Screening Assessment for the Challenge

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2-Cyclohexen-1-one, 3,5,5-trimethyl-
(Isophorone)

Chemical Abstracts Service Registry Number
78-59-1

Environment Canada
Health Canada

March 2010

(PDF Version - 334 KB)

1. Synopsis
2. Introduction
3. Substance Identity
4. Physical and Chemical Properties
5. Sources
6. Uses
7. Releases to the Environment
8. Environmental Fate
9. Persistence and Bioaccumulation Potential
10. Potential to Cause Ecological Harm
11. Potential to Cause Harm to Human Health
12. Conclusions
13. References
14. Appendix 1a: Upper-bounding estimates of daily intake of isophorone by the general population in Canada
15. Appendix 1b: Concentrations of isophorone reported in various food items
16. Appendix 2: Summary of health effects information for isophorone

Synopsis

Pursuant to section 74 of the Canadian Environmental Protection Act, 1999 (CEPA 1999), the Ministers of the Environment and of Health have conducted a screening assessment of 2-cyclohexen-1-one, 3,5,5-trimethyl- (isophorone), Chemical Abstracts Service Registry Number 78-59-1. The substance isophorone was identified in the categorization of the Domestic Substances List as a high priority for action under the Ministerial Challenge. Isophorone was identified as a high priority as it was classified by the European Commission and the US Environmental Protection Agency on the basis of carcinogenicity. The substance did not meet the ecological categorization criteria for persistence, bioaccumulation potential or inherent toxicity to aquatic organisms. Therefore, the focus of this assessment of isophorone relates primarily to human health risks.

According to information submitted under section 71 of CEPA 1999, isophorone was not manufactured by any company in Canada in the calendar year 2006. However, approximately 10 000–100 000 kg of the substance was imported in 2006, and approximately 1 000–10 000 kg was reported to be released to the atmosphere in the same year. The major use of isophorone is industrial. However, it was determined that, for the general population of Canada , the highest estimated exposure to isophorone would result from the use of isophorone as a food flavour.

Isophorone is used as a solvent for automotive and industrial coatings, including industrial metal coatings and food packaging, and in adhesives for plastics, polyvinyl chloride and polystyrene materials. Isophorone is used as a formulant in one registered pest control product in Canada , but the registration of this product was discontinued December 31, 2009.

As isophorone was classified on the basis of carcinogenicity by other national and international agencies, carcinogenicity was a key focus for this screening assessment. In long-term studies, rats showed some evidence of increased incidences of renal tubular cell adenomas and adenocarcinomas and of preputial gland carcinomas, whereas mice showed equivocal evidence of increased incidences of hepatocellular adenomas or carcinomas and of mesenchymal tumours in the integumentary system. However, the renal tumours induced by isophorone in rats involved a species-specific mechanism, the preputial gland tumours in rats were observed only at higher doses and the tumour incidence in mice were significantly increased only at higher doses. Consideration of the available information regarding genotoxicity and the conclusions of other agencies indicate that isophorone is not likely to be genotoxic. Accordingly, although the mode of induction of tumours is not fully elucidated, the tumours observed are not considered to have resulted from direct interaction with genetic material. Therefore, a threshold approach is used to assess risk to human health.

Non-neoplastic effects were observed in the kidneys of rats and in the liver of mice orally exposed to isophorone in repeated-dose studies. The margin between the highest upper-bounding estimate of exposure from food and beverages and critical effect levels is considered to be adequately protective to account for data gaps and uncertainties in the human health risk assessment for both cancer and non-cancer effects. Based on the available information on the potential to cause harm to human health and the resulting margin of exposure, it is concluded that isophorone is a substance that is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

On the basis of the low ecological hazard posed by isophorone, as well as information on releases of isophorone to the environment, it is concluded that the substance is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends. Isophorone does not meet the criteria for persistence or bioaccumulation as set out in the Persistence and Bioaccumulation Regulations.

It is therefore concluded that isophorone does not meet any of the criteria set out in section 64 of CEPA 1999.

This substance will be considered for inclusion in the Domestic Substances List inventory update initiative. In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessment.

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Introduction

The Canadian Environmental Protection Act, 1999(CEPA 1999) (Canada 1999) requires the Minister of the Environment and the Minister of Health to conduct screening assessments of substances that have met the categorization criteria set out in the Act to determine whether these substances present or may present a risk to the environment or to human health.

Based on the information obtained through the categorization process, the Ministers identified a number of substances as high priorities for action. These include substances that

• met all of the ecological categorization criteria, including persistence (P), bioaccumulation potential (B) and inherent toxicity to aquatic organisms (iT), and were believed to be in commerce in Canada ; and/or
• met the categorization criteria for greatest potential for exposure (GPE) or presented an intermediate potential for exposure (IPE) and had been identified as posing a high hazard to human health based on classifications by other national or international agencies for carcinogenicity, genotoxicity, developmental toxicity or reproductive toxicity.

The Ministers therefore published a notice of intent in the Canada Gazette, Part I, on December 9, 2006 (Canada 2006), which challenged industry and other interested stakeholders to submit, within specified timelines, specific information that may be used to inform risk assessment and to develop and benchmark best practices for the risk management and product stewardship of those substances identified as high priorities.

The substance 2-cyclohexen-1-one, 3,5,5-trimethyl- (isophorone) was identified as a high priority for screening assessment of human health risk because it was considered to present GPE and had been classified by other agencies on the basis of carcinogenicity. The Challenge for this substance was published in the Canada Gazette on August 30, 2008 (Canada 2008). A substance profile was released at the same time. The substance profile presented the technical information available prior to December 2005 that formed the basis for categorization of this substance. As a result of the Challenge, submissions of information pertaining to the substance were received.

