990; Boogaard et al., 1999) or 2-hydroxyethylmercapturic acid in urine (Gérin and Tardif, 1986).


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3.1 Acute Toxicity

High concentrations of ethylene oxide cause central nervous system (CNS) depression and irritation of the eyes and mucous membranes. Symptoms of acute ethylene oxide toxicity include weakness, nausea, vomiting, convulsions, neurological disorders or even death (U.S. EPA, 1985). Biomarkers for acute effects of ethylene oxide have not been identified (ATSDR, 1990). A number of animal species have been examined for the acute effects of inhaled ethylene oxide. The 4-hour LC50 values for rats, mice, and dogs were reported to be 2,630-7,200, 1,500, and 1,730 mg/m3, respectively (Carpenter et al., 1949; Jacobson et al., 1956). Mice exposed to 1,440 mg/m3 ethylene oxide for 4 hours resulted in 80 to 100% mortality, while no mice died at 720 mg/m3 after 14 days of exposure (NTP, 1987).

3.2 Subchronic and Chronic Toxicity

The subchronic and chronic effects of ethylene oxide include irritation of the eyes, skin, and mucous membranes, neurological and haematological effects, and the formation of cataracts (ATSDR, 1990).

Epidemiological studies have attributed several toxicological effects to exposure to ethylene oxide in the work place, including development of cataracts in 4 male sterilizer operators exposed to 1,260 mg/m3 for up to 2 months (Gross et al., 1979; Jay et al., 1982). Longer term exposures of hospital sterilizer workers have been associated with reduced performance on tests of physical and neuropsychological health, at exposure levels of 9 mg/m3 ethylene oxide for 5-20 years (Estrin et al., 1987), 8.46 mg/m3 for 6.13 years (range 1-11 years) (Klees et al., 1990), or 27 to 450 mg/m3 for 0.5 to 10 years (average 5 years) (Estrin et al., 1990). Effects included bilateral reflex reduction in the ankle, reduction in finger tapping speed, and poor performance on tests of spatial and visual abilities and of visual motor function. There were no differences in nerve conduction tests between exposed and control workers. Other effects associated with occupational exposure to ethylene oxide have included decreases in haematocrit and haemoglobin (8-hr TWA of 0.31 mg/m3, for 10 years) (Schulte et al., 1995), nasal irritation and peripheral neuropathy (18 mg/m3 for two years) (Zampollo et al., 1984). Occupational exposure to 18 mg/m3 was not associated with haematological effects after 2 years exposure (Zampollo et al., 1984), or renal or hepatic effects after 10 years (Joyner, 1964). A recent study by Shaham et al. (2000) reported significantly decreased levels of white blood cells in workers exposed to ethylene oxide levels ranging from 18 to 108 µg/m3. The authors also noted a positive dose-response between cumulative dose exposure and the absolute mean number of eosinophils.


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Subchronic studies with mice have indicated that inhalation exposure to ethylene oxide may result in adverse effects including neurological effects such as decreased locomotor activity and reflex activity, significantly decreased absolute organ weights, tubular necrosis and regeneration, nasal inflammation and hypoplasia, thymic lymphocyte and pulmonary necrosis and alterations in haematological indices (NTP, 1987; Snellings et al., 1984a).

Mice (30 per sex) were exposed to 0, 18, 90, 180, 450 mg/m3 of ethylene oxide for 6 hours/day, 5 days/week, for 10 weeks (males) or 11 weeks (females) (Snellings et al., 1984a). Neuromuscular screening was conducted and samples of urine and blood were collected. A significantly greater percent of exposed mice exhibited abnormal posture during gait and reduced locomotor activity. A dose-response was observed for these effects, with significant changes at 90 mg/m3 and greater. An abnormal righting reflex was observed in a significantly greater percent of mice exposed to 180 mg/m3 and above. Reduced or absent toe and tail pinch reflexes were observed in a significantly greater percent of mice exposed to 450 mg/m3 ethylene oxide. Haematological changes observed in mice exposed to 250 mg/m3 include slight, yet significant, decreases in red blood cell count, packed cell volume, and haemoglobin concentration. Absolute and relative spleen weights were significantly decreased in female mice exposed to 180 and 450 mg/m3 and in male mice exposed to 450 mg/m3 ethylene oxide. A significant increase in relative liver weight was observed in female mice exposed to 450 mg/m3 ethylene oxide. Male mice exhibited a significant decrease in body weight at 10, 50, and 450 mg/m3 and a significant decrease in absolute testes weights at 90, 180, or 450 mg/m3 ethylene oxide. The NOAEL identified for neurological effects in this study was 18 mg/m3 of ethylene oxide.

In a chronic bioassay, NTP (1987) did not observe any mortality or renal effects in mice exposed to 180 mg/m3 ethylene oxide for 6 hours per day, 5 days per week, for 2 years. Similarly, Lynch et al. (1984a) did not observe any mortality, cardiovascular effects, or haematological effects in monkeys exposed to 180 mg/m3 ethylene oxide for 7 hours per day, 5 days per week, for 2 years. Slight demyelination of the monkeys was observed at 180 mg/m3 but not at 90 mg/m3. The subchronic NOAEL and LOAEL in Lynch et al. (1984a) were 90 and 180 mg/m3, respectively.

Lynch et al. (1984b) exposed 80 male rats to 0, 90, or 180 mg/m3 ethylene oxide for 7 hours per day, 5 days per week, for 104 weeks. Rats exposed to 90 or 180 mg/m3 had significantly lower mean body weights and higher mortality, and exhibited neoplastic changes and inflammatory lesions of the lung, nasal cavity, trachea and inner ear. Rats exposed to 180 mg/m3 exhibited atrophy and degeneration of skeletal muscle fibres. The chronic LOAEL identified from this study was 90 mg/m3 ethylene oxide, which was the lowest dose tested.


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3.3 Developmental and Reproductive Toxicity

There is limited evidence that acute and chronic inhalation exposures to ethylene oxide may cause adverse reproductive effects. Increased rate of miscarriages has been observed in human studies following acute and chronic exposures. Animal studies have shown decreased number of implantation sites, decreased testicular weights and sperm concentration, and testicular degeneration.

Several epidemiological studies have indicated a possible association of ethylene oxide and spontaneous abortion, however exposure data is lacking. Hemminki et al. (1982) analysed spontaneous abortions in Finnish hospital sterilizing staff using data from a questionnaire and from a hospital discharge register. The study included all sterilizing staff employed in Finnish hospitals in 1980, with the controls being nursing auxiliaries. When the women were involved in sterilizing procedures during their pregnancies, the frequency of spontaneous abortion was 16.7% versus 5.6% for the controls. The independent analysis of spontaneous abortions using the hospital discharge register confirmed the findings. The authors concluded that ethylene oxide exposure may be associated with an increased risk of spontaneous abortion among sterilizing staff.

In a similar study of dental assistants, Rowland et al. (1996) examined 1320 women whose most recent pregnancy was conceived while working full-time. Thirty-two women reported exposure to ethylene oxide. Among the exposed women, the age-adjusted relative risk (RR) of spontaneous abortion was found to be 2.5 (95% CI = 1.0-6.3). The RR for pre-term birth was 2.7 (95% CI = 0.8-8.8) and the RR for post-term birth was 2.1 (95% CI = 0.7-5.9). It should be noted that none of the results were found to be statistically significant from the controls.

In the only study identified in which the effect of paternal exposure to ethylene oxide on reproductive outcome was assessed, Lindbolm et al. (1991) reported a significantly increased risk of spontaneous abortion (odds ratio = 4.7; 95% CI = 1.2-18.4) among Finnish women whose partners had been exposed to ethylene oxide. In total, 99186 pregnancies were included in the analysis. Paternal exposure to ethylene oxide was based upon the job and industry in which the men were employed. Quantitative data on exposure were not available and the numbers of spontaneous abortions (n = 3) and pregnancies (n = 10) in the paternal ethylene oxide-exposed group were small. Other potential confounding factors, such as previous abortions and alcohol and tobacco consumption were not considered in the analysis.

Exposure of females during gestation has been associated with decreased fetal weight, decreased fetal implants and increased resorptions were observed at 180 mg/m3 and up in rats but not rabbits (Hardin et al., 1983; Snellings et al., 1982a; 1982b). Generoso et al. (1987) investigated the effects of ethylene oxide in conceptuses of female mice that


11

were exposed by inhalation prior to or during gestation, under treatment regimes of 2160 mg/m3 for 1.5 hours per day for 4 days or 540 mg/m3 for 6 hours per day, 5 days per week, for 2 weeks. Mated females exhibited a high incidence of mortality among conceptuses and of congenital abnormalities among dead and surviving fetuses only if exposure was at the time of fertilization or during early pronuclear stage of the zygote.

In a study conducted by the NTP (1983), ethylene oxide (0, 9, 18 or 36 mg/kg/day) was administered intravenously to rabbits on gestational days 6 through 14. Exposure to ethylene oxide resulted in mortality rates of 0% (controls), 8.3% (9 mg/kg/day ethylene oxide), 4.2% (18 mg/kg/day ethylene oxide) and 22.2% (36 mg/kg/day ethylene oxide). Measures of maternal body weight, maternal weight gain and gravid uterine weight were all found to be decreased in a dose-related manner. Examination of uterine contents exhibited significant dose-related increases in the percentage of resorptions, non-viable and affected fetuses per litter. Average live litter size was found to be decreased in a dose-related manner, as was the percentage of males per litter. No evidence of a treatment-related teratogenic effect was observed, even at dosages found to produce maternal and fetal toxicity.

No reproductive effects were noted in male Fischer-344 rats exposed to 60 mg/m3 ethylene oxide for 6 hours per day for 12 weeks prior to mating (Snellings et al., 1982a, 1982b). At concentrations of 900 mg/m3 (6 hours per day, 3 days per week, for 2, 4, 6, or 13 weeks), male rats exhibited a dose-related decrease in testes weight after 4 weeks; a severe loss of germ cells and marked morphological changes in remaining germ cells after 6 weeks; an awkward gait after 6-9 weeks; and progressive degeneration and loss of germ cells at 13 weeks of exposure (Kaido et al., 1992). The intact spermatids after 13 weeks suggest recovery of spermatogenesis (OEHHA, 2000). No significant changes in body weight were observed. Similarly, male monkeys exposed to 90 mg/m3 ethylene oxide for 7 hours per day, 5 days per week, for 2 years exhibited decreased sperm counts and motility (Lynch et al., 1984a).

A recent study by Evans et al. (2001) reported the results of a meta-analysis of the available animal reproductive and developmental data concerning the effects of ethylene oxide. The study reported a range of values for the Effective Dose (ED10), which is defined by the U.S. EPA as the dose corresponding to a 10% increase in an adverse effect. The reproductive endpoints examined were resorptions and fetal deaths with ranges of ED10 values of 8.5-19.8 mg/m3. The developmental endpoint examined was body weight reduction with ranges of ED10 values of 12.6-216 mg/m3. The study concluded that the reproductive studies yielded ED10s on the order of 9 to 18 mg/m3 for fetal death, and values only slightly higher than this for resorption. The developmental studies suggest that a 5% reduction in mean fetal weight occurs at concentrations on the order of 9 to 54 mg/m3. The authors concluded that reference concentrations, based on these values and computed applying standard regulatory approaches (e.g., such as those of the U.S. EPA) to data for the critical effect in the critical study, would be in range of 54 to 90 µg/m3.


12

3.4 Genotoxicity and Mutagenicity

Ethylene oxide alkylates DNA and is considered to be a direct-acting mutagen based on overwhelmingly positive in vivo responses in mutagenic and clastogenic assays (ATSDR, 1990; CEPA, 2001; U.S. EPA, 1985; WHO, 1985).

In ethylene oxide-exposed humans, examination of peripheral blood lymphocytes revealed chromosomal aberrations including breaks, gaps, and exchanges, supernumerary chromosomes, and increased incidence of sister chromatid exchange (SCE) (Ashby and Richardson, 1985; Clare et al., 1985; Galloway et al., 1986; Garry et al., 1979; Lambert and Lindblad, 1980; Laurent, 1988; Pero et al., 1981; Richmond et al. 1985; Sarto et al., 1984a, 1984b; Stolley et al., 1984; Thiess et al., 1981; Tucher et al., 1986; Yager et al., 1983). de Jong et al. (1988) did not find any biologically significant increase in the frequencies of chromosome aberrations in genotoxin-exposed populations (including ethylene oxide-exposed populations) relative to control populations, and suggested the method is not sufficiently sensitive for routine monitoring of cytogenetic effects.

More recent studies examining the genotoxicity and mutagenicity of ethylene oxide in occupationally exposed humans (3.7 - 60.4 mg/m3) have reported increases in micronuclei in peripheral blood (Tates et al., 1991; Ribeiro et al., 1994). However, in the majority of studies involving exposure to lower levels of ethylene oxide, no effect on the frequency of micronuclei was observed (CEPA, 2001).

