Screening Assessment for the Challenge

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2-Butanone, oxime
(Butanone oxime)

Chemical Abstracts Service Registry Number
96-29-7

Environment Canada
Health Canada

March 2010

(PDF Version - 299 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 1: Upper-bounding estimates of exposure to butanone oxime in consumer products
15. Appendix 2: Summary of health effects information for butanone oxime

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-butanone, oxime (butanone oxime), Chemical Abstracts Service Registry Number 96-29-7. This substance was identified in the categorization of the Domestic Substances List as a high priority for action under the Ministerial Challenge. Butanone oxime was identified as a high priority as it was considered to pose greatest potential for exposure of individuals in Canada and had been classified by the European Commission on the basis of carcinogenicity. Although butanone oxime met the ecological categorization criteria for persistence, it did not meet the criteria for bioaccumulation potential or inherent toxicity to aquatic organisms. Therefore, the focus of this assessment of 2-butanone, oxime relates primarily to human health risks.

Butanone oxime is widely used as an anti-skinning agent in the formulation of alkyd paints, varnishes, stains and coatings for both industrial and consumer use. In Canada , the substance has also been reported in a number of pesticide products, namely wood preservatives and antifouling marine paints, as well as in some adhesives, silicone sealants and printing inks. Furthermore, butanone oxime is used as a corrosion inhibitor in industrial boilers and water treatment systems and serves as a blocking agent in the manufacturing process of urethane polymers.

According to the information submitted under section 71 of CEPA 1999, butanone oxime was not manufactured by any company in Canada in the 2006 calendar year. However, approximately 500 000 kg of the substance was imported in 2006, and nearly 120 000 kg was used in the same reporting year. There are few data on the release and fate of butanone oxime in environmental media in Canada or elsewhere. Butanone oxime is not a naturally occurring substance; thus, releases of the substance to the environment are expected to result directly from anthropogenic activities. Considering the quantity of butanone oxime in commerce in Canada and its use in a variety of consumer products, exposure of the general population to the substance is expected to be moderate.

As butanone oxime was classified on the basis of carcinogenicity by the European Commission, carcinogenicity was a key focus for this screening assessment. Increased incidences of liver tumours were observed in rat and mouse lifetime studies, and there was also an increased incidence of mammary gland tumours in female rats; however, this was seen only at moderate and/or high concentrations of butanone oxime. Consideration of the available information regarding genotoxicity indicates that butanone oxime 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 nasal cavity of rats and/or mice in inhalation studies of short-term through to chronic exposure duration. Also, repeated-dose studies based on oral exposure showed effects in the spleen, liver and kidney of rats as well as hematological effects in both rats and rabbits. Based on comparison of estimated exposures to butanone oxime in Canada with the critical effect levels, and taking into account the uncertainties in the databases on exposure and effects, it is considered that the resulting margins of exposure, particularly for consumer exposure from products containing the substance, may not be adequately protective of human health for non-cancer effects.

On the basis of the potential inadequacy of the margins between estimated exposures to butanone oxime and critical effect levels, it is concluded that butanone oxime is a substance that may be 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 ecological hazard and estimated releases of butanone oxime, 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. Butanone oxime does meet the criteria for persistence but does not meet the criteria for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations.

Based on the information available, it is concluded that butanone oxime meets one or more 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 and, where appropriate, the performance of potential control measures identified during the risk management phase.

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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; 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-butanone, oxime (butanone oxime) was identified as a high priority for assessment of human health risk because it was considered to present GPE and had been classified by another agency on the basis of carcinogenicity.

The Challenge for butanone oxime 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 were received.

Although butanone oxime was determined to be a high priority for assessment with respect to human health and met the ecological categorization criteria for persistence, it did not meet the criteria for bioaccumulation or inherent toxicity to aquatic organisms. Therefore, this assessment focuses principally on information relevant to the evaluation of risks to human health.

Screening assessments examine scientific information and develop conclusions by incorporating a weight of evidence approach and precaution.

This 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 and stakeholder research reports and from recent literature searches, up to November 2008 for the human health sections and May 2009 for the ecological sections. 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) of 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 prioritizing 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 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 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. Both the human health and ecological 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. Michael Jayjock (The LifeLine Group) and Dr. Glenn Talaska (University of Cincinnati). Additionally, the draft of this screening assessment was subject to a 60-day 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 assessment is based are summarized below.