Although isophorone was determined to be a high priority for assessment with respect to human health, it did not meet the criteria for persistence, bioaccumulation or inherent toxicity to aquatic organisms.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of CEPA 1999. Screening assessments examine scientific information and develop conclusions by incorporating a weight-of-evidence approach and precaution.

This final screening assessment includes consideration of information on chemical properties, hazards, uses and exposure, including the additional information submitted under the Challenge. Data relevant to the screening assessment of this substance were identified in original literature, review and assessment documents, stakeholder research reports and from recent literature searches, up to March 2009 for human health and ecological sections of the document. Key studies were critically evaluated; modelling results may have been used to reach conclusions.

Evaluation of risk to human health involves consideration of data relevant to estimation of exposure (non-occupational) for the general population, as well as information on health hazards (based principally on the weight of evidence assessments of other agencies that were used for prioritization of the substance). Decisions for human health are based on the nature of the critical effect and/or margins between conservative effect levels and estimates of exposure, taking into account confidence in the completeness of the identified databases on both exposure and effects, within a screening context. The final screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents a summary of the critical information upon which the conclusion is based.

This final screening assessment was prepared by staff in the Existing Substances Programs at Health Canada and Environment Canada and incorporates input from other programs within these departments. The ecological and human health portions of this assessment have undergone external written peer review/consultation. Comments on the technical portions relevant to human health were received from scientific experts selected and directed by Toxicology Excellence for Risk Assessment (TERA), including Ms. Joan Strawson (TERA), Dr. Pam Williams (E Risk Sciences) and Dr. Harlee Strauss (Strauss Associates). Additionally, the draft of this screening assessment was subject to a 60-day public comment period. While external comments were taken into consideration, the final content and outcome of the screening risk assessment remain the responsibility of Health Canada and Environment Canada.

The critical information and considerations upon which the final assessment is based are summarized below.

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Substance Identity

For the purposes of this document, this substance will be referred to as isophorone, based on the Philippine Inventory of Chemicals and Chemical Substances name. Information on the identity of isophorone is summarized in Table 1.

Table 1. Substance identity for isophorone

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Physical and Chemical Properties

Table 2 contains experimental and modelled physical and chemical properties of isophorone that are relevant to its environmental fate. When available, acceptable experimental data for a property are used in preference to data generated through modelling.

Table 2. Physical and chemical properties of isophorone

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Sources

Isophorone enters the environment through anthropogenic activities and to a lesser extent from naturally occurring sources.

Based on information submitted under section 71 of CEPA 1999, isophorone was not manufactured in Canada in 2006 above the reporting threshold of 100 kg. The total quantity imported into Canada in the same calendar year was 10 000–100 000 kg (Environment Canada 2008). According to Statistics Canada (2009), global importation of isophorone into Canada in the calendar year 2000 was 81 422 kg, which decreased to around 20 000 kg by 2003. From 2003, the global importation of isophorone into Canada remained steady at around 20 000 kg (Statistics Canada 2009).

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) noted that natural occurrences of isophorone in food have been reported (JECFA 2002). Isophorone is thought to occur naturally in several types of European honey (Guyot et al. 1999; Jerkovic et al. 2006; Alissandrakis et al. 2007; Castro-Vázquez et al. 2007; de la Fuente et al. 2007), but its presence in honey sold in Canada has not been established.

Isophorone has also been identified in the combustion products of a coal-burning generating station (Harrison et al. 1985).

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Uses

Based on the available scientific and technical literature, isophorone is used globally as a solvent for coating systems and as a component in metal paints and adhesives for plastics, polyvinyl chloride and polystyrene materials (ATSDR 1989).

According to information collected under section 71 of CEPA 1999, isophorone is used in industrial settings in Canada , but not in consumer products (Environment Canada 2008). Industrial applications involve a drying or curing step that reduces the amount of isophorone to very low residual levels; therefore, exposure of the Canadian population to isophorone from these applications is expected to be minimal. Isophorone is used as a solvent in the automotive and industrial coatings processes, including food packaging and metal coatings (Felcht U-H. 2006; Montebello 2009).

In Canada, isophorone is permitted as a non-medicinal ingredient for use as a flavour enhancer in licensed natural health products; however, as it is not listed as an ingredient in the licensed natural health products database, it is not found in current licensed natural health products (2009 personal communication from Natural Health Products Directorate, Health Canada, to Risk Management Bureau, Health Canada; unreferenced).

It is possible that isophorone is used as a flavour in foods sold in Canada . Food flavours are not regulated as food additives, nor are they required under the Food and Drug Regulationsto undergo a pre-market review (2009 personal communication from Food Directorate, Health Canada , to Risk Management Bureau, Health Canada ; unreferenced).

Isophorone use in cosmetics is prohibited in Canada (Health Canada 2007).

As recently as 2009, there was one post-emergent pesticide available for commercial use in Canada that contained isophorone as a formulant. However, the product registration expired on December 31, 2009, with phase-out to be completed by December 31, 2013 (2010 personal communication from Pest Management Regulatory Agency, Health Canada , to Risk Assessment Bureau, Health Canada ; unreferenced). In the United States , isophorone is permitted in pesticide formulations that have restricted use (US EPA 2006).

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Releases to the Environment

In response to a notice issued under section 71 of CEPA 1999 for 2006, 6 537 kg of isophorone was reported to be released to the atmosphere in 2006, whereas 587 kg of the substance was transferred to hazardous waste facilities. Based on section 71 responses, there were no releases to either land or water and no transfers to non-hazardous waste facilities (Environment Canada 2008).