Acute and chronic animal studies also give evidence of genotoxicity which show increased incidences of SCE and chromosomal aberrations (Kelsey et al., 1988; Kligerman et al., 1983; Lynch et al., 1984c; Ribeiro et al. 1987a). A positive mutagenic response in mice and rats was observed in dominant lethal assays for inhalation exposure to ethylene oxide (Cumming and Michaud, 1979; Embree et al., 1977; Generoso et al., 1986, 1988). Based on studies by Generoso et al. (1986), acute exposure to high concentrations of ethylene oxide is more likely to cause germ cell damage than chronic low-level exposure. Lewis et al. (1986) observed that the offspring of male rats repeatedly exposed to ethylene oxide by inhalation during spermatogenesis had an increased incidence of mutations which suggests that ethylene oxide may cause heritable damage. Similarly, Sega and Generoso (1988) and Ribeiro et al. (1987b) observed DNA breakage or sperm head morphology changes in spermiogenic stages of the mouse after exposure to ethylene oxide. Increases in the frequency of gene mutations in the lung (lacI locus) (Sisk et al., 1997) and in T-lymphocytes (Hprt locus) (Walker et al., 1997a,b) in mice exposed to ethylene oxide via inhalation, at concentrations of 0, 90, 180, 360 mg/m3 for a period of 4 weeks (6 hours/day, 5 days/week). In a recent study, a 5-fold increase in the frequency of lacI mutations was observed in bone marrow cells in mice following exposure to 360 mg/m3 of ethylene oxide, 6 hours/day, 5 days/week, for 48 weeks (Recio et al., 1999). However, the study


13

results did not exhibit an increase in mutation frequency following exposures either to lower concentrations or shorter durations. van Sittert et al. (2000) examined the formation of DNA adducts and the induction of mutagenic effects in rats exposed to 0, 90, 180, 360 mg/m3 in a 4-week study. Statistically significant linear relationships between DNA adduct formation [N7-(2-hydroxyethyl)guanine] and Hprt mutant frequencies were reported. However, no statistically significant dose-response relationships were found for induction of micronuclei, chromosome breaks or translocations. The authors concluded that long-term exposure to ethylene oxide at or below 1800 µg/m3 (1 ppm) does not likely represent an unacceptable risk in humans (van Sittert et al. 2000).

In vitro studies reported positive dose-related mutagenic responses of ethylene oxide to Salmonella typhimurium strains TA100 and TA1535, and E. coli , but not S. typhimurium strains TA1537, TA97, or TA98 (Hughes et al., 1984; Hussain, 1984; Pfeiffer and Dunkelberg, 1980; Victorin and StDhlberg, 1988). Treatment of Chinese hamster V79 cells and Syrian hamster embryo cells with gaseous ethylene oxide yielded concentration-related, quantitative mutagenicity (Hatch et al., 1986).

3.5 Carcinogenicity

Ethylene oxide is classified as a probable human carcinogen of medium carcinogenicity (Group B1, probably carcinogenic to humans) by the U.S. EPA (1985). IARC (1994) has classified ethylene oxide in Group 2A (probable human carcinogen) based on limited evidence in humans and sufficient evidence in animal studies. Health Canada in a recently completed toxicological review of ethylene oxide concludes that this substance is highly likely to be carcinogenic to humans (CEPA, 2001). Occupational exposure data show an increase in the incidence of leukemia, stomach cancer, cancer of the pancreas, and Hodgkin’s disease. Animal data show increases in lung, gland, and uterine tumours. Biomarkers for carcinogenicity of ethylene oxide have not been identified (ATSDR, 1990).

Human studies

Morgan et al. (1981) examined mortality due to cancer in 767 workers potentially exposed to ethylene oxide in a Texaco plant with a minimum of 5 years of exposure. Time-Weighted Averages (TWAs) were estimated to be less than 18 mg/m3, though exposure to peak concentrations of ethylene oxide would also be expected (Golberg, 1986). No increases of mortality due to cancer were observed.

Thiess et al. (1981) examined mortality due to cancer in 602 workers exposed to alkylene oxides and their derivatives between 1928 and 1980 at 8 German production plants with an average operation period of 14 years. On average, exposures were less than 18 mg/m3 with occasional peaks as high as 3,600 mg/m3. No mortality was


14

observed in greater than 50% of individuals in the 10-year observation period. No increases of mortality due to cancer were observed.

Högstedt et al. (1979a) examined mortality of male workers in an ethylene oxide production plant. Average exposures ranged from 9 to 36 mg/m3, with occasional peaks above the odour threshold (1,260 mg/m3). No mortality was observed within a 10-year latent period following first exposure at the plant for 89 men directly exposed, 86 men intermittently exposed, and 66 men never exposed. Following the latency period, the authors observed an increased incidence of deaths due to cancer in the directly exposed group including malignant neoplasms, stomach cancer, leukemia, and circulatory diseases. No effects were observed in the intermittently and non-exposed groups.

Högstedt et al. (1979b) reported that three employees developed chronic myeloid leukemia, acute myelogenous leukemia, or macroglobulinemia following exposure to 50-50 mixture of ethylene oxide and methyl formate in a sterilization plant. The authors reported that the incidence of leukemia (3/230) is higher than the expected 0.2/230. Golberg (1986) noted that it is difficult to attribute risks to ethylene oxide since a rigorous statistical analysis was not possible, a cohort was not identified, health experience was not traced over time, and exposure was to a chemical mixture.

Greenberg et al. (1990) conducted a study of 2174 workers employed at ethylene oxide production plants in the United States, for which a 10-year update of this cohort, which excluded 278 chlorohydrin workers, was reported by Teta et al. (1993). Comparisons were with both the general population and unexposed workers in the plants. In this cohort, there were no statistically significant increases in deaths from any cause for the entire cohort. The study reported standardized mortality ratios (SMRs) for cancer of the stomach and pancreas, brain and nervous system, and leukemia were 160 (95% CI = 69-315; 8 observed deaths), 61 (95% CI = 17-156; 4 observed deaths) and 150 (95% CI = 55-327; 6 observed deaths), respectively (Teta et al., 1993). Although no increased mortality was observed among men from the high-exposure departments, a statistically significant excess of deaths due to stomach cancer was observed in the intermediate-exposure group (SMR = 364; 95% CI = 102-957; 4 observed deaths). When risks associated with duration of assignment were examined, there were no significant trends for all cancers, leukemia, brain, or stomach cancers. However, the relative risk for stomach cancer (2.77; 95% CI = 1.11-6.93; 5 observed deaths) was found to be significantly elevated for those exposed from 2 to 9 years.

In a large cohort consisting of 18254 male and female workers, Steenland et al. (1991) examined mortality in those workers exposed to ethylene oxide at 14 plants producing sterilized medical supplies and spices in the United States. Comparisons were made with the U.S. general population. A more detailed analysis of exposures in this cohort was subsequently performed by Stayner et al. (1993), being restricted to workers from 13 of the 14 original facilites having adequate information for estimating historical


15

exposures. The predicted exposures to ethylene oxide were estimated to be 2.0 mg/m3 (standard deviation of 6.8 mg/m3) from a sample size of 2350 individual Time-Weighted Average (TWA) exposure values acquired from 18 facilities between 1976 and 1985 (Greife et al., 1988). For the entire cohort, there was no increase in mortality from hematopoietic cancer. There was a slight, but significant increase among men, however, but a decrease among women (Steenland et al., 1991). The SMR for deaths due to “all hematopoietic neoplasms” among the groups with the highest cumulative exposure was 124 (not statistically significant; 95% CI = 66-213). For the group with the highest cumulative exposure, the SMRs for non-Hogkin’s lymphoma and leukemia were 192 (95% CI = 77-395) and 75 (95% CI = 15-218), respectively. Increased mortality from kidney cancer (SMR = 322; 95% CI = 139-635) was observed in the mid-cumulative exposure group; however, no trend with exposure was observed (Stayner et al., 1993).

Cancer risks were not found to be significantly increased in a cohort of 2170 male and female Swedish workers exposed to ethylene oxide at two plants producing disposable medical equipment (Hagmar et al., 1995). The risk of lymphopoietic/haematopoietic cancers was elevated (standardized incidence ratio [SIR] = 1.78; 95% CI = 0.65-3.88; 6 observed cases); two of the cases had leukemia (SIR = 2.44; 95% CI = 0.3-8.81). Cases with leukemia were reported to have a slightly higher cumulative exposure to ethylene oxide than the average cohort member (median exposure = 234 µg/m3-year). The study reported that the exposure levels were relatively low for most of the workers, as fewer than 200 workers had more than 1800 µg/m3-year of cumulative exposure.

A cohort consisting of 1361 male workers in ethylene oxide and propylene oxide production plants were examined by Olsen et al. (1997). Individuals that were included in the cohort were considered to have had a minimum of 30 days of workplace experience during the period of 1940-1992 within the ethylene chlorohydrin and propylene chlorohydrin process areas. A total of 300 deaths was observed up until the end of 1992. The SMR for all malignant neoplasms was reported as 94 (95% CI = 74-118). One case of pancreatic cancer death was reported compared with 4.0 that were expected (SMR = 25; 95% CI = 1-140). Ten cases of lymphopoietic and haematopoietic deaths were also reported compared with 7.7 that were expected (SMR = 129; 95% CI = 62-238).

A meta-analysis of results from 13 epidemiological studies published between 1979 and 1993 was conducted by Shore et al. (1993). The magnitude and the consistency (heterogeneity) of the relative risks were evaluated for the individual and combined studies, along with any trends associated with intensity or frequency of exposure or duration of exposure for the cancers of greatest interest (cancers of the pancreas, brain, stomach, leukemia and non-Hodgkin’s lymphoma). For leukemia the summary SMR (sSMR) was 1.06 (95% CI = 0.73-1.48). Similarly, the sSMR for non-Hodgkin’s lymphoma was not significantly increased (1.35; 95% CI = 0.93-1.90). Although risks associated with the frequency or intensity of ethylene oxide exposure could be


16

examined in only three studies, no trends were observed in either the individual or combined studies, although a positive trend by cumulative exposure in the largest study was noted. No trends with respect to duration of exposure or latency were noted. The overall sSMR for stomach cancer for all of the studies was reported as 1.28 (95% CI = 0.73-2.26), while the sSMRs for pancreatic cancer (0.98; 95% CI = 0.69-1.36), brain and nervous system cancer (0.89; 95% CI = 0.39-2.04) and all cancers (0.94; 95% CI = 0.88-1.01) were not increased, nor were any trends observed (Shore et al., 1993). The authors also noted that data on exposure to ethylene oxide were inadequate in most of the studies, but that the cumulative exposure analysis by Stayner et al. (1993) represented a significant advance in the quantitative analysis of effects of ethylene oxide.

Teta et al. (1999) reported on an update of the Shore et al. (1993) meta-analysis, using methods and studies similar to those employed by Shore et al. (1993), and in addition, data from two more recent studies of Hagmar et al. (1995) and Olsen et al. (1997) were also included. Similar to the findings reported by Shore et al. (1993), the meta-SMRs for non-Hodgkin’s lymphoma, leukemia, and cancer of the pancreas, brain and stomach were 1.34 (5% CI = 0.96-1.89), 1.08 (95% CI = 0.61-1.93), 0.95 (95% CI = 0.69-1.31), 0.96 (95% CI = 0.49-1.91) and 1.23 (95% CI = 0.71-2.13), respectively. The study by Teta et al. (1999) found that there were no statistically significant trends with respect to duration, intensity or latency of exposure, except there was a statistically significant trend observed with respect to latency for brain cancer. This latter observation was obtained from results of four studies with latency data for brain cancer included in this meta-analysis study of Teta et al. (1999).

Animal studies

NTP (1987) observed mammary gland tumours, harderian gland papillary cystadenomas, and alveolar/bronchiolar carcinomas and adenomas in mice exposed to 90 mg/m3 ethylene oxide for 6 hours per day, 5 days per week, for 2 years. Females exhibited malignant lymphomas and uterine adenocarcinomas at 180 mg/m3. Lynch et al. (1984b) observed peritoneal mesothelioma and mononuclear cell leukemia in rats at 90 mg/m3 and brain tumours at 180 mg/m3 when exposed to ethylene oxide for 7 hours per day, 5 days per week for 2 years.

Six-week old Fisher 344 rats, in five groups of 120 animals of each sex, were exposed to ethylene oxide vapour by inhalation at 0, 10, 33, 100 ppm (0, 18, 60 and 180 mg/m3) for 6 hours per day, 5 days per week, for approximately 2 years (Snellings et al., 1984b). Two control groups were exposed to room air. A significant depression in body weight gain was observed in rats treated with 60 and 180 mg/m3 ethylene oxide and there was a significant increase in mortality in the 180 mg/m3 group. An increased incidence of primary brain tumour was observed in rats of both sexes after 18 months of exposure to 60 and 180 mg/m3 ethylene oxide. However, at 24 months, there were no statistically significant differences in the prevalence of brain tumours between groups for either sex


17

groups, except a numerical increase in the 180 mg/m3 group. After 24 months, haematologic evidence indicated dose-related increases of mononuclear cell leukemia in the three ethylene oxide-treated groups. Statistical significance was observed only in the females of the 180 mg/m3 group for this tumour type, however, the tumour frequencies of the various ethylene oxide exposed groups were dose-related. An increased frequency of peritoneal mesothelioma in male rats exposed to 60 and 180 mg/m3 was observed.

Garman et al. (1985) observed a dose-related carcinogenic response of F344 rats to ethylene oxide concentrations greater than 18 mg/m3. An increased incidence of brain tumours was observed in rats exposed to 60 mg/m3 and above. Adkins et al. (1986) observed significant increases in pulmonary adenoma formation in A/J mice following exposure to 126 and 360 mg/m3 for 6 hours per day, 5 days per week, for 6 months.

3.6 Environmental Effects

Based on empirical data, release of ethylene oxide to the atmosphere is unlikely to result in transfer to either soil or water in significant quantities (CEPA, 2001). While degradation reactions in the atmosphere may have long half-lives (38 to 382 days), there is also evidence that if it is washed out by precipitation that hydrolysis will quickly degrade ethylene oxide (half-life of 9 to 14 days). Revolatilization from the water will also be rapid (half-life about 1 hour). Based on a low Kow, the potential for bioaccumulation of ethylene oxide is likely very low (CEPA, 2001). It is also not expected to bioaccumulate or accumulate in sediment or soil due to its high water solubility and vapour pressure (CEPA, 2001).