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Substance Identity

2-Butanone, oxime is also commonly known as methyl ethyl ketoxime (MEKO). However, for the purposes of this document, this substance will be referred to as butanone oxime, based on the European Inventory of Existing Commercial Chemical Substances (EINECS) name. Information on the identity of butanone oxime is summarized in Table 1.

Table 1. Substance identity for butanone oxime

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Physical and Chemical Properties

Table 2 contains experimental and modelled physical and chemical properties of butanone oxime that are relevant to its environmental fate. When experimental data were not available, the property was estimated using models, as indicated in Table 2. Although butanone oxime is a weak acid and will dissociate, it does so only at very high pH (>12). Therefore, it is in the neutral form at environmentally relevant pH values (6–9), and the neutral form of butanone oxime was used for model estimation.

Table 2. Physical and chemical properties for butanone oxime

Although two geometrical isomers are possible for butanone oxime, the trans isomer predominates (>99%) (OECD 2003).

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Sources

Butanone oxime is an anthropogenic substance and is considered to be a high production volume chemical by the Organisation for Economic Co-operation and Development (OECD 2004), the US Environmental Protection Agency (US EPA 2006) and the European Commission (ESIS 2006). Worldwide production of butanone oxime is estimated at between 10 000 and 20 000 tonnes per year (OECD 2003). According to the information submitted under section 71 of CEPA 1999, butanone oxime was not manufactured by any company in Canada in the 2006 calendar year. However, imports of the substance into Canada above the reporting threshold of 100 kg were approximately 500 000 kg in the same year (Environment Canada 2009a).

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Uses

The most prevalent use of butanone oxime is as an anti-skinning agent in the formulation of alkyd paints, primers, varnishes and stains, to prevent oxidative drying and the formation of hard, gelatinous films on the surface of the paint product in the container. According to the information submitted under section 71 of CEPA 1999, nearly 120 000 kg of butanone oxime was used in Canada in 2006 (Environment Canada 2009a). The majority of these uses were in the manufacture of alkyd paint products for both industrial and consumer applications. Based on available information, the concentration of butanone oxime in alkyd paint products in Canada is =1% by weight (w/w), while a typical concentration ranges from 0.02 to 0.5% w/w (2009 personal communication from Canadian Paints and Coatings Assocation Working Group to Environment Canada; unreferenced). According to the section 71 responses, butanone oxime is also present in colorants or pigments used in alkyd paints or printing inks at concentrations of 0.1% and 0.2% w/w, respectively (Environment Canada 2009a).

The substance is also present as a formulant in several pesticide products, namely wood preservatives and antifouling marine paints, in use in Canada (2009 personal communication from Pest Management Regulatory Agency, Health Canada, to Risk Management Bureau, Health Canada; unreferenced). In addition, it is a minor component of some sealants and adhesives manufactured in Canada and, to a lesser degree, of some fillers and artists’ paint and printing materials (Environment Canada 2009a).

Butanone oxime is also used as a corrosion inhibitor in industrial boilers (Rumpf 1993) and water treatment systems (Newton et al. 2001; Derelanko et al. 2003) and as a blocking agent in the manufacturing process of urethane polymers (Subramani et al. 2004). According to the information submitted under section 71 of CEPA 1999, butanone oxime is used as a corrosion inhibitor and as a blocking agent in the manufacture of urethane polymers in Canada (Environment Canada 2009a).

No current use of butanone oxime in cosmetics has been notified in Canada . Internationally, the use of butanone oxime in cosmetics is prohibited in Denmark (Danish Ministry of the Environment 2004) and in the United Kingdom (U.K. Secretary of State 2008) in accordance with an amendment to Directive 76/768/EEC of the European Commission (European Commission 2004). Butanone oxime is found in some printing inks used in the manufacture of food packaging materials, but there is no direct contact of butanone oxime with food.

Releases to the Environment

According to the information submitted under section 71 of CEPA 1999, butanone oxime was not manufactured by any company in Canada in 2006. In addition, there were no reports of any significant industrial releases of butanone oxime in the same calendar year in the section 71 responses (Environment Canada 2009a). The Canadian Chemical Producers’ Association (CCPA 2009) reported the release of 356 kg of butanone oxime to the environment in 2007. The reporting of industrial releases of butanone oxime to the National Pollutant Release Inventory (NPRI 2007) is not required. The total industrial releases of butanone oxime are expected to be low, and the most significant releases of butanone oxime are expected to take place at the consumer use stage.