Isophorone was not listed in either the National Pollutant Release Inventory for the 2001–2008 reporting years (NPRI 2009) or the US Toxics Release Inventory Program for the 2001–2006 reporting years (TRI 2009).

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Environmental Fate

The results of Level III fugacity modelling, based on information on physical and chemical properties, indicate that isophorone will reside predominantly in the medium to which it is released (Table 3).

Table 3. Results of Level III fugacity modelling (EQC 2003) for isophorone

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Persistence and Bioaccumulation Potential

Environmental Persistence

Results from several empirical degradation tests with isophorone are summarized in OECD (2003). In a test for ready biodegradability, 95% degradation was observed after 28 days, indicating that the ultimate degradation half-life of the substance is much less than 182 days (6.5 days, assuming first-order degradation kinetics). Similarly, in a test of inherent biodegradability, 89% of the substance was degraded after 14 days; in a 33-day simulation test, 69% degradation was noted.

Some empirical biodegradation data (NITE 2002) show very low biodegradation of isophorone over 28 days in a ready biodegradation test. However, as stated in OECD (2003), tests on the toxicity of isophorone to microorganisms show inhibitory effects at the initial concentration used for testing (100 mg/L) and therefore, the NITE (2002) ready biodegradability test results are considered to be invalid (OECD 2003).

To complement the experimental data for the degradation of isophorone, a quantitative structure–activity relationship (QSAR)-based weight of evidence approach (Environment Canada 2007) was applied. Table 4 summarizes the results of available QSAR models for degradation in air and water. Isophorone does not contain functional groups expected to undergo hydrolysis.

Table 4. Modelled data for degradation of isophorone

In air, a predicted atmospheric oxidation half-life value of 0.133 day (see Table 4) suggests that isophorone is likely to be rapidly oxidized by reaction with hydroxyl radicals. Furthermore, a predicted ozone reaction half-life of 0.155 day (see Table 4) suggests that this substance is also likely to be rapidly oxidized by ozone. Isophorone is not likely to degrade via direct photolysis. Therefore, it is expected that reactions with hydroxyl radicals and ozone will be the most important fate processes in the atmosphere. With half-lives of 0.133 and 0.155 day via reaction with hydroxyl radicals and ozone, respectively, isophorone is considered to be not persistent in air.

There are conflicting model results for biodegradation. Two of the four ready biodegradation models (CATABOL and TOPKAT) indicate that biodegradation is very slow and that the half-life in water would be =182 days, whereas four BIOWIN submodels indicate a half-life of <182 days (Environment Canada 2009).

Because of the conflicting model results, it is difficult to evaluate persistence based on modelled data alone. However, as noted previously, there is clear evidence from empirical biodegradation testing that the biodegradation half-life of isophorone in water is much less than 182 days (6.5 days, assuming first-order degradation kinetics).

Using an extrapolation ratio of 1:1 for water:soil biodegradation half-lives (Boethling et al. 1995) and the half-life of 6.5 days in water estimated from results of the 28-day ready biodegradation test, the ultimate biodegradation half-life in soil is also =182 days. Using an extrapolation ratio of 1:4 for water:sediment biodegradation half-lives (Boethling et al. 1995), the half-life in sediment is =365 days. These results indicate that isophorone is not expected to be persistent in soil or sediment.

Based on the modelled data, isophorone does not meet the persistence criteria in air, water, soil or sediment (half-life in air = 2 days, half-lives in soil and water =182 days and half-life in sediment =365 days) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

Potential for Bioaccumulation

A low experimental log K_ow value of 1.67 for isophorone suggests that this chemical has low potential to bioaccumulate in biota (see Table 2).

Table 5a presents two empirical bioconcentration factor (BCF) values for fish. No other experimental bioaccumulation data were identified.

Table 5a. Empirical data for bioaccumulation of isophorone

As few empirical bioaccumulation data were available for isophorone, a predictive approach was applied using available bioaccumulation factor (BAF) and BCF models, as shown in Table 5b.

Table 5b. Modelled data for bioaccumulation of isophorone

The modified Gobas BAF middle trophic level model for fish (taking into account metabolic degradation) predicted a BAF of 2.05 L/kg, indicating that isophorone does not have the potential to bioaccumulate in fish and to biomagnify in food webs. The results of BCF model calculations provide additional data supporting the low bioaccumulation potential of this substance.

Based on the available empirical and kinetic-based modelled values, isophorone does not meet the bioaccumulation criteria (BAF or BCF =5 000) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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Potential to Cause Ecological Harm

Thee are modelled predictions and experimental evidence that suggest isophorone has the potential to exert only low to moderate toxicity to aquatic organisms following short-term (acute) exposure. Although modelled calculations for aquatic toxicity were performed for this substance, they are not needed for this assessment, given the numerous experimental data available (see Table 6). The modelled values--ranging from 36 mg/L (acute median lethal concentration [LC₅₀] for fish) to 798 mg/L (acute median effective concentration [EC₅₀] to water flea)]--are, to a fair degree, in concurrence with the experimental results.

Table 6. Empirical data for aquatic toxicity

A range of acute aquatic toxicity values was obtained from the various experimental studies that were identified. These results indicate that the substance is not highly hazardous to aquatic organisms (acute LC₅₀/EC₅₀>1.0 mg/L).

The effect of isophorone on four crops (cotton, soybean, corn and wheat) was also studied (Krenek and King 1987). Undiluted isophorone was sprayed at a dose of
3.27 mL/m². Although some leaves were damaged a few hours after application, all plants showed evidence of recovery after 56 hours.