Death of five plant species occurred with atmospheric concentrations as high as 1,742 mg/m³ after seven days of exposure, whereas no effects were observed at 174.2 mg/m³ (Heck and Pires, 1962). Ethylene oxide was also reported to affect germination of seeds, and to show mutagenic activity in plants (EPS, 1985). A 5-fold increase in sterility caused by chromosomal aberrations occurred when barley seeds were exposed to a gaseous ethylene oxide concentration of 1,500,000 mg/m³ (80%) for 6 days (Ehrenberg et al., 1956).

In aquatic organisms, slight to moderate adverse effects of ethylene oxide on survival occur in several species of bacteria, fish and invertebrates. Toxicity tests indicated a 16-hour IC50 for activated sludge microorganisms of 10 to 100 mg/L (Conway et al., 1983), 24-hour LC50 of 90 mg/L for goldfish (Bridie et al., 1979), 24-hour LC50 ranging from 260 to 300 mg/L and 48-hour LC50 ranging from 137 to 300 mg/L for the crustacean Daphnia magna (Conway et al., 1983), 24-hour LC50 of 274 mg/L and 90 mg/L (aerated and no aeration) and 96-hour LC50 ranging from 57 mg/L to 84 mg/L (no aeration) for fathead minnows (Conway et al., 1983; Dow, 1975).


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4.0

Due to the rapid loss of ethylene oxide from soil and water, it is unlikely that it will be accumulated to any significant degree in terrestrial or aquatic organisms. In addition, it has low to moderate toxicity and is therefore unlikely to have a significant impact on ecological receptors at a level that is protective of human health.

Review of Existing Air Quality Criteria

4.1 Overview

Currently in Ontario, the 24-hour AAQC and half-hour Point of Impingement standards are 5 and 15 μg/m3, respectively, based on health considerations.

In revising the air quality standards for Ontario, the Ministry of the Environment is considering risk assessments and the scientific rationale of guidelines and criteria used by other environmental protection agencies. This report reviewed the scientific basis for air quality guidelines and criteria developed by from Environment Canada and Health Canada, Alberta, Newfoundland, Quebec, U.S. EPA, California, Massachusetts, Michigan, New York, North Carolina, Texas and some other U.S. state jurisdictions as well as in the European Community. Agency-specific summaries of guidelines are presented in Section 10. A brief summary of available criteria is presented in Table 1.

In reviewing the air quality guidelines and exposure limits presented in Table 1, it should be noted that the Ministry of the Environment typically uses a factor of 15 to convert from guidelines based on annual average concentrations to half-hour point-of-impingement limits and a factor of 3 to convert from guidelines based on 24-hour average concentrations. These factors are derived from empirical measurements and are selected to ensure that if the short-term limit is met, air quality guidelines based on longer-term exposures will not be exceeded. However, depending on the health end-point being considered, other conversion factors may also be employed.

A few of the Canadian provincial jurisdictions (e.g. Alberta and Newfoundland/ Labrador) appear to have adopted the Ontario limits for ethylene oxide (Table 1). The province of Quebec has an annual average air guideline of 0.01 μg/m3 for ethylene oxide that was derived from a provisional U.S. EPA inhalation unit risk factor of 1.0x10-4 (µg/m3)-1. A Priority Substance List Assessment Report has recently been released by Environment Canada and Health Canada for ethylene oxide (CEPA, 2001). A TC05 (Tumourigenic Concentration; the concentration of ethylene oxide causing a 5% increase in tumour incidence over background) of 2200 µg/m3 based on their evaluation of a number of animal studies (Garman et al., 1985; Garman and Snellings, 1986; Lynch et al., 1984a, b; NTP, 1987; Snellings et al., 1984b) was determined. With the application of an appropriate uncertainty factor, the TC05 value can be used to derive a corresponding air


19

concentration of 0.04 μg/m3, which is associated with an increased lifetime risk of cancer at one in a million.

The United States has no federally implemented air guidelines for ethylene oxide, although the state of Louisiana has adopted a guideline value based on the provisional inhalation unit risk value of 1.0 x10-4 (µg/m3)-1 derived by the U.S. EPA in an early health assessment for ethylene oxide (U.S. EPA, 1985). The U.S. EPA is reassessing the toxicological information for ethylene oxide in an effort to update their Integrated Risk Information System (IRIS). Currently, the U.S. EPA is proposing to reference to the State of California’s chronic REL and inhalation unit risk value for ethylene oxide (U.S. EPA, 2002). The state of North Carolina is currently using an air quality guideline based on an older U.S. EPA provisional inhalation unit risk factor of 3.6x10-4 (µg/m3)-1, which is equivalent to an air concentration of 0.027µg/m3 for a cancer risk of 10-5.

The California EPA (CalEPA) has developed both a non-cancer, chronic Reference Exposure Level (REL; OEHHA, 2000) and an inhalation unit risk factor (OEHHA, 1999) for ethylene oxide for ambient air. The chronic REL value of 30 µg/m3 was developed based on neurobehavioural effects observed in mice in the study by Snellings et al. (1984a). The study by Snellings et al. (1984b) formed the basis of the inhalation unit risk value of 8.8x10-5 (µg/m3)-1 derived based on the development of mononuclear cell leukemia in rats chronically exposed to ethylene oxide via inhalation (OEHHA, 1999). As mentioned previously, the U.S. EPA is proposing to adopt both of these guideline values. The State of New Jersey has also adopted the CalEPA guideline values (chronic REL and inhalation unit risk) as their air guidelines.

Table 1: Summary of Existing Air Quality Guidelines1 for Ethylene Oxide

Agency Guideline Value Basis of Guideline Date2 Comments

Canada (CEPA)

2200 µg/m3

(TC05)

Mononuclear cell leukemia in rats (Snellings et al., 1984b; Garman et al., 1985; Garman and Snellings, 1986).

2001 The TC05 is the Tumorigenic Concentration associated with a 5% increase in incidence or mortality due to tumours. The TC05, after the application of an uncertainty factor of 50,000, corresponds to an air concentration of 0.04 µg/m3, which is associated with a 10-6 increased risk of cancer

15 µg/m3

(half-hour average, POI limit)

Reproduction, mutagenicity, carcinogenicity.

1986 Half-hour Point of Impingement limit

Ontario

(MOE)

5 µg/m3

(24-hour AAQC)

Reproduction, mutagenicity, carcinogenicity.

1986 Ambient Air Quality Criteria


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Alberta

15 μg/m3

(half-hour average)

Derived from Ontario guideline 2000 Ambient Air Quality Guideline

Newfoundland and Labrador

5 µg/m3

(24-hr standard)

Derived from Ontario guideline 1996

Quebec 0.01 µg/m3

(Annual criterion)

Based on a provisional U.S. EPA inhalation unit risk factor of 1.0 × 10-4 (µg/m3) -1

1990 The annual criterion corresponds to a unit risk factor of 1.0x10-4 µg/m3, with an associated lifetime cancer risk of 10-6

2004 An RfC of 30 µg/m3, based on the chronic REL of the CalEPA, has been proposed by the U.S. EPA (2002). This value is not available on IRIS.

U.S. EPA

(IRIS)

2004 A unit risk factor of 8.8x10-5, (µg/m3)-1 based on the CalEPA’s unit risk factor, has been proposed by the U.S. EPA (2002). This proposed unit risk factor is not available on IRIS.

8.8x10-5 (µg/m3)-1

(unit risk factor)

Mononuclear cell leukemia in rats (Snellings et al., 1984b).

1999

The unit risk factor corresponds to an air concentration of 0.01 µg/m3, which is associated with a 10-6 increased risk of cancer

California

(OEHHA)

30 µg/m3

(Chronic REL)

Neurobehavioural (CNS) effects in mice (Snellings et al., 1984a).

2000

Chronic Reference Exposure Level.

Louisiana

(DEQ)

1 µg/m3

(Annual AAS)

Based on a provisional U.S. EPA inhalation unit risk of

1.0x10-4 (µg/m3) -1

1995 AAS corresponds to an acceptable cancer risk of 10 -4.

Massachusetts

(DEP)

No guideline listed.

0.03 µg/m3

(Annual IRSL)

Michigan

(DEQ)

0.3 µg/m3

(Annual SRSL)

Mononuclear cell leukemia in rats (Snellings et al., 1984b).

1982

Initial Risk Screening Level is based on a 10-6 cancer risk and the Secondary Risk Screening Level is based on a 10-5 cancer risk.


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42 µg/m3

(1-hour RfC)

Based on a U.S. EPA assessment (U.S. EPA, 1992) that derived an acute value to protect against development effects

2001 1-hour Reference Concentration based on acute exposure

30 µg/m3

(annual RfC)

Based on the CalEPA’s Chronic REL

2001 Long-term Reference Concentration

New Jersey

(DEP)

8.8x10-5 (µg/m3)-1

(unit risk factor)

Based on the CalEPA’s unit risk factor

2001 The unit risk factor corresponds to an air concentration of 0.01 µg/m3, which is associated with a 10-6 increased risk of cancer

18 µg/m3

(1-hour SGC)

1995 Short-term Guideline Concentration.

New York

(DEC)

0.019 µg/m3

(AGC)

Based on cancer risk associated with the use of sterilizers in hospitals. The limits were developed for specific use within the State of New York only. 1995 Annual Guideline Concentration.

North Carolina

(DENR)

0.027 µg/m3

(annual AAL)

Out-dated EPA inhalation unit risk of 0.00036 (µg/m3) -1

1998 AAL based on target cancer risk level of 10-5.

Ohio

(OEPA)

43 μg/m3

(1-hour MAGLC)

Derived from the ACGIH’s TLV-TWA of 1800 μg/m3

1999 MAGLC - Maximum Acceptable Ground-Level Concentration

20 μg/m3

(1-hr ESL)

Texas

(TCEQ)

2 μg/m3

(Annual ESL)

Derived from the ACGIH’s TLV-TWA of 1800 μg/m3

2003 ESL - Effects Screening Level

0.03 µg/m3

(target value)

No information. 1999 A target value is the ultimate objective that might eventually become similar to the limit value.

The Netherlands

3 µg/m3

(limit value)

No information. 1999 A limit value may not be exceeded (unless impossible).


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Sweden 0.09 µg/m3

(long-term guideline)

Based on a U.S. EPA (1985) assessment of Snellings et al. (1981)

1992 The long-term guideline corresponds to a unit risk factor of 1.0x10-4 (µg/m3)-1, with an associated lifetime cancer risk of 10-5

WHO

(Europe)

No guideline listed. No guideline listed.

WHO

(PHE)

No guideline listed. No guideline listed.

1. Guidelines in this table can refer to: guidelines, risk-specific concentrations based on cancer potencies, and non-cancer based reference concentrations.

2. Date here refers to when the health-based guideline background report or original legislative initiative was issued. The sources were the respective agency documents. For the U.S. EPA, date refers to when the latest review of the RfC was conducted, if applicable, or the date the IRIS database was accessed, in the case where no RfC has been developed.

The states of New York and Michigan have derived air guidelines for ethylene oxide in air. New York has developed both a short-term guideline (18 µg/m3) and an annual guideline (0.019 µg/m3 for carcinogenic effects). The guidelines derived by the Sate of New York were based on a state specific case on the use of sterilizers in hospitals. These values were derived by the state for their own specific use and are not applicable to ambient air situations (De Santis, 2002). The State of Michigan derived air guidelines with data from the study of Snellings et al. (1984b). The annual guideline value of 0.03 µg/m3 corresponds to increases in lifetime cancer risk at one in a million.

The remaining U.S. states, for example Ohio and Texas, derived respective air guidelines based on occupational exposure limits from the Threshold Limit Value-Time Weighted Average (TLV-TWA) of 1800 μg/m3 of the American Conference of Governmental Industrial Hygienists (ACGIH). The ACGIH TLV-TWA value was based on reduction of the potential oncogenic risk and the risk from potential non-neoplastic adverse effects on lungs, liver, kidneys, endocrine system, haematopoietic system and the CNS (ACGIH, 2002a).

The Netherlands has also developed both target and limit values of 0.03 and 3 µg/m3, respectively, for ethylene oxide. However, the basis of these values is not known, as no supporting documentation was available. Sweden has also developed a long-term guideline for ethylene oxide based on its carcinogenic potential. The guideline value of 0.09 µg/m3 was derived based on the U.S. EPA’s health assessment document of 1985 (U.S. EPA, 1985), which described the carcinogenic potential of ethylene oxide as


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reported in the 1981 study of Snellings et al. (Victorin, 1998). The long-term guideline value corresponds to an increased lifetime cancer risk of 10-5 (Victorin, 1998).

4.2 Evaluation of Existing Criteria

There appears to be a common agreement among the various agencies that carcinogenicity is the most sensitive endpoint for air guidelines development. The CalEPA has also developed a guideline based on a noncancer endpoint for neurobehavioural changes in mice that has been adopted by some U.S. states.

The carcinogenicity of ethylene oxide has recently been reviewed and discussed by Environment Canada and Health Canada in the Priority Substance List Assessment Report for Ethylene oxide (CEPA, 2001). Most of the epidemiological cancer data come from occupational studies.