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Environmental Fate

Based on its physical and chemical properties (Table 2), butanone oxime is characterized by high water solubility (100 000 mg/L), moderate vapour pressure (350 Pa), low log Kow (0.65), and low Henry’s Law constant (0.30 Pa·m³/mol). Half-lives in air (modelled as 7.21 days, see Table 4b) and in water (measured as 18 days based on the hydrolysis rate, see Table 4a) are used in Level III fugacity modelling. The results are summarized in Table 3 and suggest that butanone oxime will reside largely or predominantly in the compartment to which it is released. There is somewhat moderate partitioning in water and soil, when the substance is released to air; and moderate partitioning in water if released to soil.

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

Butanone oxime is considered to be a non-ionizing compound due to its high acid dissociation constant (pK_a >12); thus, it will be in the neutral form at environmentally relevant pHs (6–9).

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Persistence and Bioaccumulation Potential

Environmental Persistence

Table 4a presents the empirical biodegradation and hydrolysis data for butanone oxime in water. This substance may hydrolyse, depending on the pH. At 20°C, butanone oxime is hydrolytically unstable at pH 4, whereas no hydrolysis occurs at pH 9. At pH 7, 14% of the substance was hydrolysed after 4 days (Environment Canada 2009b), which translates to a half-life of 18 days based on hydrolysis in the aquatic environment. Therefore, at neutral to acidic environmental conditions, hydrolysis may be an important degradation pathway for this substance. Hydrolysis products are 2-butanone (CAS RN 78-93-3) and hydroxylamine (CAS RN 7803-49-8) (ECB 2000a and 2000b).

The inherent biodegradation study (MITI 1992) suggests that this substance undergoes primary biodegradation, but that ultimate biodegradation is, at best, slow (Table 4a).

Table 4a. Empirical data for degradation ofbutanone oxime

The European Chemicals Bureau (ECB) published a datasheet on butanone oxime, reporting degradation studies with alternative OECD approved tests with conclusions of inherent, primary and ultimate biodegradability (2000a). Studies report 70% degradation related to dissolved organic carbon (DOC) in 14 days, while only ~25% degradation related to biological oxygen demand (BOD).

In addition to experimental data on the degradation of butanone oxime as above, a quantitative structure–activity relationship (QSAR)-based weight of evidence approach (Environment Canada 2007) was applied using the degradation models shown in Table 4b.

Table 4b. Modelled data for degradation of butanone oxime

 The BIOWIN (2008) aerobic biodegradation models (BIOWIN submodels 3, 4, 5 and 6) suggest that butanone oxime biodegrades rapidly. The BIOWIN submodels 5 and 6 probability results are both greater than 0.3, the cut-off suggested by Aronson et al. (2006) to identify substances as having a half-life <60 days (based on the MITI probability models). However TOPKAT predicts that the substance may not biodegrade rapidly in water, while CATABOL suggests that the substance is just between the cut-offs for ‘biodegrades slowly’ (BOD < 20%) and ‘may biodegrade fast’ (BOD > 21%). Given the existence of experimental data, more weight is given to the empirical measures, the results of which are also supported by aerobic BIOWIN submodels 3, 4, 5 and 6. There is sufficient confidence, based on the experimental data, when taken together with the BIOWIN model predictions, to expect that there is significant biodegradation with a half-life that is likely well below 182 days.

Although little butanone oxime is expected to partition to sediment, it may remain in soil if released to this environmental compartment (see Table 3). Since BIOWIN (2008) biodegradation prediction is expected to be fast, along with a moderate potential for hydrolysis, these data suggest that the degradation half-life in water is likely = 90 days, thus the degradation half-lives for soil and sediments extrapolated using Boethling et al.’s (1995) factors (t_{½ water} : t_{½ soil} : t_{½ sediment} = 1:1:4), are = 180 days and = 365 days, respectively.

Based on the empirical and modelled data (see Tables 4a and 4b above), it is concluded that butanone oxime meets the persistence criterion in air (half-life in air ³2 days), but does not meet the criteria for water, soil or sediment (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).

The long-range transport potential (LRTP) of this substance was predicted using two models: the Transport and Persistence Level III Model (TaPL3 v.3.00) and the OECD Pov and LRTP Screening Tool. Results are presented in Table 4c.