No recent monitoring data for the concentration of isophorone in Canadian surface water bodies were found, although there are limited historical monitoring data. A concentration of 69 ng/L in the St. Lawrence River in 1987 was reported (Germain and Langlois 1988). No monitoring data for the presence of isophorone in Canadian air or sediment have been identified. In 1992, “trace” amounts (unquantified) of isophorone were found in 30 agricultural soil samples treated with wastewater treatment plant sludge from Hamilton, Ontario (Webber 1994). Monitoring data from other countries (e.g., United States ) have been reported; the highest concentration reported (10 µg/L) was detected in urban runoff in Washington, DC (OECD 2003).

Based on information received under section 71 of CEPA1999, releases of isophorone to outdoor air are occurring in Canada (Environment Canada 2008). These are point source emissions occurring at industrial facilities where isophorone is used as a solvent. Furthermore, isophorone has a half-life in air of 0.133–0.155 day and is therefore not considered to be persistent in this medium. Consequently, atmospheric emissions of isophorone are not likely to be causing harm.

Given the current uses of isophorone, releases to water could also occur. Environment Canada ’s Industrial Generic Exposure Tool – Aquatic (Environment Canada 2007) was therefore used to conservatively estimate local exposure in the vicinity of a potential industrial source of release to water. The site-specific scenario is based on the largest amount used at a single industrial facility and assumes that conservative fractions are released to water and removed at the sewage treatment plant and that the subsequent discharge is to a relatively small receiving water body. This exposure tool yielded a predicted environmental concentration (PEC) of 0.15 mg/L. Details regarding the inputs used to estimate this concentration and the output of the model are described in Environment Canada (2008b).

A conservative predicted no-effect concentration (PNEC) was derived from the geometric mean of the lowest empirical toxicity values identified. The critical toxicity values for this assessment are the 35-day no-observed-effect concentration (NOEC) (11 mg/L) and lowest-observed-effect concentration (LOEC) (19 mg/L) for chronic toxicity to the fathead minnow (Cairns and Nebeker 1982). The geometric mean is 14.5 mg/L. An application factor of 10 is used to account for uncertainty in extrapolating from laboratory to field conditions and for intraspecies and interspecies variations in sensitivity, giving a PNEC of 1.45 mg/L.

The resulting conservative risk quotient (PEC/PNEC) of 0.1 for an industrial scenario indicates that these exposure values are unlikely to cause harm to aquatic organisms.

The approach taken in this ecological screening assessment was to examine various scientific and technical information and develop conclusions based on a weight of evidence approach and using precaution as required under CEPA 1999. Lines of evidence considered include results from a conservative risk quotient calculation as well as information on persistence, bioaccumulation, toxicity, sources and fate of the substance.

Isophorone is not expected to be persistent in air, water, soil or sediment, and it is also expected to have a low bioaccumulation potential. The high importation volumes of isophorone into Canada , along with information on its uses, indicate potential for widespread release into the Canadian environment. Once released into the environment, isophorone will be found mainly in air and water. It has also been demonstrated to have low to moderate potential for toxicity to aquatic organisms. A risk quotient analysis integrating conservative estimates of exposure with toxicity information was performed for the aquatic medium, resulting in a risk quotient (PEC/PNEC) of 0.1. Therefore, harm to aquatic organisms is unlikely.

This information indicates that isophorone is unlikely to cause ecological harm in Canada .

It should be noted that this conclusion was reached despite the conservative assumptions that were made in response to uncertainties encountered in the assessment. One uncertainty relates to the lack of empirical data for environmental concentrations in Canada , which was addressed by predicting an upper-bounding concentration in water using an exposure model. Regarding ecotoxicity, the significance of soil as a potentially important medium of exposure is not well addressed by the effects data available, but exposure in this medium is not expected to be significant.

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Potential to Cause Harm to Human Health

Exposure Assessment

Environmental Media and Food

Upper-bounding estimates of isophorone intake from environmental media and food for each age group in the general population of Canada are presented in Appendix 1a. These upper-bounding estimates of intake range from 0.03 µg/kg body weight (kg-bw) per day (0–6 months old [formula fed]) to 0.84 µg/kg-bw per day (20–59 years old). For the majority of the age groups, food and beverages were estimated to be the major contributors to isophorone exposure, albeit at very low levels, based on non-Canadian data for isophorone in foods (including beverages).

A survey of isophorone levels in Canadian ambient air was not identified in a review of the literature. However, isophorone was screened for but not detected (detection limit not stated) in a US survey of ambient air levels of 189 hazardous air pollutants conducted from 1967 through 1992 (Kelly et al. 1994). In a 1984 study of a contaminated industrial site, isophorone was present in the wastewater but not in the headspace above the wastewater or in ambient air samples taken at nearby urban and rural locations (Hawthorne and Sleevers 1984). The short half-life of 0.133 day may account for the absence of atmospheric monitoring data (ATSDR 1989).

In the absence of experimental data, an isophorone concentration in outdoor air of 7.63 × 10^-5 µg/m³ was estimated based on an atmospheric release of 6 537 kg of isophorone in 2006 (Environment Canada 2008) and using exposure modelling software (ChemCAN 2003). This modelled estimate was used to determine the upper-bounding exposure estimate from ambient air.