Environment Canada and Health Canada commented on the inconsistent evidence of increases in reported mortality due to liver, colon, breast, bladder, kidney, oesophageal, stomach, brain or pancreatic cancer from epidemiological studies. There is, however, suggestive but inconclusive evidence for an association of ethylene oxide exposure and lymphopoietic/haematopoietic cancers in occupationally exposed populations (CEPA, 2001). Based on a small number of observations, the excess cases of cancer were noted in workers who were exposed primarily to ethylene oxide from the sterilization of medical supplies and equipment facilities, rather than from facilities associated with the production or use of ethylene oxide where workers may have been exposed to many other substances. There is a weak association between ethylene oxide exposure and haematological cancers in view of traditional criteria for causality including exposure-response and temporal relationship. These agencies stated that there is rather consistent evidence that ethylene oxide interacts with the genome of cells within the circulatory system in occupationally exposed humans. This observation is overwhelmingly supported by evidence of biological plausibility from carcinogenicity and genotoxicity studies in experimental animals. In view of these considerations and the lack of qualitative differences in the metabolism between humans and laboratory animals, ethylene oxide is considered highly likely to be carcinogenic to humans.

In a recent review of toxicological data, Environment Canada and Health Canada considered that it is more appropriate to use animal data rather than epidemiological data to derive a cancer-based guideline. The weak epidemiological evidence of association between ethylene oxide exposure and incidence of cancers, the limitation of available human dose-response human data for a quantitative assessment, the consideration that the parent compound is the putative toxic entity, and the lack of definitive difference in the metabolism of ethylene oxide in humans and animals, Environment Canada and Health Canada have opted to employ animal carcinogenicity data from inhalation studies in their quantitative dose-response analysis.


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Environment Canada & Health Canada evaluated cancer risk estimates for different types of cancer from a number of animal studies. Environment Canada and Health Canada used linearized multistage modelling to fit the animal study data (as was also done by Michigan, CalEPA and the U.S. EPA in deriving their respective cancer-based guideline values). A number of TC05 values were calculated, following an examination of a number of tumour sites. A few examples are: mononuclear leukaemia, peritoneal mesothelioma, brain tumours in rats; malignant lymphomas, uterine adenocarcinoma and lung carcinomas in mice. Environment Canada and Health Canada determined that the TC05 of 2.2 mg/m3, based on leukaemia in female rats was the most appropriate basis for the cancer risk evaluation for ethylene oxide. No interspecies scaling to account for variations between inhalation rate to body weight ratios or body surface areas of human to animals has been incorporated. Environment Canada and Health Canada considered that:

1. the metabolism of ethylene oxide appears to be qualitatively similar in humans and in animals and that quantitative variations have not been well characterized;

2. the few PBPK models available for rats have not been scaled to humans; and

3. the parent compound (ethylene oxide) is the toxic entity and exposures of the same concentration and duration are expected to result in equivalent toxicity across species.

It would appear that Environment Canada and Health Canada rationalized the use of the most conservative TC05 value on the basis that the Exposure Potency Index (EPI) used in the prioritization for action in ethylene oxide risk management was similar if the next greatest potency from the studies in rats and mice with optimum characterization of exposure-response was used (CEPA, 2001). A risk-specific air concentration of 0.04 µg/m3, corresponding to an increased lifetime cancer risk of one in a million, can be derived from the TC05 value of 2.2 mg/m3 after applying an uncertainty factor of 50,000. The difficulty with values developed by Environment Canada and Health Canada is that their method of derivation is not characterized in detail for an evaluation. No details have been provided regarding the use or the disregard for the metabolic study of Tyler and McKelvey (1980) in deriving equivalent human doses. Therefore, caution should be exercised in the use of the TC05 value in the development of air quality standards.

Other jurisdictions that have developed cancer-based criteria, such as the U.S. EPA, the CalEPA and the Michigan State, also derived their respective guidelines for ethylene oxide from the study of Snellings et al. (1984b). Determination of the cancer-based guideline values among these jurisdictions varies. Methodological differences in risk assessment may account for the varying values. The U.S. EPA and CalEPA employed a linearized multistage model to fit the female rat leukemia dose-response data. The U.S. EPA derived its provisional cancer unit risk value based on the data of Snellings et al. (1984b) and used the metabolic data from the study of Tyler and McKelvey (1980) to


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5.0

convert exposed doses in ppm to equivalent human absorbed doses in mg/kg (U.S. EPA, 1985).

An inhalation unit risk value was originally developed by the CalEPA in 1987. The documentation supporting the unit risk value had been updated in a following review; however, the guideline value remained unchanged (OEHHA, 1999). The CalEPA made the assumption that the percentage of ethylene oxide absorbed by inhalation is the same for rats and for humans. The extrapolation of animal data from the Snellings et al. (1984b) study to equivalent human doses was accomplished using an average human body weight of 60 kg and an average air intake of 18 m3/day. The CalEPA also employed metabolic data from Tyler and McKelvey (1980) to convert exposed doses in ppm to equivalent human lifetime doses in mg/kg/d.

The State of Michigan derived its cancer-based guideline value with data reported by Snellings et al. (1984b). The State of Michigan disagreed with the CalEPA’s approach (and therefore, also the U.S. EPA’s approach) in the conversion of exposed doses to absorbed doses. The State of Michigan considered that the U.S. EPA used unpublished metabolic data from the Tyler and McKelvey study (1980) that was unavailability for a validation and therefore its use in developing a guideline value is inappropriate (MDEQ, 1991).

Non-cancer endpoints such as developmental effects (see New Jersey’s 1-hour RfC) and neurobehavioural effects (see CalEPA’s chronic REL) have been developed. The levels of ethylene oxide at which these non-cancer effects have been observed are many magnitudes above those having significant cancer risks.

From the information reviewed, no jurisdiction for which data was available specifically acknowledged an ecological component in the development of air standards for ethylene oxide. Based on the known chemical properties of ethylene oxide, the development of air quality criteria that are protective of human health (specifically the long-term guidelines) are, in all likelihood, protective of ecosystems as well.

Responses of Stakeholders to the Information Draft

In August 2005, the Ministry posted Information Draft documents for twelve chemicals, including ethylene oxide, for air standards development under the Standards Plan (MOEE, 1996; MOE, 1999) to the Environmental Registry. The Ministry requested input regarding: the completeness of relevant inhalation toxicological information examined by the Ministry; the rationale of the agencies that the Ministry has considered appropriate for the development of air quality standards; and specifically the application of interspecies metabolic conversion in the quantitative cancer risk analysis for humans.


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6.0

During the consultation period the Ministry received no submission from stakeholders regarding the Information Draft document for ethylene oxide.

Responses of Stakeholders to the Rationale Document

In June, 2006, the Ministry posted to the Environmental Registry a document titled “Rationale for the Development of Ontario Air Standards for Ethylene Oxide” and requested public comments over a period of 90 days. The Ministry received comments from five (5) stakeholders. There are two ethylene oxide-specific comments and three general comments. Highlights from these two comments are summarized below.

Comments Specific to ethylene oxide: Comment: • The use of rat mononuclear cell leukaemia data was not appropriate for human

cancer extrapolation. • The use of an uncertainty factor of 50,000 is overly conservative. • Epidemiological data do not unequivocally identify ethylene oxide as a carcinogen. • It was suggested to the MOE that more up-to-date technical and scientific data,

other than the unit risk factor of the CalEPA and Health Canada and Environment Canada, be used for the standards development for ethylene oxide.

• It was suggested that epidemiological data should be considered for air standards development.

• MOE should consider that ethylene oxide exposure and the development of leukaemia may be related in a nonlinear fashion and therefore a “quadratic”, rather than a “linear” quantitative model should be used to analyze the dose-response relationship. The arguments are:

– If the MOE considers less reliable incomplete data in its risk assessment, it may need to revisit critical issues once the risk assessment of the U.S. EPA is released to the Integrated Risk Information System (IRIS).

– Mode of action and empirical data support a nonlinear dose-response relationship for ethylene oxide exposure and leukaemia

– Chromosome aberrations and gene mutations are both important in the pathogenesis of human leukaemia.

– Chromosome aberrations require more than one hit from a monofunctional alkylating agent such as ethylene oxide and are expected to be proportionate to the square of the dose, i.e. a quadratic dose-response relationship.


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– Efficient DNA lesion repair may fix genotoxic effects (mutations and chromosome aberrations) and a threshold is expected for the carcinogenic response.

– Chromosome aberrations in human peripheral lymphocytes are not the key events in the production of leukaemia. Peripheral blood lymphocytes are not the target cells for leukaemia; for the in vitro cell culture system, stimulated proliferation of lymphocytes does not allow sufficient time for DNA repair to work.

– Three sources of empirical evidence of nonlinearity are as follows: ▪ Evidence of nonlinearity observed from exposure-response data

analyses from the epidemiological studies of Kirman et al., (2004) and Teta et al., (1999); substantial change in slope of the response with increasing exposure.

▪ Nonlinear relationship observed between ethylene oxide exposure and heritable chromosome translocations in mice (Generoso et al., 1990)

▪ Improved interspecies concordance between human and animals dose-response data with the use of a quadratic model (Kirman et al, 2004)

• The risk-based concentrations at a one in a million risk level for ethylene oxide in the air may be too stringent with the use of rodent data for dose-response analysis, e.g. (U.S. EPA, OEHHA, HC) RSC: 0.0055, 0.0063, 0.017 ppb (0.01, 0.011, 0.03 µg/m3) respectively. MOE’s proposed annual AAQC of 0.04 µg/m3, based on old rodent data, can result in risk-based concentrations that are below those associated with background levels of ethylene oxide and endogenous production of ethylene oxide. Data on ambient air background concentrations and endogenous concentrations are available or can be predicted:

– In southern Ontario, estimated concentration of ethylene oxide is 0.0034 ppb

(0.006 µg/m3), based on fugacity model Level 3 with the use of air concentration data from the US: Michigan – 0.0027 ppb (0.005 µg/m3) and New York – 0.0033 ppb (0.006 µg/m3.)

– Atmospheric background: 0.0016 ppb (0.003 µg/m3) at remote costal locations of California in 1987.

– Atmospheric concentration estimate obtained from residential samples collected in Canada, based on one-half of the limit of detection, as reported by Health Canada and Environment Canada was 0.095 µg/m3.

– Endogenous ethylene oxide: range of endogenous concentrations estimated to be equivalent to exposure to 0.14 – 0.6 ppb (0.25 – 1.1 µg/m3) of ethylene oxide.

– Exposure to ambient ethylene (0.0107 – 0.498 ppm or 0.03 – 0.089 mg/m3) and PBPK extrapolation corresponds to equivalent ethylene oxide inhalation exposure of 0.18 – 7.9 ppb (0.32 – 14.2 µg/m3) for air.


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Response: In developing air standards the Ministry generally considers the most sensitive endpoint in protecting human health or the environment (e.g., endpoints may be related to human health, odour, effects on vegetation, soiling of property). This way less sensitive endpoints are also protected. For ethylene oxide, the MOE is proposing air standards based on the carcinogenic effects of this chemical.

The MOE is aware of the fact that a few controversial carcinogenic assessment issues have developed between the U.S. EPA and the Ethylene Oxide/Ethylene Glycols Panel of the American Chemistry Council (representing a variety of chemical industries using or manufacturing ethylene oxide in the US) shortly following the Ministry’s public consultation period in September 2006. Many of the issues are related to the stakeholder comments summarized in this section.

In the following, the Ministry is responding to comments that are not clearly dependent on the outcome of these controversial risk assessment issues. Comments pertinent to the recent carcinogenic risk assessment debate will be highlighted, but not responded to:

• The cancer risk-specific concentration of 0.04 µg/m3, as the basis of the MOE air standard derivation, is about an order of magnitude greater than those described by the U.S. EPA and OEHHA; it is also greater (especially when the 0.2 µg/m3, 24-hour average concentration is considered) than the ambient concentrations described in the above comments.

• Due to the lack of reliable toxicodynamic methods to assess the contribution of

endogenous ethylene oxide in the standards development for this chemical, this factor will not be considered.

• The suggestion to use epidemiological data, rather than the rodent data, to derive an air standard for ethylene oxide is not feasible in view of the controversial issues raised by the American Chemistry Council on the use of epidemiological data for cancer risk assessment.

• The key controversial issues around the carcinogenic risk analysis include: the selection of data sets; choice of males only as the study subject for risk analysis; overstated mutagenicity and carcinogenicity potency of ethylene oxide in EPA’s analysis; inappropriate policy change related to exposure in carcinogenicity assessment;

• The use of a quadratic or linear model for dose-response analysis of the epidemiological data will likely be investigated by the U.S. EPA in response to the challenge from the Ethylene Oxide/Ethylene Glycols Panel.

• More study and data are required to ascertain the possibility of a threshold mode of action for the carcinogenicity of ethylene oxide.


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• The U.S. EPA placed on the Federal Register in September/October 2006 a draft report on the “Evaluation of the Carcinogenicity of Ethylene Oxide” for public consultation. The carcinogenic risk analysis was performed based on recent dose-response analysis using epidemiological information. The Ethylene Oxide/Ethylene Glycols Panel has challenged the carcinogenic risk assessment of the U.S. EPA and advocates the nonlinear dose-response analysis of Kirman et al. (2004). Kirman et al (2004) used data from the Union Carbide Corp. ethylene oxide production facility (Greenberg et al., 1990; Teta et al.,1993 & 1999) for their analysis. The U.S. EPA provided major comments on the risk analysis approach employed by Kirman et al. (2004) that include the slight trend, but lack of statistical significance, in the risk of leukaemia, in multi-exposure to many other chemicals, and the lack of ethylene oxide measurements and the lack of a clear dose-response relationship (U.S. EPA , 2006). The U.S. EPA derived inhalation unit risk estimates based on the epidemiological study of the National Institute of Occupational Safety and Health (NIOSH) in 2004 who analyzed data of 18,254 workers from 14 plants using ethylene oxide as a sterilizing agent (Steenland et al. 1991; Stayner et al., 1993; Steenland et al., 2004). The U.S. EPA reported that using the internal Cox regression and internal categorical analyses, and log cumulative exposure (ppm-days), statistically significant trends of haematopoietic and lymphoid cancers in males were observed. In this recent analysis, a supralinear dose-response relationship for haematopoietic cancers was observed.