Table 4c. Model predictions and level of concern of the long-range transport potential of butanone oxime

The TaPL3 model provides an estimate of the characteristic travel distance (CTD) only for the substance, defined as the maximum distance travelled by 63% of the substance, of 1376 km. Beyer et al. (2000) proposed characteristic travel distances of > 2000 km as representing high long-range transport potential, 700–2000 km as moderate and < 700 km as low. Based on the modelled result from TaPL3, this substance is expected to have a moderate long-range transport potential.

The LRTP of butanone oxime was also assessed using the OECD tool, based on a combination of overall environmental persistence (P_ov) and CTD or transfer efficiency (TE). P_ov has been introduced as a concept to weigh half-lives according to partitioning behaviour and is a kind of average of all the half-lives in air, water, sediment and soil (Mackay 2006). This parameter is found to closely link to the potential for long-range transport, but is not currently used for decision making in hazard assessment as most regulatory authorities rely on the single-media half-life approach. TE is a measure, expressed as percentage, for the extent of the deposition of a substance onto the surface media of a target area after being transported away from the region of release (Klasmeier et al. 2006). Based on the level of concern rating system (Scheringer et al. 2006), the long-range transport potential of butanone oxime is expected to be moderate as well.

Potential for Bioaccumulation

Experimental log K_ow values (0.59-0.65) for butanone oxime (see Table 2 above) suggest that this chemical has low potential to bioaccumulate in biota. Experimentally derived bioconcentration factors (BCF) of 0.5–5.8 for carp (Cyprinus carpio) and Japanese medaka (Oryzias latipes) (MITI 1992; ECB 2000a) indicate that butanone oxime is not bioaccumulative. This conclusion is also supported by modelled BCF and bioaccumulation factor (BAF) values (Table 5) using the default of no metabolism, which were used in a weight of evidence approach (Environment Canada 2007) for evaluating the bioaccumulation potential of this substance.

Table 5. Fish BAF and BCF predictions for butanone oxime with default of no metabolism

Furthermore, log K_ow values for the hydrolysis products 2-butanone and hydroxylamine are very low (ECB 2000; OECD 2008), indicating that the hydrolytic products of butanone oxime also have low potentials to bioaccumulate.

Based on the available empirical and kinetic-based modelled values, it is concluded that butanone oxime does not meet the bioaccumulation criteria (BAF or BCF =5000) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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Potential to Cause Ecological Harm

The approach taken in this assessment was to examine the available scientific 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 site-specific aquatic risk quotient calculations as well as information on the persistence, bioaccumulation, inherent toxicity, sources and fate of the substance.

As described previously, butanone oxime is persistent in air, but not in water, soil or sediment compartments. It is also expected to have a low bioaccumulation potential. The most sensitive experimental ecological effects data for a range of species, as well as modelled data, are summarized in Table 6. Robust study summaries were not prepared for the empirical studies, as the studies were not available. However, the lowest value of all ecotoxicity data (6.1 mg/L) collected was used as a conservative estimate of the critical toxicity value (CTV) to characterize the potential for effects on sensitive species. The modelled data generally support the empirical results.

Table 6. Empirical and modelled data for aquatic toxicity of butanone oxime

The toxicity data indicate that butanone oxime has a moderate potential to be toxic to algae and a low potential for most other aquatic organisms. Furthermore, considering the toxicity of the hydrolysis products (2-butanone and hydroxylamine) to sensitive aquatic species, as well as the comparatively low rate of hydrolysis (14% in 4 days) under environmental conditions, the risk due to the hydrolysis products of butanone oxime is not expected to be significantly higher than that of the compound itself (ECB 2000b; OECD 2008).

Toxicity data were not found for the organisms in the soil or sediment compartments.

The high importation volume of butanone oxime into Canada , together with information on its uses, indicates potential for widespread release of this substance into the Canadian environment. If released to water, butanone oxime is expected to remain in water (>99%; see Table 3). In this screening assessment, site-specific aquatic exposure scenarios were developed to estimate releases into the aquatic environment from industrial operations and resulting aquatic concentrations.