One Canadian study reported isophorone levels in indoor air (Otson and Benoit 1986). In this study, 10 homes in Montreal, Quebec, were sampled in the fall and winter of 1983–1984. Based on occupant habits, houses were designated as either smoking or non-smoking. Isophorone was not detected in samples taken from any of the homes. The detection limit of 5 ng/m³ from this study was used as a conservative value for calculating the upper-bounding estimate of exposure to isophorone in indoor air. No other Canadian or US studies were located.

No reports of detectable amounts of isophorone were found in drinking water surveys from Toronto, Ontario, for the periods January 2001 through September 2003 (City of Toronto, 2001, 2002, 2003). Isophorone levels reported in drinking water from New Orleans, Louisiana, in 1978 ranged from 1.5 to 2.9 µg/L (US EPA 1978).

The detection limit of 0.3 µg/L from the Toronto reports was used to calculate upper-bounding estimates of exposure to isophorone in drinking water, as the data were from a recent Canadian study (City of Toronto 2001, 2002, 2003).

In 1992, 30 agricultural soil samples treated with wastewater treatment plant sludge from Hamilton, Ontario, were analysed for industrial organic compounds, including isophorone. One sample was reported to contain a “trace” amount, but the amount was not quantified (detection limit 0.09 mg/kg dry weight) (Webber 1994).

In the absence of more recent soil data, the detection limit of 0.09 mg/kg dry weight from the Webber (1994) study was used for estimating the upper-bounding daily intake of isophorone from soil.

Studies of municipal sludge and sludge composts across Canada from 1993 to 1996 reported no incidence of isophorone. One hundred and two samples were analysed, with the maximum detection limit being 7.0 mg/kg dry weight (Webber and Nichols 1995; Webber and Bedford 1996). More recent Canadian data were not identified.

In the United States , isophorone was quantified at 489 µg/kg in the electrostatic precipitator fly ash from a coal-burning power station. In contrast, isophorone was not detected (detection limit not stated) in the wet scrubber fly ash generated from the same facility (Harrison et al. 1985).

No studies reporting isophorone in Canadian foods were identified. However, isophorone was reported in various food items from food in Japan (Kataoka et al. 2007). The authors noted that isophorone was present in some packaged foods at levels ranging from 2 × 10^-5 to 13 × 10^-3 µg/g, but not in fresh vegetables (detection limit 5 × 10^-7µg/g).

In the United States , eight species of fish were collected from Lake Michigan estuaries that were known to be contaminated by pollutants from commercial sources. The samples, collected in 1983, had a mean isophorone concentration of 1.17 mg/kg wet weight. The maximum isophorone concentration was 3.61 mg/kg wet weight, based on 14 composite fish samples from 140 fishes (Camanzo et al. 1987).

In Europe, isophorone has been reported in saffron at levels as high as 254 µg/g dry weight and in honey at levels ranging from 0.05 to 1.45 µg/g (mean concentration 0.36 µg/g) (Guyot et al. 1999; Lechtenberg et al. 2008).

In the absence of current Canadian data, information on the occurrence of isophorone in food from the above non-Canadian studies (Camanzo et al. 1987; Guyot et al. 1999; Kataoka et al. 2007; Lechtenberg et al. 2008) was included in the calculations for estimating upper-bounding exposure from food. For most food groups, the isophorone intake from the group was estimated using the highest concentration of isophorone that was identified from the foods that could reasonably be assigned to the group. For food categories in which isophorone was not detected in a food, the analytical detection limit was used as the concentration of isophorone in the food category. Food items in which isophorone concentrations were measured are tabulated in Appendix 1b.

Based on information received from section 71 surveys, isophorone may be present in food packaging (Environment Canada 2008). Specifically, isophorone may be used as a processing aid in the manufacture of some linings or coatings for beverage cans, metal spice tins or other food packaging (Montebello 2009; 2009 personal communication from Food Directorate, Health Canada, to Risk Management Bureau, Health Canada; unreferenced). Isophorone is not commonly used as a solvent for food can coatings. If it were to be used, it would not be expected to remain in the properly dried and cured coating. However, considering a conservative scenario where a minimum residual level of isophorone would remain in the coating, a probable daily intake of isophorone from beverage cans was estimated to be =3.6 × 10^-3 µg/kg-bw per day (2009 personal communication from Food Directorate, Health Canada, to Risk Management Bureau, Health Canada; unreferenced). The contribution of this source to total intake was considered to be negligible. A probable daily intake estimate for the spice tins application was considered not necessary due to the fact that significant migration to dry foods is not expected (2009 personal communication from Food Directorate, Health Canada, to Risk Management Bureau, Health Canada; unreferenced).

The extent to which the exposure assessment in this report captures the presence of isophorone as a result of its use as a flavour in foods sold in Canada , if such use exists, is not known. Most of the data on the levels of isophorone in foods were taken from the Japanese study (Kataoka et al. 2007), and the source of the isophorone in the foods in that study was not conclusively identified in the paper that reported the results.

For most flavours, including isophorone, there are no provisions in the Food and Drug Regulations that control their addition to foods, although such use must not result in a violation of a food’s standard of identity and composition in the Regulations or of section 4 of the Food and Drugs Act. “Usual” uses for isophorone as a food flavour ranging from 0.50 to 16.80 parts per million (ppm) have been reported (FEMA 1994), but it is unknown if such uses reflect the Canadian situation (2009 personal communication from Food Directorate, Health Canada , to Risk Assessment Bureau, Health Canada , unreferenced).

Isophorone is used primarily as an industrial substance (ATSDR 1989; Kelly et al. 1994). According to information obtained from submissions under section 71 of CEPA 1999, isophorone is released only to the atmosphere in Canada (Environment Canada 2008). The short atmospheric half-life (<5 hours) of isophorone and Canadian drinking water data suggest that environmental exposure of the general population in Canada to the substance is minimal (ATSDR 1989; City of Toronto 2001, 2002, 2003).