The carcinogenic risk assessment of the U.S. EPA (U.S. EPA, 2006) was criticized by the Ethylene Oxide/Ethylene Glycols Panel with two sets of comment submissions to the U.S. EPA (ACC, 2006) and to the Science Advisory Board (ACC, 2007).

In view of the challenging technical issues with the on-going carcinogenic risk assessment review, the MOE has decided not to provide comments on the current risk assessment results of the U.S. EPA and the American Chemistry Council and the information will not be employed at present to derive an air standard for Ontario. However, the Ministry may review the carcinogenic data of the U.S. EPA once the results are finalized and available on the Integrated Risk Information System (IRIS). In the mean time, the Ministry considers that there is sufficient positive genotoxic data (in both in vitro and in vivo studies and in animal and human tissues) for ethylene oxide to be classified as a human carcinogen. Thus, the TC05 of 2.2 mg/m3, derived based on mononuclear cell leukaemia in female rats, may be viewed as conservative, is maintained as the basis for the derivation of air standards to ensure the protection of health.


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General Comments:

In addition to technical comments on this specific substance, MOE received ‘general’ comments related to the standard setting process, implementation of standards and odour issues. Some of these comments formed part of the response to the Rationale Documents, which were posted from June 26, 2006 to September 25, 2006. Other comments were in response to the "Proposal to amend Ontario Regulation 419/05: Air Pollution-Local Air Quality" posted from June 15 to September 25, 2006, with a subsequent posting April 7, 2007 to May 7, 2007 of the proposed draft amendments to O. Reg. 419/05. With the June to September, 2006 posting the MOE also introduced a “Proposed Approach for the Implementation of Odour-Based Standards and Guidelines” to which it also received comments.

A detailed summary of these general comments and MOE’s responses to them can be found in the following two related postings:

1) EBR #: 010-0000 – Proposal to Amend Ontario Regulation 419/05:Air Pollution-

Local Air Quality under the Environmental Protection Act; and 2) EBR #: RA06E0006 – Proposed Approach for the Implementation of Odour-

Based Standards and Guidelines.

7.0 Considerations in the Development of an Ambient Air Quality Criterion for Ethylene Oxide

Currently in Ontario, the 24-hour AAQC and half-hour Point of Impingement standards are 5 and 15 μg/m3, respectively, based on health considerations.

Ethylene oxide is classified as a probable human carcinogen by the U.S. EPA (1985) and the IARC (1994) based on limited carcinogenic evidence in humans and sufficient evidence in animal studies. Environment Canada and Health Canada evaluated ethylene oxide as highly likely to be carcinogenic to humans and declared that this substance is “toxic” under the Environmental Protection Act of 1999, Paragraph 64(c) (CEPA, 2001). A toxic reduction management programme is under way for options to reduce exposure, particularly in the vicinity of point sources. Considering the general use of ethylene oxide in the sterilization of hospital and medical equipment, the epidemiological cancer case reports, the facts that releases of ethylene oxide has not been significantly reduced in Ontario in past years, the potential carcinogenic and

http://www.ebr.gov.on.ca/ERS-WEB-External/displaynoticecontent.do?noticeId=MTAwMDAw&statusId=MTQ5Mzgx&language=en

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genotoxic effects of ethylene oxide, and the fact that many jurisdictions that were reviewed have developed cancer-based air guidelines, a revision of the existing air guidelines is warranted.

Ethylene oxide is a highly volatile substance and essentially all releases are to the atmosphere, thus, inhalation can be considered as the major exposure route. Ethylene oxide is readily and rapidly absorbed following inhalation exposure. It has been found to widely distribute following absorption, with the majority found in the lungs, kidney, bladder, blood and adrenal glands. Ethylene oxide is metabolized via hydrolysis or glutathione conjugation to be rapidly excreted from the body following inhalation.

Acute inhalation exposure to high concentrations of ethylene oxide has been found to result in CNS depression and irritation of the eyes and mucous membranes. Lethal concentrations of ethylene oxide in experimental animals were found to be in the range of 1500 to 7200 mg/m3. The NTP study reported no mortality occurred in mice with exposure to 720 mg/m3 for a period of 14 days (NTP, 1987). Subchronic and chronic exposure of humans to ethylene oxide exhibits effects similar to those observed in animals in acute exposures; in addition, haematological effects (18 mg/m3 with no haematological effects in 2 years; 18 – 108 μg/m3 decreased levels of white blood cells) and the development of cataracts (1260 mg/m3 up to 2 months) have also been noted with chronic occupational exposure. NOAELs of 18 mg/m3 for neurological effects in mice and 90 mg/m3 for haematological effects in monkeys for subchronic exposures have been reported.

Human studies have suggested that there may be a link between ethylene oxide exposure and increased risk of miscarriage, however exposure data is lacking and a mechanistic explanation for such an effect requires further study. A meta-analysis of animal studies yielded ED10 for foetal deaths on the order of 9 – 18 mg/m3 in rats and of developmental studies suggested that a 5% reduction in mean foetal weight may occur on the order of 9 – 54 mg/m3. New Jersey was the only jurisdiction that has developed a short-term guideline value for ethylene oxide based on developmental effects. Only limited evidence suggests that acute or chronic inhalation exposure can result in such effects.

A number of agencies have concluded that ethylene oxide is probably carcinogenic to humans, based on epidemiological studies, animal bioassays and evidence of mutagenicity. Ethylene oxide has been clearly shown, in a number of in vivo and in vitro studies, to alkylate DNA and causes a number of mutagenic and genotoxic effects (e.g., SCE, chromosomal aberrations, etc.). However, many authors have noted that these mutagenic and genotoxic effects are observed at high concentrations of ethylene oxide, while exposure to low concentrations does not yield a significant effect (Thier and Bolt, 2000). Available epidemiological data does not indicate a clear causal relationship between ethylene oxide exposure and cancer and does not provide sufficient dose-response data for a quantitative analysis. In view of the lack of available human data,


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regulatory agencies have continued to rely on animal data to derive their respective cancer-based air quality guidelines. The U.S. EPA, the States of California, Michigan and Environment Canada and Health Canada have derived unique cancer based guideline values for ethylene oxide using the study of Snellings et al. (1984b). In this two-year carcinogenicity bioassay, rats exposed to ethylene oxide for 6 hours per day, 5 days a week to 0, 18, 60 and 180 mg/m3 resulted in dose-related increases of mononuclear cell leukemia in all the ethylene oxide-dosed groups, but reached a statistically significant level in the female rats at the 180 mg/m3 dose group only (Snellings et al., 1984b). The use of dose-response analytical methods and the practice of animal to human dose extrapolation with data from the Snellings et al. (1984b) study have resulted in differences in jurisdiction guideline values among these agencies. The U.S. EPA and the CalEPA employed un-reviewed metabolic data for dose conversion between species. Environment Canada and Health Canada and the State of Michigan considered the physiological difference in the absorption of ethylene oxide by animals and humans is minor and dose conversion may not be necessary. No physiologically based pharmacokinetic models are currently available to resolve the issue of animal to human metabolic extrapolations in dose-response analysis for ethylene oxide. However, the differences in metabolic conversion in dose-response analysis only result in a narrow range of cancer risk-specific concentrations, e.g. 0.01 -0.04 μg/m3, that are associated with a 10-6 lifetime excess cancer risk.

Recently, the carcinogenicity of ethylene oxide has been assessed using data of leukaemia associated with ethylene oxide-exposed workers. Based on these risk assessments, the U.S. EPA has evaluated the carcinogenicity of ethylene oxide in a draft report that is currently under a public review (U.S. EPA, 2006). The U.S. EPA reported that the National Institute of Occupational Safety and Health conducted a study of 18,254 workers from 14 plants across the USA at which ethylene oxide was used in sterilizing medical supplies and in treating spices, and in the manufacturing and testing of medical sterilizers (Steenland et al., 1991; Stayner et al., 1993; Steenland et al., 2004). The overall SMR for cancer was 0.98, based on 860deaths (Steenland et al., 2004). The SMR for (lympho)haematopoietic cancer was 1, based on 79 cases. Exposure-response analyses on males revealed increases in haematopoietic cancer mortality risk. In categorical life-table analysis, men with >than 13,500 ppm-days of cumulative exposure had an SMR of 1.46 (n=13). Using internal Cox regression analyses with exposure as a continuous variable and using log cumulative exposure (ppm-days) with a 15-year lag, statistically significant trends in males for all haematopoietic cancer (p=0.02) and for ‘lymphoid” cancer (non-Hodgkin’s lymphoma, lymphocytic leukaemia, and myeloma) (p=0.02) were observed. In internal categorical analyses, statistically significant odds ratios (ODs) were observed in the highest cumulative exposure quartile (with a 15-year lag) in males for all haematopoietic cancer (OD=3.42; 95% CI=1.09-10.73) and “lymphoid” cancer (OD=3.76; 95% CI=1.03-13.64). Based on the lymphohaematopoietic cancer incidence, the U.S. EPA derived a cancer


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8.0 Decision

unit risk estimate of 9.0 x 10-4 (µg/m3)-1 from the NIOSH study, using a linear dose-response analysis.

The Ethylene Oxide/Ethylene Glycols Panel of the American Chemistry Council of the USA supports the nonlinear dose-response cancer risk assessment proposed by Kirman et al. (2004). Kirman et al. (2004) summarized a follow-up analysis of leukaemia and lymphoid tumour mortality by Teta et al. (1999) of the Union Carbide study (Teta et al., 1993) and of the NIOSH cohort study (Stayner et al., 1993). The epidemiological data were assessed using cumulative external concentration (ppm-years) that covered a range of 0.001 – 1760 ppm-years. Response data were assessed in terms of relative risk (rate ratio). A Poisson regression model that adjusted for factors of age, sex and calendar year was used to assess the rate ratio responses. Based on a proposed mode of action for ethylene oxide induced leukaemia, the events leading to the development of leukaemia are expected to be proportional to the square of the dose, and therefore, a nonlinear quadratic dose-response model provided the best fit of data. A unit risk value of 4.5 x 10-8 (µg/m3)-1 was derived for ethylene oxide, with range of unit risk values of 1.4 x 10-8 to 1.4 x 10 -7 (µg/m3)-1.

The Ministry of the Environment has reviewed and considered air quality guidelines and standards used by leading agencies worldwide. After reviewing additional toxicological information, the Ministry considers that ethylene oxide is genotoxic and is likely to be carcinogenic to humans. In addition, in terms of the path forward, the Ministry gave consideration to the lack of consistent and reliable human carcinogenicity information, the cancer risk assessment of the U.S. EPA that is currently under review, the challenge that EPA’s risk assessment is facing and to the uncertain timing of a final cancer risk assessment and therefore the corresponding unit risk estimate. Since at this stage there is sufficient data from laboratory studies to support a dose-response analysis of the carcinogenic effects of ethylene oxide, animal carcinogenicity data would appear to be the most appropriate scientific basis for the development of air standards for Ontario.

The Ministry of the Environment is in agreement with Environment Canada and Health Canada on the toxicological assessment for ethylene oxide that the cancer data from epidemiological studies are weak and inconsistent for a quantitative criteria development. Among the various TC05 derived, by these federal jurisdictions, from selected animal carcinogenicity studies with different reported types of tumours, the TC05 of 2,200 µg/m3 based on leukaemia in female rats is appropriate for the derivation of an AAQC for Ontario. The Ministry also concurs with these Canadian federal jurisdictions that metabolism of ethylene oxide between rats and humans is not significantly different and that ethylene oxide is likely the active toxicant for the carcinogenesis of this compound and thus no metabolic conversion is necessary in the


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extrapolation of carcinogenic data from animal to humans (see section 4.2). An uncertainty factor of 50,000 is applied to this TC05 to obtain a risk-specific concentration of 0.04 µg/m3, representing a lifetime excess cancer risk of one in a million. This risk-specific concentration of 0.04 µg/m3 becomes the annual AAQC.

The Ministry of the Environment uses a factor of 3 to convert from criteria based on 24-hour average concentrations to half-hour POI standards. This factor is derived from empirical measurements and is selected to ensure that if the short-term limit is met, air quality standards based on longer-term exposures will not be exceeded (MOE, 1987; MOEE, 1994).

After an evaluation of the scientific rationale of air guidelines from leading agencies and an examination of current toxicological research for the review of air quality standards for ethylene oxide (CAS# 75-21-8) for Ontario, the standards for ethylene oxide are as follows:

• An annual average AAQC of 0.04 µg/m3 (micrograms per cubic of air), based on the carcinogenic effects of ethylene oxide;

• A 24-hour average AAQC of 0.2 μg/m3 (micrograms per cubic metre of air) based on the carcinogenic effects of ethylene oxide; and

• A half-hour standard of 0.6 μg/m3 (micrograms per cubic metre of air) based on the carcinogenic effects of ethylene oxide.

These effects-based AAQCs and the corresponding effects-based half hour standards will be incorporated as standards into Ontario Regulation 419/05: Air Pollution – Local Air Quality (O. Reg. 419/05). The AAQCs (except the annual AAQC) will be incorporated into Schedule 3 of O. Reg. 419/05; the half-hour standard will be incorporated into Schedule 2.