Two sewage treatment plants (STPs) were identified as having the highest releases of butanone oxime, as determined from information obtained through the section 71 survey (Environment Canada 2009a). Each site includes discharges from a certain number of industrial users of butanone oxime. One site releases to a relatively large receiving water body, whereas the other site releases to a considerably smaller one. The predicted environmental concentrations (PECs) for both sites were estimated based on the quantity of butanone oxime used by all facilities served by each STP, the fraction estimated to be discharged to the STP, the STP removal rate, the STP effluent flow and the dilution capacity of the receiving water. The key value in the PEC estimate is the fraction of the substance discharged to the STP. This fraction is 0.3%, resulting from the cleaning of semi-bulk containers or totes that are used for the transportation of the substance, and is assumed by default (Great Western Containers 2005). The higher calculated PEC for the two sites was 0.010 mg/L.

A predicted no-effect concentration (PNEC) was derived from the chronic algal toxicity value of 6.1 mg/L for Pseudokirchneriella subcapitata (see Table 6). An assessment factor of 100 was applied to account for uncertainties related to interspecies and intraspecies variability in sensitivity and extrapolation from a laboratory EC₅₀ to a no-effect value in the field. This yielded a PNEC of 0.06 mg/L. The highest resulting risk quotient, calculated as the ratio of the PEC to PNEC, was 0.17, indicating that the substance is not anticipated to harm aquatic organisms.

Butanone oxime is thus considered unlikely to be causing ecological harm in Canada . Considering the comparatively low hydrolysis rate of butanone oxime, the hydrolysis products are not expected to pose a threat either.

It should be noted that this conclusion was reached despite the conservative assumptions that were made in response to uncertainties encountered in the assessment. A key uncertainty relates to the lack of empirical data on environmental concentrations in Canada , which was addressed by predicting realistic worst-case concentrations in water using an industrial exposure model. There is also uncertainty associated with the PNECused in the risk quotient calculation, because details of the study were not available. However, the CTV used is considered to be conservative, as it is the lowest empirical value observed and is at least one order of magnitude lower than the next lowest toxicity value. In addition, an assessment factor of 100 was applied to the CTV to derive the PNEC.

Also, regarding ecotoxicity, based on the predicted partitioning behaviour of this chemical, the significance of soil and sediments as important media of exposure is not well addressed by the effects data available. However, exposures near industrial point sources are expected to be highest in the aquatic compartment.

Uncertainties also exist with the conclusion for persistence. Very limited empirical data were available, and some model results were contradictory. These data were nevertheless used to estimate approximate half-lives for water, soil and sediment. However, the weight of evidence, considering both the empirical and modelled data, indicates that this substance does not meet the persistence criteria for water, soil or sediment.

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Potential to Cause Harm to Human Health

Exposure Assessment

Environmental Media and Food

No measured concentrations of butanone oxime in environmental media in Canada or elsewhere were identified. Based on its high vapour pressure and half-life in air, butanone oxime is expected to exist primarily as a vapour and to persist in ambient air. However, as no significant industrial releases of butanone oxime to the air were reported in 2006, the concentration of butanone oxime in ambient air is expected to be low. Modelled estimates based on current information also predict that the concentration of butanone oxime in air is low, at approximately 1.79 ng/m³(ChemCAN 2003). Similarly, the predicted concentrations for water and soil are very low (0.550 ng/L and 7.08 × 10^-4 ng/g, respectively).

No measured concentrations of butanone oxime in food in Canada or elsewhere were identified. Based on the uses of butanone oxime in Canada , food is unlikely to be a source of exposure. Given that the experimental log K_ow values for butanone oxime are low, the substance is not expected to bioaccumulate in biota, and accumulation of butanone oxime in the food chain is not considered likely.

Due to the lack of empirical data on concentrations in environmental media and food, upper-bounding daily intake estimates for the general population were not derived.

Consumer Products

With regard to consumer products, butanone oxime is most prevalent in alkyd paints, stains, varnishes and coatings, according to information submitted under section 71 of CEPA 1999. Butanone oxime is also present in a few sealants, adhesives and fillers that are used mainly by industry, but which may also be available to the general population for home maintenance and do-it-yourself applications. Accordingly, use of alkyd paint containing butanone oxime was the primary scenario used to characterize exposure from products.