Confidence in the assessment of environmental exposure is moderate, based on a limited number of recent Canadian studies that are available. Exposure to isophorone from ambient air was estimated using exposure modelling software, but confidence is high in the low estimate obtained, because isophorone was not detected in the headspace above a contaminated wastewater site in the United States (Hawthorne and Sleevers 1984). In addition, isophorone is believed to have a short atmospheric half-life and therefore, would not be expected to persist in air.

Consumer Products

According to section 71 submissions, the main isophorone activity in Canada is for the processing of industrial paint and coating formulations (Environment Canada 2008). Isophorone is not part of the formulation for consumer paints or coatings (2009 personal communication from Environment Canada to Risk Assessment Bureau, Health Canada ). Once dried and cured, any residual isophorone remaining in the hardened surface is at an extremely low concentration, which is not considered to be hazardous to the consumer.

In Canada , isophorone is not permitted in cosmetic products (Health Canada 2007). However, in Denmark , where isophorone use in cosmetic products was reported, isophorone levels were not a concern for health (Svendsen et al. 2005).

The presence of isophorone in consumer products is not expected to be at a significant level. In Canada , isophorone use is limited, and exposure beyond industrial settings is expected to be at very low residual levels.

Health Effects Assessment

An overview of health effects information for isophorone is presented in Appendix 2.

The European Commission has classified isophorone as a Category 3 carcinogen (causes concern for humans owing to possible carcinogenic effects) with risk phrase 40 (limited evidence of a carcinogenic effect), based on limited evidence of carcinogenicity in animal studies (European Commission 1998a, b; ESIS 2009). The US Environmental Protection Agency (US EPA) classifies isophorone as a Category C carcinogen (possible human carcinogen), based on no data in humans and limited evidence of carcinogenicity in laboratory animals (US EPA 1992).

The carcinogenicity of isophorone was investigated in a 2-year oral (gavage) study in both sexes of rats and mice, at doses of 0, 250 and 500 mg/kg-bw per day. There was evidence of carcinogenicity of isophorone in male Fischer 344 rats, as shown by a statistically significant increase of renal tubular cell adenomas and adenocarcinomas (combined) at 250 and 500 mg/kg-bw per day and carcinomas of the preputial gland at the high dose. In male B6C3F1 mice, there was a statistically significant increase in the incidence of hepatocellular adenomas or carcinomas (combined) and of mesenchymal tumours (fibroma, sarcoma, fibrosarcoma and neurofibrosarcoma combined) of the integumentary system at 500 mg/kg-bw per day. An increased incidence of lymphomas or leukemias was noted in low-dose male mice only. No evidence of carcinogenicity was seen in female rats or female mice (NTP 1986). No inhalation carcinogenicity bioassays or human epidemiological studies were identified.

Isophorone was not genotoxic in in vivo studies or in the majority of in vitro assays in mammalian cells and bacteria. In vivo assays on chromosomal damage, deoxyribonucleic acid (DNA) binding in liver and kidney and sex-linked recessive lethal mutations were all negative (Hossack et al. 1978a; Microbiological Associates 1984a; O’Donoghue et al. 1988; Thier et al. 1990; Foureman et al. 1994). In vitroassays for mutagenicity, chromosomal aberrations and DNA damage or repair in mammalian cells were primarily negative (Microbiological Associates 1984b, c; NTP 1986; O’Donoghue et al. 1988; Gulati et al. 1989; Honma et al. 1999a). Ames tests for mutagenicity in Salmonella typhimurium with and without metabolic activation were negative (Hossack et al. 1978b; Mortelmans et al. 1986; NTP 1986; Hüls 1988a). There were several positive results in mammalian cell assays in vitro, but only at cytotoxic concentrations or in non-standard studies (NTP 1986; Tennant et al. 1987; McGregor et al. 1988; Gulati et al. 1989; Ono et al. 1991; Selden et al. 1994; Matsuoka et al. 1996; Honma et al. 1999a, b; Yasunaga et al. 2004). The weight of evidence of all genotoxicity data, especially the negative in vivo results, indicates that isophorone is not genotoxic and suggests that it is not a DNA reactive compound. Other national and international agencies have concluded that isophorone is not mutagenic (IPCS 1995a; OECD 2003; US EPA 2006).

The mode of action for the isophorone-induced kidney tumours in male rats has been associated with a2u-globulin (Strasser et al. 1988; ATSDR 1989; Short 1993; Tennant 1993; IPCS 1995a; OECD 2003; Lock and Hard 2004; US EPA 2008). However, a2u-globulin is not detected at significant levels in plasma and urine of female rats, male or female mice, or humans (Swenberg et al. 1989). Chemicals that induce a2u-globulin nephropathy in male rats bind to the protein in the liver; these conjugates are difficult to hydrolyse and induce the formation of hyaline droplets, which accumulate in the tubules, resulting in a nephrotoxic response and a sustained increase in cell turnover (Swenberg et al. 1989, 1992). Isophorone and its proposed metabolites isophorol and dihydroisophorone bind to a2u-globulin in vivo, resulting in an increased accumulation of hyaline droplets in renal tubular cells (Strasser et al. 1988; Saito et al. 1996). Administration of isophorone has induced renal tubular tumours in male rats, but not in female rats or either sex of mice (NTP 1986). Detailed review and analysis by the US EPA showed that the isophorone-induced male rat kidney tumours met their criteria for associating renal tumours with a2u-globulin (US EPA 1991a, b, 2008). Therefore, the increase in the incidence of renal tubular tumours observed in male rats following isophorone administration was caused by the accumulation of a2u-globulin and was sex and species specific; hence, it is likely not relevant to humans (Strasser et al. 1988; ATSDR 1989; Tennant 1993; IPCS 1995a; OECD 2003; US EPA 2008).