MOE generally proposes a phase-in period for new standards or standards that will be more stringent than the current standard or guideline. The phase-in for this compound is as set out in O. Reg. 419/05.

Among other things, O. Reg. 419/05 sets out the applicability of standards and appropriate averaging times, phase-in periods, types of air dispersion models and when various sectors are to use these models. There are 3 guidelines that support O. Reg. 419/05. These guidelines are:

• “Guideline for the Implementation of Air Standards in Ontario” (GIASO);

• “Air Dispersion Modelling Guideline for Ontario” (ADMGO); and


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• “Procedure for Preparing an Emission Summary and Dispersion Modelling Report” (ESDM Procedure).

GIASO outlines a risk-based decision making process to set site specific alternative air standards to deal with implementation barriers (time, technology and economics) associated with the introduction of new/updated air standards and new models. The alternative standard setting process is set out in section 32 of O. Reg. 419/05.

For further information on these guidelines and O. Reg. 419/05, please see the Ministry’s website http://www.ontario.ca/environment and follow the links to local air quality.

http://www.ontario.ca/environment


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9.0 References

ACC. 2006. Comments of the Ethylene oxide/Ethylene glycols Panel of the American Chemistry Council in response to EPA’s notice of availability of EPA’s evaluation of the carcinogenicity of ethylene oxide – before the United States Environmental Protection Agency. American Chemistry Council. December 8, 2006.

ACC. 2007. Comments of the ethylene oxide/ethylene glycols panel on EPA’s draft evaluation of carcinogenicity of ethylene oxide, addressing the SAB’s charge questions – before the Science Advisory Board – ethylene oxide carcinogenicity. American Chemistry Council, January 8, 2007.

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Shaham, J., Levi, Z., Gurvich, R., Shain, R. and Ribak, J. 2000. Hematological changes in hospital workers due to chronic exposure at low levels of ethylene oxide. J Occup Environ Med 42(8):843-850.

Shore, R.E., Gardner, M.J. and Pannett, B. 1993. Ethylene oxide: an assessment of the epidemiological evidence on carcinogenicity. Br J Ind Med 50:971-997. Cited In: CEPA, 2001.

Sisk, S.C., Pluat, L.J., Meyer, K.G., Wong, B.C. and Recio, L. 1997. Assessment of the in vivo mutagenicity of ethylene oxide in the tissues of B6C3F1 lacI transgenic mice following inhalation exposure. Mutat Res 391: 153-164. Cited In: CEPA, 2001.

Snellings, W.M., Maronpot, R.R., Zelenak, J.P., et al. 1982a. Teratology study in Fischer 344 rats exposed to ethylene oxide by inhalation. Toxicol Appl Pharmacol 64:476-481 Cited In: ATSDR, 1990.

Snellings, W.M., Zelenak, J.P., and Weil, C.S. 1982b. Effects on reproduction in Fischer 344 rats exposed to ethylene oxide by inhalation for one generation. Toxicol Appl Pharmacol 63:382-388. Cited In: ATSDR, 1990.

Snellings, W.M., Weil, C.S., and Maronpot, R.R. 1984a. A subchronic inhalation study of the toxicologic potential of ethylene oxide in B6C3F1 mice. Toxicol Appl Pharmacol 76:510-518. Cited In: ATSDR, 1990.

Snellings, W., Weil, C., and Maronpot, R. 1984b. A two-year inhalation study of the carcinogenic potential of ethylene oxide in Fisher 344 rats. Toxicol Appl Pharmacol 75:105-117.

Stayner, L., Steenland, K., Greife, A., Hornung, R., Hayes, R.B., Morawetz, J., Ringenburg, V., Elliot, L. and Halperin, W. 1993. Exposure-response analysis of cancer mortality in a cohort of workers exposed to ethylene oxide. Am J Epidemiol 138(10):787-798. Cited In: CEPA, 2001.

Steenland, K., Stayner, L., Greife, A., Halperin, R., Hayes, R., Hornung, R. and Nolwin, S. 1991. Mortality among workers exposed to ethylene oxide. N Engl J Med 324(20):1402-1407. Cited In: CEPA, 2001.

Steenland, K., Stayner, L., and Deddens, J., et al. 2004. Mortality analysis in a cohort of 18,235 ethylene oxide exposed workers: follow up extended from 1987 to 1998. Occup. Environ. Med. 61:2-7.


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Stolley, P.D., Soper, K.A., Galloway, S.M., et al. 1984. Sister-chromatid exchanges in association with occupational exposure to ethylene oxide. Mutat Res 129:89-102. Cited In: ATSDR, 1990.

Sykes, G. 1964. Disinfection and Sterilization. J.P. Lippincott Co., Philadelphia, Pennsylvania, pp. 202-227. Cited In: U.S. EPA, 1985.

Tardif, R., Goyal R., Brodeur, J., et al. 1987. Species differences in the urinary disposition of some metabolites of ethylene oxide. Fundam Appl Toxicol 9:448-453. Cited In: ATSDR, 1990.

Tates, A.D., Grummt, T., Tornqvist, M., Farmer, P.B., van Dam, F.J., van Mossel, H., Schoemaker, H.M., Osterman-Golkar, S., Uebel, Ch., Tang, Y.S., Zwinderman, A.H., Natarajan, A.T., and Ehrenberg, L. 1991. Biological and chemical monitoring of occupational exposure to ethylene oxide. Mutat Res 250:483-497.

Teta, M.J., Benson, L.O. and Vitale, J.N. 1993. Mortality study of ethylene oxide workers in chemical manufacturing: a 10 year update. Br J Ind Med 50:704-709. Cited In: CEPA, 2001.

Teta, M.J., Sielken, R.L. and Valdez-Flores, C. 1999. Ethylene oxide cancer risk assessment based on epidemiological data: application of revised regulatory guidelines. Risk Anal 19(6):1135-1155.

Thier, R. and Bolt, H.M. 2000. Carcinogenicity and genotoxicity of ethylene oxide: New aspects and recent advances. Crit Rev Toxicol 30(5):595-608.

Thiess, A.M., Schweglen H., Fleig, I., et al. 1981. Mutagenicity study on workers exposed to alkene oxides (ethylene oxide/propylene oxide) and derivatives. J Occup Med 23:343-347. Cited In: ATSDR, 1990.

Tucker, J.D., Xu, J., Stewart, J., Baciu, P.C. and Ong, T.-M.. 1986. Detection of sister chromatid exchanges induced by volatile genotoxicants. Teratog Carcinog Mutag 6:15-21.

Tyler, T.R. and McKelvey, J.A.. 1980. Dose-dependent disposition of 14C labeled ethylene oxide in rats. Bushy Run Research Center, Export, PA. TSCATS/017061. EPA/OTS Document Number 878212056.

U.S. EPA. 1985. Health assessment document for ethylene oxide. Final report (EPA 600/8-84-009F). Office of Health and Environmental Assessment, United States Environmental Protection Agency (U.S. EPA), Washington, DC.


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U.S. EPA. 1986. Locating and estimating air emissions from sources of ethylene oxide (EPA Report No. EPA-450/4-84-0071; U.S. NTIS PB87-113973), Research Triangle Park, NC, Office of Air Quality Planning and Standards. Cited In: IARC, 1994.

U.S. EPA. 1992. Technical background document to support rulemaking pursuant to the Clean Air Act - Section 112(g) (draft). Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA-45/3-92-010.

U.S. EPA. 1993. Ambient Concentration Summaries for Clean Air Act Title III Hazardous Air Pollutants. Kelly, T.J., Ramamurthi, M., Pollack, A.J., Spicer, C.W. and LT. Cupitt. United States Environmental Protection Agency (U.S. EPA). U.S. EPA Contract No. 687-D80082. Cited in: ARB, 1997.

U.S. EPA. 2002. Health effects information used in cancer and noncancer risk characterization for the NATA 1996 national-scale assessment. Technology Transfer Network, National Air Toxics Assessment, United States Environmental Protection Agency. Accessed December 5, 2002. URL: http://www.epa.gov/ttn/atw/nata/nettables.pdf

U.S. EPA. 2006. Evaluation of the Carcinogenicity of Ethylene Oxide. United States Environmental Protection Agency. Washington. EPA/635/R-06/003. External Review Draft, August 2006.

U.S. National Library of Medicine. 1993. Toxic Chemical Release Inventory (TRI) Data Banks [TRI187, TRI188, TRI189, TRI190, TRI191], Bethesda MD. Cited In: IARC, 1994.

van Sittert, N.J., Boogaard, P.J., Natarajan, A.T., Tates, A.D., Ehrenberg, L.G. and Tornqvist, M.A. 2000. Formation of DNA adducts and induction of mutagenic effects in rats following 4 weeks inhalation exposure to ethylene oxide as a basis for cancer risk assessment. Mutat Res 447:27-48.

Verschueren, K. (Ed.) 1983. Handbook of Environmental Data on Organic Chemicals. (2nd Ed.) Van Nostrand Reinhold Co., New York, NY.

Victorin, K. 1998. Risk assessment of carcinogenic air pollutants. Institute of Environmental Medicine. IMM-rapport 1/98.

Victorin, K., and Stahlberg, M. 1988. A method for studying the mutagenicity of some gaseous compounds in salmonella typhimurium. Environ Molec Mutagen 11(1):65-77.

Walker, V.E., Sisk, S.C., Upton, P.B., Wong, B.A. and Recio, L. 1997a. In vivo mutagenicity of ethylene oxide at the hprt locus in T-lymphocytes of B6C3F1 mice lacI

http://www.epa.gov/ttn/atw/nata/nettables.pdf


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transgenic mice following inhalation exposure. Mutat Res 392:211-222. Cited In: CEPA, 2001.

Walker, V.E., Meng, Q. and Clement, N.L. 1997b. Spectra of mutations in HPRT exon 3 of T-cells from F344 rats and LAC I transgenic and nontransgenic B6C3F1 mice exposed by inhalation to ethylene oxide. Environ Mol Mutagen 29(S28): 54. Cited In: CEPA, 2001.

Weast, R.C. (Ed.) 1985. CRC Handbook of Chemistry and Physics: A ready reference book of chemical and physical data. Boca Raton, FL. CRC Press Inc. C-273. Cited In: ATSDR, 1990.

Whelton, R., Phaff, H., Mruk, E., and Fisher, C. 1946. Control of microbiological food spoilage by fumigation with epoxides. Food Ind 18:23-25. Cited In: U.S. EPA, 1985.

WHO. 1985. Ethylene oxide. Environmental Health Criteria No. 55. World Health Organization. Geneva.

WHO. 1999. Air quality guidelines. Protection of the Human Environment, World Health Organization, Geneva.

URL: www.who.int/peh/air/Airqualitygd.htm

WHO. 2000. Air quality guidelines for Europe. World Health Organization (WHO), Regional Office for Europe, Copenhagen. WHO regional publications.

URL: http://www.who.dk/air/Activities/20020620_1

Winer, A.M., Atkinson, R., Arey, J., Aschmann, S.M. and Goodman, M.A. 1987. Lifetimes and fates of toxic chemicals in California’s atmosphere. Statewide Air Pollution Research Center, University of California (Report No. ARB-R-88/345).

Yager, J.W., Hines C.J., and Spear, R.C. 1983. Exposure to ethylene oxide at work increases sister chromatid exchanges in human peripheral lymphocytes. Science 219:1221-1223. Cited In: ATSDR, 1990.

Young, H and Busbey, R. 1935. References to the use of ethylene oxide for pest control. U.S. Department of Agriculture, Bureau of Entomology. Plant Quarantine, April 1935. Cited In: U.S. EPA, 1985.

Zampollo, A., Zacchetti, O., and Pisati, G. 1984. On ethylene oxide neurotoxicity: Report of two cases of peripheral neuropathy. Ital J Neurol Sci 5:59-62. Cited In: ATSDR, 1990.

http://www.who.dk/air/Activities/20020620_1


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Zetzsch, C. 1985. Personal communication. Presented at Bunsen Colloquium, Göttingen, West Germany. Cited In: Atkinson, 1986.


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10.0 Appendix: Agency-Specific Reviews of Air Quality Guidelines

10.1 Agency-Specific Summary: Federal Government of Canada

1. Name of Chemical: Ethylene oxide (CAS no. 75-21-8)

2. Agency: Canadian Environmental Protection Act (CEPA) under the auspices of Health Canada and Environment Canada and Canadian Council of Ministers of the Environment (CCME)

3. Guideline Value(s):

A Tumourigenic Concentration (TC05) of 2.2 mg/m3 has been established. The TC05 is defined as the air concentration generally in air, associated with a 5% increase in incidence or mortality due to tumours. The division of the TC05 by a margin of 5,000 or 50,000 will yield risk-specific concentrations of 0.4 or 0.04 µg/m3, that are equivalent to life time additional risks of one in a hundred thousand or one in a million, respectively.

4. Application:

Under the Canadian Environmental Protection Act (CEPA), the Ministers of the Environment and Health are advised to investigate various substances with the potential to cause adverse effects on the environment and human health. In 1994, 44 chemicals were on the first Priority Substances List (PSL 1). Further to this, in 1995, the second PSL list was established and it identified other substances which were scheduled to be evaluated over the upcoming years.

Some of the substances listed in Health Canada (1996) have Tolerable Concentrations (TC) in mg/m3 for non-carcinogenic effects. These values are airborne concentrations which can be exposed to a person, continuously over a lifetime without adverse health effects.