A limited number of studies report concentrations of butanone oxime during manufacture and use of products such as alkyd paints. A US study of consumer exposure to butanone oxime (Chang 1998) predicted a maximum concentration of butanone oxime in indoor air of 18 mg/m³ based on the use of alkyd paint containing 0.293% w/w butanone oxime, the highest level of butanone oxime that was present in the products tested. A limited unpublished study measured butanone oxime concentrations of up to 9.9 ppm (30 mg/m³) during a simulation using an indoor painting scenario with an alkyd paint containing approximately 0.2% butanome oxime (unpublished study submitted to Environment Canada, 2009b; unreferenced).

However, as butanone oxime content of alkyd paints used in Canada can be higher (up to 1% (2009 personal communication from Canadian Paints and Coatings Association to Environment Canada; unreferenced)) potential exposure at this level was modelled.

Exposure estimates were therefore derived using ConsExpo v. 4.1 software (ConsExpo 2007). Resulting estimated air concentrations and dermal exposure (external) are summarized in Table 7. The inputs and assumptions used in ConsExpo v. 4.1 modelling of each of the consumer product scenarios are provided in Appendix 1, where both external and internal exposure estimates during use of these products are presented. There were no identified data on absorption of butanone oxime following inhalation exposure. While dermal absorption have been reported to range between 13% and 29% in a study conducted in rats (Burka et al. 1998), the estimates of internal exposure were derived using 100% uptake for inhalation and dermal absorption.

Table 7. Summary of estimated air concentrations and dermal external applied dose of butanone oxime during use of consumer products

The US EPA’s Wall Paint Exposure Assessment Model v. 3.2 (WPEM 2001) predicted a maximum indoor air concentration of butanone oxime of 227 mg/m³ for the alkyd paints and an 8-hour average concentration of 195 mg/m³.

Based on the available information, the most likely route of exposure to butanone oxime for the general population is likely from inhalation during use of alkyd paints and coatings, based on the maximum mean event concentration. However, in light of the limited data available on concentrations in environmental media, confidence in this estimate is very low.

Health Effects Assessment

Appendix 2 contains a summary of the available health effects information for butanone oxime.

The European Commission has classified butanone oxime as Category 3 for carcinogenicity (causes concern for humans owing to possible carcinogenic effects) (European Commission 2000, 2001). In chronic lifetime studies in both rats and mice exposed by inhalation to butanone oxime, there was an increased incidence of liver tumours (adenomas and carcinomas) in both species at all tested exposure concentrations. However, statistically significant increases in incidence were observed only at 267 and 1333 mg/m³ for liver adenomas in male rats and at 1333 mg/m³ for liver carcinomas in male rats and mice. A statistically significant increased incidence of mammary gland fibroadenomas was also observed in female rats at 1333 mg/m³. Non-neoplastic effects observed in rats included histopathological effects in the spleen (congestion, increased pigmentation in the reticuloendothelial cells and extramedullary hematopoiesis) and in the nasal turbinates (degeneration of the olfactory epithelium) at all exposure concentrations, in the liver (increased incidences of basophilic foci and hepatocyte vacuoles) at 267 and 1333 mg/m³, changes in blood parameters at 1333 mg/m³ and enlarged testes in males at 267 and 1333 mg/m³. Non-neoplastic effects observed in mice included dose-related increases in liver hypertrophy and necrosis as well as in olfactory epithelium degeneration in the nasal turbinates at all exposure concentrations, changes in blood parameters at 267 and 1333 mg/m³ and changes in serum chemistry parameters at 1333 mg/m³. The lowest-observed-adverse-effect concentration (LOAEC) for non-neoplastic effects was 53 mg/m³ (15 ppm), based on effects in the spleen and nasal turbinates of rats and effects in the liver and nasal turbinates of mice (Newton et al. 2001). Long-term oral or dermal studies using butanone oxime were not identified.

Butanone oxime was not mutagenic in the majority of bacterial mutation assays using Salmonella typhimurium, but it was positive in a mouse lymphoma cell mutation assay with and without activation (Allied Corporation 1983b; Rogers-Back et al. 1988; JETOC 1999; NTP 1999). In vitro assays for chromosomal aberration in Chinese hamster ovary and lung cells, for sister chromatid exchange in Chinese hamster ovary cells and for unscheduled deoxyribonucleic acid (DNA) synthesis in rat hepatocytes all showed negative responses (Allied Corporation 1983a; IHF Inc. 1995; JETOC 1999; NTP 1999). In vivoassays for micronuclei were both negative for bone marrow cells in rats and for peripheral blood cells in mice; rats and mice were dosed orally (Microbiological Associates Inc. 1990; NTP 1999). In an in vivo assay in rats exposed by inhalation, butanone oxime was negative for DNA adducts but positive for ribonucleic acid (RNA) adducts in rat liver cells (Honeywell International Inc. 2000).