The significance of the apparent higher incidence of preputial gland tumours that was observed only in male rats in the high dose group (500 mg/kg-bw per day) cannot be determined. As the gland was investigated histopathologically only when gross lesions were found, the actual incidence of all types of proliferative lesions of the prepuce in either the historical or concurrent controls is not precisely known (NTP 1986). As high levels of a2u-globulin are present in the preputial gland of both male and female rats (Murthy et al. 1987), the isophorone-induced preputial gland tumours in male rats may also have been associated with a2u-globulin accumulation (IPCS 1995a, b).

In terms of liver tumours, only high-dose male mice showed an increased incidence of combined adenomas and carcinomas. Female mice and rats of both sexes did not show any evidence of increased incidence of liver tumours (NTP 1986). Increased incidences of mesenchymal tumours of the integumentary system were shown in high-dose male mice only; the marginally increased incidence of lymphomas or leukemias was observed only in low-dose male mice, without dose–response evidence. The high mortality in male mice also makes the results difficult to evaluate. Although the liver and mesenchymal tumours may be treatment related, there is no clear evidence that the lymphomas or leukemias in male mice were treatment related. Also, there is evidence to indicate that isophorone does not bind to DNA in vivo (Thier et al. 1990), suggesting that isophorone may exert its toxic effects through a mechanism other than direct interaction with DNA (Topping et al. 2001). In addition, the US EPA considered the carcinogenicity test results in male mice to be “equivocal” (US EPA 2008).

The lowest inhalation LOEC in laboratory animals has been identified as 208 mg/m³ (36 ppm) from a 4-week study in male and female rats, based on reduced growth and liver weights in male rats and blood effects (increased lymphocytes and decreased neutrophils) in both sexes of rats (Exxon 1968). In a subchronic inhalation study, increased mortality was observed in rats exposed to isophorone at 2873 mg/m³ (500 ppm) for 4 or 6 months (only one exposure level tested) (Dutertre-Catella 1976). Microvacuolization of the liver in rats and rabbits was observed in a chronic inhalation study, following 18 months of exposure to isophorone at 1436 mg/m³ (250 ppm; only one exposure level tested) (Dutertre-Catella 1976).

In humans, complaints of fatigue and malaise from employees exposed for 1 month to isophorone concentrations ranging from 28 to 45 mg/m³ (5 to 8 ppm) were reported; the complaints stopped when isophorone concentrations decreased to 6–22 mg/m³ (l–4 ppm) (Ware 1973). However, no further details were available, including exposure conditions of the employees and potential co-exposures.

By the oral route, the lowest-observed-effect level (LOEL) for chronic exposure is 250 mg/kg-bw per day, based on a statistically significant increase in the incidence of female rats with nephropathy and increased incidences of coagulative liver necrosis and hepatocytomegaly in male mice in the 2-year study (NTP 1986). At a dose level of 1000 mg/kg-bw per day, reduced body weight gain in male rats and increased mortality in female mice were observed in a subchronic (90 days) study (NTP 1986). In another subchronic study, no toxicologically relevant effects were observed at doses up to 150 mg/kg-bw per day (except for a mild intermittent incidence of soft stools at 75 and 150 mg/kg-bw per day), which was the highest dose administered to Beagle dogs for 90 days (Rohm & Haas Co. 1972). For 16-day exposures, the lowest LOEL was 250 mg/kg-bw per day, based on reduced body weight gain in female mice. In the same study, at 1000 mg/kg-bw per day, sluggishness and lethargy in rats and staggering in mice were observed (NTP 1986).

In terms of dermal exposure, the lowest LOEL of 658 mg/kg-bw per day was identified based on erythema and crusted skin in the only repeated-dose dermal exposure study identified, in which isophorone was applied daily for 8 weeks to shaved and abraded (occluded) skin of rats (Dutertre-Catella 1976).

Developmental effects following isophorone exposure were observed only above the concentrations associated with maternal toxicity. There was evidence of maternal toxicity at 664 mg/m³ (115 ppm), but there were no developmental effects observed at this exposure level (Exxon 1984a). Teratogenicity (exencephaly) was observed at 866 mg/m³ (150 ppm) in a few mouse and rat fetuses in the pilot study (Exxon 1984b). However, this dose exceeded the concentration that was shown to cause maternal toxicity in the main study (Exxon 1984a). Therefore, isophorone does not appear to be a developmental toxicant.

Isophorone did not influence litter sizes, nor were there any abnormalities observed in the pups in a limited one-generation study in Wistar rats exposed by inhalation to isophorone at 2873 mg/m³ (500 ppm) (Dutertre-Catella 1976). However, only one concentration was used, the group size was small and no information was provided on reproductive success. No other studies on reproductive toxicity were identified. In 90-day oral studies, no changes were observed in histopathological examinations of the reproductive organs in Beagle dogs exposed to up to 150 mg/kg-bw per day (Rohm & Haas Co. 1972) or in rats exposed to up to 1000 mg/kg-bw per day (NTP 1986). Overall, isophorone does not appear to be a reproductive toxicant.