Canadian Council of Ministers of the Environment (CCME) is in the process of developing new Canada-Wide Standards (CWSs) which include qualitative or quantitative standards, guidelines, objectives, and criteria for protecting the environment and reducing the risk to human health. The focus of the Standards Sub-Agreement is on ambient standards which will include air as a media. The CWSs will not be legally enforceable and governments will be responsible for implementing them.


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5. Documentation Available:


Health Canada. 1996. Health-based Tolerable Daily Intakes/Concentrations and Tumorigenic Doses/Concentrations for Priority Substances. Environmental Health Directorate Health Protection Branch, Health Canada.

Key Reference(s):


6. Peer Review Process and Public Consultation:

The assessment report has undergone both internal and external peer reviews by a number of different regulatory agencies and industrial associations. A draft of the assessment report was also made available for public comment prior to its final release.

7. Status of Guideline:

Current.

8. Key Risk Assessment Considerations:

Health Canada developed a TC05 value for ethylene oxide by evaluating a number of laboratory animal studies, in view of limitations in the existing epidemiological data for a quantitative assessment based on human data. Health Canada considered the data from two carcinogenesis bioassays in rats (Garman et al., 1985; Garman and Snellings, 1986; Lynch et al., 1984a, b; Snellings et al., 1984b) and one in mice (NTP, 1987) suitable for of exposure-response analysis. In the rat studies, there were dose-related increases in the incidence of mononuclear leukemias, peritoneal mesotheliomas and brain tumours; in mice, the incidence of lung carcinomas, malignant lymphomas, uterine adenocarcinomas and Harderian cystadenomas were increased (CEPA, 2001).

Concentrations of ethylene oxide causing a 5% increase in tumour incidence over background (e.g., Tumorigenic Concentration05s, or TC05s) were calculated by Health Canada by first fitting the multistage model to the dose-response data. The models were fit using GLOBAL82 (Howe and Crump, 1982). The TC05s and the corresponding 95% lower confidence limit (95% LCL) were adjusted for continuous


55

exposure by multiplying the values by either 7/24 x 5/7 (for the study reported by Lynch et al. [1984a,b], in which animals were exposed for 7 hours/day, 5 days/week) or 6/24 x 5/7 (for the studies reported by Snellings et al. [1984b], Garman et al. [1985], Garman and Snellings [1986] and NTP [1987], in which animals were exposed for 6 hours/day, 5 days/week).

For the study in rats in which exposure-response was best characterized (Snellings et al., 1984b; Garman et al., 1985; Garman and Snellings, 1986), the TC05s ranged from 2.2 mg/m3 (95% LCL = 1.5 mg/m3) for mononuclear leukemia in rats to 31.0 mg/m3 (95% LCL = 16.1 mg/m3) for brain tumours. TC05s for comparable tumours in the study in which exposure-response was less well characterized (Lynch et al., 1984a,b) were reported by Health Canada to be somewhat higher (12.5 - 31.9 mg/m3, respectively).

Values of the TC05s in mice ranged from 6.7 mg/m3 (95% LCL = 4.2 mg/m3) for Harderian cystadenomas in males to 22.7 mg/m3 (95% LCL = 11.4 mg/m3) for uterine adenocarcinomas. Health Canada notes that the characterization of exposure-response in the NTP (1987) study on which these values were based was not optimal, as there were only two dose groups and controls with the lowest administered concentration being 92 mg/m3 (CEPA, 2001).

The lowest TC05 in the study in rats with optimal characterization of exposure-response (Snellings et al., 1984b; Garman et al., 1985; Garman and Snellings, 1986) and in mice (NTP, 1987) of 2.2 mg/m3 based on the development of mononuclear leukemias in female rats was chosen as the guideline value. Health Canada took the most conservative value as their guideline to address the many uncertainties identified including, the extrapolation of the data to humans and the lack of exposure-response data in humans.

9. Key Risk Management Considerations: No information.

10. Multimedia Considerations of Guidelines: No information.

11. Other Relevant Factors: No information.


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10.2 Agency-Specific Summary: Federal Government of the United States


2. Agency: United States Environmental Protection Agency (U.S. EPA)


No ambient air exposure limits are currently promulgated. The U.S. EPA has National Ambient Air Quality Standards (NAAQS) for some “criteria pollutants” (i.e. carbon dioxide) but not for hazardous air pollutants. However, under the auspices of the U.S. EPA is the Integrated Risk Information System (IRIS) database (on-line) in which inhalation and oral exposure limits are derived which can be used towards the derivation of ambient air guidelines or standards. To date, the U.S. EPA has not assessed ethylene oxide for the IRIS database. However, the U.S. EPA is currently performing an assessment of ethylene oxide and has proposed adopting both the chronic REL (30 µg/m3) and the inhalation unit risk value of the California EPA (8.8x10-5 (µg/m3)-1) (U.S. EPA, 2002).

In September 2006, the U.S. EPA posted a report of Evaluation of Carcinogenicity of Ethylene Oxide for public review. An inhalation unit risk of 9.0 x 10-4 (µg/m3)-1 has been proposed (U.S. EPA, 2006).

4. Application:

The IRIS database is designed to provide consistent information on chemical substances used in risk assessments, decision-making and regulatory activities. The main intention of IRIS is to provide information which can be used towards the protection of public health through risk assessment and risk management. The values presented in IRIS do not represent guidelines on their own. IRIS also contains a summary of current American government regulatory actions under various mandates.


Not applicable.

Key Reference(s):

Not applicable.

Current External Review Draft:


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U.S. EPA. 2006. Evaluation of the Carcinogenicity of Ethylene Oxide. United States Environmental Protection Agency. Washington. EPA/635/R-06/003. External Review Draft, August 2006.


The U.S. EPA makes use of peer-reviewed scientific research data, analyses, and evaluations from various sources, including a variety of public and government agencies from around the world and the published scientific literature. Both the general assessment methodologies and the chemical-specific information found in IRIS undergo extensive scientific and policy reviews, both within the U.S. EPA and within other science-based U.S. regulatory agencies. Information is put on IRIS after results of the public review and comments on draft documents/information have been addressed.


Proposed guidelines only.

The 2006 inhalation unit risk for ethylene oxide is currently under an external review process.


The chronic REL and cancer unit risk value proposed by the U.S. EPA were derived directly from those derived by the California EPA.

9. Key Risk Management Considerations:

No information

10. Multimedia Considerations of Guidelines:

No information.

11. Other Relevant Factors:

No information.


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10.3 Agency-Specific Summary: California


2. Agency: California Environmental Protection Agency (CalEPA)


A unit risk factor of 8.8x10-5 (µg/m3)-1 and a chronic toxicity reference exposure level (REL) of 30 µg/m3 have been established by the Office of Environmental Health Hazard Assessment (OEHHA). Chronic RELs should be compared with modelled annual average air concentrations.

4. Application:

“The intent of the Committee in developing the guideline was to provide risk assessment procedures for use in the Air Toxics ‘Hot Spots’ program.” (CAPCOA, 1993). This program is based on a California State Law, the Air Toxics ‘Hot Spots’ Information and Assessment Act of 1987 (Health and Safety Code Section 44360 et Seq.). The act specifies how local Air Pollution Control Districts determine which facilities in the area will prepare a health risk assessment, how such health risk assessments should be prepared, and how the results are to be prioritized. These Guidelines were prepared to provide consistent risk assessment methods and report presentation to: 1) compare one facility against another, 2) expedite the review of risk assessments by reviewing agencies, and 3) minimize revisions and re-submission of risk assessments. The various health-based exposure levels developed for and employed in this program should not be used outside the framework of the program. The State of California does not consider them to be general, independent, legally enforceable air quality guidelines or limit values at this time.


CalEPA. 1997. Toxic air contaminant identification list compound summaries. Final Report. State of California, California Environmental Protection Agency (CalEPA), Air Resources Board, Stationary Sources Division.

CAPCOA. 1993. Air toxics “hot spots” program: revised 1992 risk assessment guidelines. Prepared by CAPCOA (California Air Pollution Control Officers Association), the Office of Environmental Health Hazard Assessment and the California Air Resources Board.


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Crump, K., and Howe, R. 1982. GLOBAL82: a computer program to extrapolate quantal animal toxicity data to low dose. KS Crump and Company, Ruston, LA. Cited In: OEHHA, 1999.

OEHHA. 1999. Air toxics hot spots program risk assessment guidelines. Part II: Technical support document for describing available cancer potency factors. April 1999. Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency (CalEPA), Berkeley, CA.

OEHHA. 2000. Air toxics hot spots program risk assessment guidelines. Part III: Technical support document for the determination of noncancer chronic reference exposure levels. Batch 2A, December 2000. Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency (CalEPA), Berkeley, CA.


Key Reference(s):

Schulte, P.A., Walker, J.T., Boeniger, M.F., Tsuchiya, Y., and Halperin, W.E. 1995. Molecular, cytogenetic, and hematologic effects of ethylene oxide on female hospital workers. J Occup Environ Med 37(3):313-320.

Snellings, W.M., Weil, C.S., and Maronpot, R.R. 1984a. A subchronic inhalation study of the toxicologic potential of ethylene oxide in B6C3F1 mice. Toxicol Appl Pharmacol 76:510-518. Cited In: ATSDR, 1990.



Cancer potency slope factors and acute and chronic reference levels were prepared by the California Office of Environmental Health Hazard Assessment (OEHHA) using peer-reviewed scientific data. Both the exposure and health assessments have undergone public review and comment prior to finalization. Under the CAPCOA risk assessment process, each assessment is site-specific and public notice to all exposed individuals is required when the assessment concludes that a significant health risk is associated with emissions from a facility. Public input is obtained in identifying and ranking areas and facilities for risk assessment screening. Further additional input is expected as the process moves forward.


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7. Status of Guideline: Current.


The unit risk factor was based on a two-year inhalation rat study by Snellings et al. (1984b) in which the critical effect was mononuclear cell leukemia in female rats. Approximately 6-week-old Fischer F344 rats (120 per dose per sex) were exposed to ethylene oxide via inhalation for two years, six hours per day and five days per week. Treatments included two control groups and 18, 60, or 180 mg/m3 of 99.9% pure ethylene oxide. A mortality-adjusted trend analysis revealed a positive dose-related increase in mononuclear cell leukemia incidence. Using this study, the CalEPA calculated human cancer potency factors using the computer software Global 82 (Crump and Howe, 1982). The upper 95% confidence limit was converted to a unit risk factor using a reference human body weight of 60 kg and an inhalation rate of 18 m3/day. The resultant cancer unit risk was 8.8x10-5 (µg/m3)-1.

The chronic toxicity REL is based on the study by Snellings et al. (1984a) in which female mice were exposed to 0, 18, 90, 180 or 450 mg/m3 of ethylene oxide for 6 hours/day, 5 days/week, for 10 weeks (males) or 11 weeks (females). Neuromuscular screening was conducted and samples of urine and blood were collected. A significantly greater percent of exposed mice exhibited abnormal posture during gait and reduced locomotor activity. A dose-response was observed for these effects, with significant changes at 90 mg/m3 and greater. An abnormal righting reflex was observed in a significantly greater percent of mice exposed to 180 mg/m3 and above. Reduced or absent toe and tail pinch reflexes were observed in a significantly greater percent of mice exposed to 450 mg/m3 ethylene oxide. Hematological changes observed in mice exposed to 250 mg/m3 include slight, yet significant, decreases in red blood cell count, packed cell volume, and haemoglobin concentration. Absolute and relative spleen weights were significantly decreased in female mice exposed to 180 and 450 mg/m3 and in male mice exposed to 450 mg/m3 ethylene oxide. A significant increase in relative liver weight was observed in female mice exposed to 450 mg/m3 ethylene oxide. Male mice exhibited a significant decrease in body weight at 10, 50, and 450 mg/m3 and a significant decrease in absolute testes weights at 90, 180, or 450 mg/m3 ethylene oxide.

The NOAEL identified for neurological effects in this study was 18 mg/m3 of ethylene oxide. The NOAEL was adjusted from discontinuous exposure to continuous exposure:

NOAELADJ = NOAEL × (6 hours / 24 hours) × (5 days / 7 days)

= 18 mg/m3 × (6 hours / 24 hours) × (5 days / 7 days)

= 3.21 mg/m3


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To derive the REL, an uncertainty factor of 100 (3 to account for the extrapolation from subchronic to chronic effects, 3 for interspecies variability and 10 for intraspecies variability) was applied to the NOAELADJ:

Chronic REL = NOAELADJ / UF

= (3.21 mg/m3) / 100

= 0.032 mg/m3

–30 µg/m3


The exposure guidelines were prepared for both non-cancer and cancer-based endpoints. The cancer-based value is used in a screening risk assessment to determine the maximum offsite cancer risk for exposed human population. The process is not readily comparable to the air quality guideline approach to non-carcinogens. The non-cancer guidelines are based on the most sensitive adverse health effect report in the scientific literature and are designed to protect the most sensitive individuals in the population.

The State of California allows local options to address the possible economic impacts of emission control. It appears that the options are under local control and are based on local risk, socioeconomic analyses, and feedback from public workshops and hearings. The enforcement mechanism is via operating permits. Thus, the process is primarily directed towards site-specific evaluations and development of further regulatory tools rather than towards enforceable levels in themselves.

10. Multimedia Considerations of Guidelines:

In the exposure modelling process, non-inhalation pathways should be considered for a number of substances (specified in Table III-5 in CAPCOA, 1993). Ethylene oxide is not one of the substances requiring non-inhalation modelling.