Fully elucidated modes of action analysis for induction of the observed tumours have not been identified. The European Commission (2000) considered that a possible mechanism for the increased incidences of liver tumours in male rats and mice was the metabolism of butanone oxime to a carcinogenic agent, mediated by sulfotransferase. The sex and organ specificity of tumour formation correlated with the typically higher activity of this enzyme in male rodents. Völkel et al. (1999) showed that the incubation of liver microsomes from mice, rats and humans with butanone oxime resulted in the formation of nitronates, but that the rates of formation did not correlate with sex and species differences in liver tumour response; they concluded that “other mechanisms of tumourigenicity not related to nitronate mutagenicity and DNA-damage may thus be operative.” The European Commission (2000) did not comment on whether the mode of action for liver tumours in rats was due to threshold mechanisms. However, the in vitro and in vivo genotoxicity results for butanone oxime were mostly negative, including an in vivo study that utilized inhalation exposure and was found to be negative for DNA adducts in rat liver cells. Therefore, based on the available data, butanone oxime appears to lack mutagenic potential. This lack of mutagenic potential may also explain why the European Commission (2000) did not comment on whether the mode of action for mammary gland tumours in rats was due to threshold mechanisms.

In a mouse inhalation study with exposures to butanone oxime for 1, 2 or 4 weeks, degeneration of the olfactory epithelium in the nasal cavity was observed in males at concentrations of 107 and 356 mg/m³ (incidence and severity increased with increasing exposure concentration) (Newton et al. 2002). In 13-week inhalation studies, degeneration of the olfactory epithelium in the nasal cavity was observed in male mice at concentrations of 36–356 mg/m³ (incidence and severity increased with increasing exposure concentration), whereas increased relative liver weights were observed in male rats at 267 and 1333 mg/m³ (Newton et al. 2001, 2002). The LOAEC for subchronic exposure was 36 mg/m³, based on degeneration of the olfactory epithelium in the nasal cavity of mice.

In a 4-week oral rat study, changes in hematological parameters (increase in reticulocytes, platelets and red blood cells) and increased relative spleen weight with accompanying histopathological abnormalities (increases in congestion, extramedullary hematopoiesis and hemosiderin granules) were observed in both sexes at 20 and 100 mg/kg body weight (kg-bw) per day, whereas hemosiderin granules in the liver were observed in females at the same doses (Japan MHW 1996; JETOC 1999). Butanone oxime was administered via drinking water in a 13-week rat study. Relative liver weights were increased in males at doses of 25–280 mg/kg-bw per day (NTP 1999). In another 13-week rat study, in which butanone oxime was administered via gavage, changes in liver and spleen weights, hemosiderosis of spleen and hematological effects were observed in both sexes at doses of 25–225 mg/kg-bw per day (Allied Signal Inc. 1977). The lowest-observed-adverse-effect level (LOAEL) for short-term and subchronic oral exposure was 20 mg/kg-bw per day, based on changes in hematological parameters, increased relative spleen weight with accompanying histopathological abnormalities, and hemosiderin granules in the liver observed in the 4-week rat study.

In a one-generation oral rat study, the LOAEL for reproductive toxicity was 100 mg/kg-bw per day, the highest dose, based on a statistically significant decrease in female delivery index (%) ^[1](Japan MHW 1998), whereas no treatment-related effects on reproductive parameters were observed in a two-generation study in which rats were dosed by gavage at 0–200 mg/kg-bw per day (Tyl et al. 1996). In both the one-generation and two-generation rat studies, a parental LOAEL of 10 mg/kg-bw per day, the lowest dose tested, was established, based on histopathological effects in the spleen and liver (and in the kidney in the one-generation study).