Irritation effects of isophorone were observed in both humans and experimental animals. In two investigations with 6 and 12 volunteers, throat irritation was reported at greater than 199 mg/m³ (Esso 1965a), and eye and nasal irritation at concentrations greater than 230 mg/m³, following acute exposure (Smyth and Seaton 1940). In a further investigation with 12 volunteers exposed to isophorone vapours for 15 minutes, eye, nose and throat irritation was reported at 144 mg/m³(Silverman et al. 1946). The results from animal bioassays on the irritating effects of isophorone have been consistent with observations in humans. Isophorone was found to be irritating to eyes at 0.1 mL undiluted (40 mg/kg-bw) and irritating to skin at 0.5 mL undiluted (200 mg/kg-bw) in rabbits (Esso 1964; Truhaut et al. 1972; Dutertre-Catella 1976).

Internationally, isophorone has been classified as an irritant to eyes and the respiratory system by the European Commission (2008).

Limited toxicokinetic studies suggest that after oral and inhalative administration, isophorone is well absorbed and rapidly distributed in rats and rabbits (Dutertre-Catella 1976). Systemic effects in acute toxicity studies indicate absorption following dermal exposure (Günzel and Richter 1968b). Methyl-oxidation, glucuronidation and hydrogenation appear to be the major transformation processes for isophorone (Truhaut et al. 1970; Dutertre-Catella et al. 1978). The tendency of isophorone to bioaccumulate is very low, as 80% of orally administered isophorone was excreted by rats within 96 hours (Thier 1991).

Confidence in the toxicity dataset is considered to be moderate to high. Data are available for acute toxicity, repeated-dose toxicity, chronic toxicity and carcinogenicity, and genetic toxicity. However, limited data are available on long-term inhalation, reproductive and developmental toxicity. There is only one chronic oral study using only two doses other than control. The only subchronic or chronic inhalation study used only one very high isophorone concentration and had small group sizes.

Characterization of Risk to Human Health

Carcinogenicity was considered in the health effects assessment for isophorone, as the substance had been classified as carcinogenic by some national or international agencies (i.e., European Commission and US EPA), but not others. These classifications were based upon the results of two animal bioassays of sufficient quality, as no sufficient epidemiological studies were available. Apparently increased incidences of tumours at multiple sites (kidney, preputial gland, liver and skin) were observed in 2-year standard carcinogenicity studies with rats and mice (NTP 1986). The induction of kidney tumours following isophorone administration was caused via the accumulation of a2u-globulin, a mechanism not relevant to humans (US EPA 1991a; IPCS 1995a; OECD 2003; US EPA 2008). Consideration of the available information regarding genotoxicity and the conclusions of other agencies indicate that isophorone is not likely to be genotoxic. Accordingly, although the mode of induction of tumours is not fully elucidated, the tumours observed in rodents are not considered to have resulted from direct interaction with genetic material. Therefore, a threshold approach is used to assess risk to human health.

For oral exposures, the lowest reported LOEL was 250 mg/kg-bw per day, based on non-neoplastic effects observed after chronic exposure (nephropathy in female rats; liver necrosis, hepatocytomegaly in male mice) in a 2-year toxicology and carcinogenicity study, whereas the potentially chemical-related increase in tumour incidence in that study was observed only at higher doses (NTP 1986).

Comparison of the critical effect level for repeated dosing via the oral route (i.e., the LOEL of 250 mg/kg-bw per day) with the upper-bounding estimate of daily intake of isophorone by the most highly exposed group (20–59 years) via environmental media and food in Canada (0.84 µg/kg-bw per day) results in a margin of exposure of approximately 298 000. Taking into account reasonable, upper-bounding estimates of exposure, the margin of exposure is considered adequately protective of human health for both cancer and non-cancer effects.

Oral ingestion, from food and drinking water, was identified as the predominant route of exposure for isophorone to the general population of Canada . Intake estimates from other sources were not as significant (Appendix 1a).

Uncertainties in Evaluation of Risk to Human Health

This screening assessment does not take into account potential human variability, nor does it consider differences between humans and experimental animals in terms of sensitivity to the potential effects of isophorone. There is not enough information to evaluate the incidences of preputial gland tumours in rats, because the true tumour incidence is not available in either historical data or the identified study (NTP 1986). Preputial gland tumours were not seen in mice, suggesting that this type of tumour may be species specific, and the relevance of rat preputial gland tumours to humans is unknown. The available study showed equivocal evidence of liver tumours in mice. The evidence for carcinogenicity is limited, but the consistently strong negative database of in vivogenotoxicity studies suggests that isophorone is not mutagenic.

Lack of recent Canadian data regarding levels of isophorone in environmental media and food is a source of uncertainty in the upper-bounding multimedia exposure estimates for the general population of Canada . However, concern about this uncertainty is reduced by taking into account the large margin of exposure between the critical effect level and the highest estimated intake of isophorone. Confidence is high that the derived multimedia exposure estimates are adequately protective of the general population of Canada , as conservative assumptions were used when recent Canadian data were unavailable.

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Conclusion

Based on the information presented in this screening assessment, it is concluded that isophorone is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.

Based on comparison of the upper-bounding estimated exposure to isophorone in Canada with the critical effect level, it is considered that the resulting margin of exposure is adequately protective of human health. It is concluded that isophorone is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

It is therefore concluded that isophorone does not meet any of the criteria set out in section 64 of CEPA 1999.

This substance will be considered for inclusion in the Domestic Substances List inventory update initiative. In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessment.

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References

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Appendix 1a: Upper-bounding estimates of daily intake of isophorone by the general population in Canada

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Appendix 1b: Concentrations of isophorone reported in various food items

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Appendix 2: Summary of health effects information for isophorone

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