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10.4 Agency-Specific Summary: Massachusetts


2. Agency: Massachusetts Department of Environmental Protection (MADEP)

3. Guideline Value(s): No guideline is listed.

4. Application:

“...The Division of Air Quality Control, which is responsible for implementing the Department’s air programs, plans to employ the AALs in the permitting, compliance, and enforcement components of the commonwealth’s air program in general, and the air toxics program in particular.” (MADEP, 1990, Volume 1, p. ix). The Massachusetts Department of Environmental Protection (MADEP) is responsible for developing, among other environmental programs, the air toxics program, the primary objective of which is to protect human health. The limits generated by the program are “health-based only and were developed without regard to production volume, exposure level, or regulatory implication. Similarly, economic and control technology issues are neither discussed nor considered here.” (MADEP, 1990, Volume 1, p. 4). Thus, the ambient air levels developed in this process are not to be considered as legally enforceable air standards; rather, they should be employed as guidelines in the development of subsequent regulatory action which does not contain a broad consideration of all relevant concerns. Thus, the ambient air levels developed in this process are not to be considered as legally-enforceable air standards; rather, they should be employed as guidelines in the development of subsequent regulatory action.

5. Documentation Available: No information.

Key Reference(s): Not applicable.

6. Peer Review Process and Public Consultation: Not applicable.

7. Status of Guideline: Not applicable.

8. Key Risk Assessment Considerations: Not applicable.

9. Key Risk Management Considerations: Not applicable.

10. 1Multimedia Considerations of Guidelines:Not applicable.



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10.5 Agency-Specific Summary: Michigan


2. Agency: Michigan Department of Environmental Quality


MDEQ has established 0.03 and 0.3 µg/m3 for its annual initial risk screening level (IRSL) and secondary risk screening level (SRSL), respectively.

4. Application:

The screening levels are health-based screening levels for non-carcinogenic effects under Michigan’s air toxic rules. These values are only used as a tool for the evaluation of ambient air impacts from new or modified air emission sources when a permit is requested. These values are not considered as general ambient air quality levels nor are they considered standards. The air toxics rules require that each source must apply the best available control technology for toxics (T-BACT) and the maximum ambient concentration of each toxic air contaminant cannot exceed its screening level. Some exceptions to the T-BACT requirement include processes emitting low potency carcinogens or non-carcinogens that have relatively low toxicity.


MDEQ. 1991. Interoffice communication from G. Butterfield to “File” regarding AAC for ethylene oxide. October 16, 1991.

MDEQ. 1998. Addendum: 97-033EQ. Air pollution control rules. Part 2. Air use approval. R 336.1224 to R 336.1232 and R 336.1299. Effective date: November 10, 1998. Michigan Department of Environmental Quality (MDEQ), Air Quality Division, Lansing, MI.

MDEQ. 1999. List of screening levels (ITSL, IRSL and SRSL). Verification date: July 6, 1999. Michigan Department of Environmental Quality (MDEQ), Air Quality Division, Lansing, MI.

Tyler, and McKelvey. 1980. Dose-dependent disposition of C14 labeled ethylene oxide in rats. Carnegie-Mellon Institute of Research, Pittsburgh, PA. Cited In: MDEQ, 1991.


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Key Reference(s):


6. Peer Review Process and Public Consultation: No information.


Current. An updated list of screening levels that have been revised or newly established is produces every two months while a complete list of all screening levels is published at the beginning of each year.


When IRSL and SRSL values are established for carcinogens, they are based on the cancer potency values published by the U.S. EPA. If these values are not available, the U.S. EPA’s HEAST values are used as the basis. If none of these are found, the toxicologist establishes the screening levels using inhalation toxicity data, if available. The Air Quality Division of MDEQ calculated its own unit risk of 0.00004 (µg/m3)-1 from Snellings et al. (1981, 1984b) rather than adopting HEAST’s unit risk of 0.0001 (µg/m3)-1 based on the same studies. MDEQ did not feel it was appropriate to use metabolic data of Tyler and McKelvey (1980) for conversion of exposed dose to absorbed dose in the derivation of the unit risk, since the data was not available for review. The unit risk was calculated using GLOBAL82.

The IRSL is calculated for an additional lifetime cancer risk of 1×10-6:

IRSL = 1×10-6 / unit risk

= 1×10-6 / 0.00004 (µg/m3)-1

= 0.03 µg/m3

The SRSL is calculated for an additional lifetime cancer risk of 1×10-5:

SRSL = 1×10-5 / unit risk

= 1×10-5 / 0.00004 (µg/m3)-1


65

= 0.3 µg/m3


These considerations are performed separately by the permitting section. No other specific information is available for this chemical assessment.




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10.6 Agency-Specific Summary: North Carolina


2. Agency: Department of Environment and Natural Resources


An annual Acceptable Ambient Level (AAL) value of 0.027 μg/m3 has been established.

4. Application:

This acceptable ambient air level is a product of initial recommendations by the Scientific Advisory Board (SAB) from which averaging times are assigned by the staff of the Toxics Protection Branch. These toxic air pollutant values are considered guidelines only and apply to all facilities that emit a toxic air pollutant that are required to have a permit under 15A NCAC 2Q.0700 of North Carolina Air Quality Rules. A facility shall not emit any toxic air pollutant under North Carolina Air Quality Rules in such quantities that may cause or contribute beyond the premises (adjacent property boundary) to any significant ambient air concentration that may adversely affect human health (NC DEHR, 1999).


NC DENR. 1998. Guidelines for factored TLV approach for non-criteria pollutants: Decision tree - Panel Proposal. State of North Carolina, Department of Environment and Natural Resources, Division of Air Quality, Technical Services Section.

NC DENR. 1999. Air Quality Rules. 15A NCAC 2D (Air pollution control requirements). 15A NCAC 2Q (Air quality permit procedures). Department of Environment and Natural Resources. Revised April 1, 1999. Raleigh, N.C.

Key Reference(s):

ACGIH. 1998. Guide to Occupational Exposure Values — 1998. Compiled by the American Conference of Governmental Industrial Hygenists (ACGIH), Inc. Cincinnati, Ohio. ISBN 1-882417-25-9.


After Scientific Advisory Board (SAB) has proposed a guideline, it is forwarded to the Rule Development Branch Planning Section for further public comment and


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eventual rule implementation. In addition, the public and any interested groups are encouraged to go to SAB meetings and participate.

7. Status of Guideline: Current.


Risk assessment methodology is used to arrive at health-based recommendations. The current AAL for ethylene oxide was derived based on an outdated U.S. EPA provisional inhalation unit risk value of 3.6x10-4 (µg/m3)-1. The AAL for ethylene oxide is based on a target risk level of 10-5. No other details on the rationale of the AAL were available.


No specific details were available. This is handled by a separate department called the Environmental Management Commission.




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10.7 Agency-Specific Summary: World Health Organization (WHO)


2. Agency: World Health Organization - Protection of the Human Environment (WHO-PHE) World Health Organization - Europe (WHO-Europe)

3. Guideline Value(s): None.

4. Application: Not applicable.


URL: http://www.who.dk/document/e71922.pdf

Key Reference(s):

Not applicable.

6. Peer Review Process and Public Consultation: Not applicable.

7. Status of Guideline: Not applicable.

8. Key Risk Assessment Considerations: Not applicable.

9. Key Risk Management Considerations: Not applicable.

10. Multimedia Considerations of Guidelines: Not applicable.

Other Relevant Factors: Not applicable.

http://www.who.dk/document/e71922.pdf


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11.0 Acronyms, Abbreviation, and Definitions

AAL Allowable Ambient Level (Massachusetts) or Acceptable Ambient Level (North Carolina)

AAQC Ambient Air Quality Criteria - used by the Ontario Ministry of the Environment to define the potential for causing an adverse effect

AAS Ambient Air Standard (Louisiana)

ACGIH American Conference of Governmental Industrial Hygienists - a non-governmental organization which establishes occupational safety exposure limits for workers

AGC Annual Guideline Concentration (New York State)

ATSDR Agency for Toxic Substances and Disease Registry - an agency of the U.S. Department of Health and Human Services

BMC05 Benchmark Concentration - a statistical lower confidence limit (5%) on the dose producing a predetermined, altered response for an effect

bw body weight

CAPCOA California Air Pollution Control Officers Association

CAS Chemical Abstracts Service - ascribes a unique, identification (registry) number to each chemical to help clarify multiple listings for the same chemical structure

CCME Canadian Council of Ministers of the Environment

CEIL Ceiling Value - used by ACGIH for the concentration that shall not be exceeded during any part of the working exposure

CEPA Canadian Environmental Protection Act

DEC Department of Environmental Conservation - Department in state agency of New York

DEL Department of Environment and Labour - Department in provincial agency of Newfoundland


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DENR Department of Environment and Natural Resources - Department in state agency of North Carolina

DEP Department of Environmental Protection - Department in state agencies of Massachusetts, New Jersey, and Florida

DEQ Department of Environmental Quality - Department in state agencies of Michigan and Louisiana

ENEV Estimated No-Effects Value - similar to a NOAEL, it is used by CCME for derivation of environmental quality guidelines

ESL Effects Screening Level (Texas)

GLC Ground Level Concentration - the concentration of contaminant predicted by dispersion modelling

HEAST Health Effects Assessment Summary Tables - prepared by U.S. EPA’s Office of Health and Environmental Assessment. HEAST contains risk assessment information on chemicals that have undergone reviews, although generally not as extensive as the reviews conduced under IRIS

HEC Human Equivalent Concentration

IARC International Agency for Research on Cancer

IHRV Inhalation Risk Value - used by Minnesota for carcinogens

IRIS Integrated Risk Information System - a database published by the U.S. EPA containing risk assessment information on a wide range of chemicals

IRSL Initial Risk Screening Level - a limit corresponding to a one in a million lifetime risk of cancer used by Michigan for screening new sources of emissions

ITSL Interim Threshold Screening Level - similar to the IRSL, however, derived for the RfC for non-carcinogens

LC50 Median Lethal Concentration - the concentration of a substance in the medium (e.g., air, water, soil) to which a test species is exposed, that will kill 50% of the population of that given species

LD50 Median Lethal Dose - the dose of a substance given to a test species, that will kill 50% of the population of that given species


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LOAEL Lowest-Observed-Adverse-Effect Level

LOEC Lowest-Observed-Effect Concentration

LOEL Lowest-Observed-Effect Level

MAC Maximum Acceptable Concentration

MACT Maximum Achievable Control Technology

MAGLC Maximum Acceptable Ground-Level Concentration (Ohio)

MDI Methane diphenyl diisocyanate (CAS# 101-68-8)

ME Manitoba Environment

MHRV Multimedia Health Risk Value (Minnesota)

MIC Maximum Immission Concentration (Netherlands)

MOEE Ontario Ministry of the Environment and Energy - as known between 1993 and 1997, which is now known as OMOE or Ontario Ministry of the Environment

MRL Minimal Risk Level - a term used by ATSDR, which defines a daily exposure (either from an inhalation or oral route) not likely to induce adverse non-carcinogenic effects within a given time period, i.e., acute, intermediate, or chronic

MTLC Maximum Tolerable Level Concentration

NIEHS National Institute of Environmental Health Sciences (USA)

NIOSH National Institute for Occupational Safety and Health (an agency of the U.S. Department of Health and Human Services)

NOAEL No-Observed-Adverse-Effect Level

NOEC No-Observed-Effect Concentration

NOEL No-Observed-Effect Level

NPRI National Pollutant Release Inventory

NRCC Natural Resource Conservation Commission - agency in state of Texas


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NTP National Toxicology Program (USA)

OEHHA Office of Environmental Health Hazard Assessment (California EPA)

OEL Occupational Exposure Limit

OSHA Occupational Safety and Health Association - a branch of the U.S. Department of Labour

PEL Permissible Exposure Limit (OSHA air standard)

PM Particulate Matter

POI Point of Impingement - used in conjunction with dispersion modelling to define the area in which the maximum ground level concentration (GLC) of a contaminant is predicted to occur

PSL1 First Priority Substances List (CCME)

PSL2 Second Priority Substances List (CCME)

RD50 Median Respiration Rate Decrease - the dose at which respiration rate is decreased 50%

REL Either Reference Exposure Limit as used by the California EPA which defines the concentration at or below which no adverse health effects are expected in the general population or Recommended Exposure Limit used by both NIOSH and ATSDR

RfC Reference Concentration - an estimate of a daily inhalation exposure not likely to induce adverse health effects during a lifetime

RfD Reference Dose - an estimate of a daily exposure to the human population that is likely to be without appreciable risk of deleterious non-cancer effects during a lifetime

RTECS Registry of Toxic Effects of Chemical Substances - database maintained by NIOSH

SGC Short-term Guideline Concentration (New York State)

SRSL Secondary Risk Screening Level - a limit corresponding to one in one-hundred-thousand lifetime risk of cancer used by Michigan for screening new sources of emissions


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STEL Short-term Exposure Limit

TC Tolerable Concentration - used by Health Canada to define the airborne concentration to which a person can be exposed for a lifetime without deleterious effects (for non-carcinogens)

TC05 Tumorigenic Concentration - the concentration of a contaminant in air generally associated with a 5% increase in incidence or mortality due to tumours

TD05 Tumorigenic Dose - the total intake of a contaminant generally associated with a 5% increase in incidence or mortality due to tumours

TEL Threshold Effects Exposure Level (Massachusetts)

TLV Threshold Limit Value - an exposure concentration that should not induce an adverse effect in a work environment

TWA Time-Weighted-Average - allowable exposure averaged over an 8-hour workday or 40-hour work week

U.S. EPA United States Environmental Protection Agency

WHO World Health Organization

ppm parts per million

ppb parts per billion

mg a milligram, one thousandth of a gram

μg a microgram, one millionth of a gram

ng a nanogram, one billionth of a gram