Teratogenicity was not observed in pregnant rats and rabbits dosed orally with butanone oxime during gestation (Springborn Laboratories 1990a, b; Mercieca et al. 1991; Derelanko et al. 2003). The lowest oral LOAEL for developmental toxicity was 40 mg/kg-bw per day, the highest dose, based on abortions in 3 of 10 adult females in pregnant rabbits dosed by gavage during gestation (Springborn Laboratories 1990b; Derelanko et al. 2003). The lowest oral LOAEL for maternal toxicity was 10 mg/kg-bw per day, based on signs of anemia (increased reticulocytes and methemoglobin) in rabbits dosed at 0–80 mg/kg-bw per day in a range-finding developmental study (Springborn Laboratories 1990b; Derelanko et al. 2003).

Studies designed to determine median lethal dose or concentration (LD₅₀ or LC₅₀) values were also able to determine lowest effect levels based on acute exposure. The lowest LOAEC for inhalation exposure was 190 mg/m³, based on decreased body weight gain in the observation period (7 or 14 days) after 4 hours of inhalation exposure in rats (Allied Corporation 1984b). The lowest LOAEL for dermal exposure was 180 mg/kg-bw, based on methemoglobin production and splenic erythrophagocytosis in a 24-hour dermal rabbit study (Allied Corporation 1984a; US EPA 1986).

Toxicokinetic studies on butanone oxime in mice and rats show that it is rapidly absorbed from the gastrointestinal tract, undergoes widespread uptake, distributes over the entire body, is extensively metabolized and does not accumulate in tissues. Excretion of butanone oxime and its metabolites occurs in the urine and bile or as volatiles in expired air (ICCA MEKO 2003). In single-dose studies in rats, significantly greater amounts of volatiles were excreted following dermal administration than after gavage or intravenous administration (NTP 1999). However, no toxicokinetic data based on repeated dosing via the oral, inhalation, nor dermal pathways were identified. The toxicokinetic studies of butanone oxime demonstrated the existence of two metabolic pathways and the possibility of a third one (based on acute oral, dermal and intravenous doses only). The major pathway is the hydrolysis of butanone oxime to 2-butanone (methyl ethyl ketone), and the second pathway is the oxidation of butanone oxime to butane 2-nitronate by microsomal monooxygenases, but this occurs at very low rates (ICCA MEKO 2003). ICCA MEKO (2003) reported that “With respect to the three [metabolic] pathways, there were no quantitative differences in the extent of MEKO [butanone oxime] metabolism between male and female rats.”

The confidence in the toxicity database for butanone oxime is considered to be low to moderate, as adequate information is available to address effects that may be of concern and identify critical endpoints based on inhalation exposures of acute to long-term duration. However, there was a lack of reproductive and developmental toxicity studies based on inhalation exposure; and limited studies via the dermal route.

Characterization of Risk to Human Health

Carcinogenicity was considered in the health effects assessment for butanone oxime, as the substance had been classified as carcinogenic by the European Commission (2000, 2001). As shown under the “Health Effects Assessment” section, increased incidences of liver tumours were observed in rat and mouse lifetime studies, and there was also an increased incidence of mammary gland tumours in female rats. However, these were seen only at mid- and/or high concentrations of butanone oxime. Consideration of the available information on genotoxicity indicates that butanone oxime 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.

With respect to non-cancer effects, the lowest inhalation LOAEC for chronic exposures was 53 mg/m³, based on degeneration of the olfactory epithelium in the nasal cavities of both mice and rats, liver cell hypertrophy and necrosis in mice, and histopathological effects in the spleen of rats observed in lifetime studies with these species. For subchronic exposures, the lowest inhalation LOAEC was 36 mg/m³, based on degeneration of the olfactory epithelium in the nasal cavity of mice observed in a 13-week inhalation study. Likewise, for short-term exposures, the lowest inhalation LOAEC was 107 mg/m³, based on degeneration of the olfactory epithelium of the nasal cavity of mice exposed to a butanone oxime exposure regime of 6 hours/day, 5 days/week, for 1, 2 or 4 weeks. The occurrence of toxicological sequelae following five exposures (30 total hours of exposure) is relevant for the acute exposure risk assessment. For acute exposures, an inhalation LOAEC of 190 mg/m³ was determined based on decreased body weight gain in rats in a 4-hour inhalation study. The changes in body weight gain were not noted at critical effect levels in short-term inhalation studies. However, an analysis of the change in the dose–response curve over time (190 mg/m³ acutely, 107 mg/m³ after 5 days and 36 mg/m³ after subchronic exposure) suggests that the body weight gain deficits occur in the appropriate dose range following acute exposure.

The lowest oral LOAEL for short-term and subchronic exposures was 10 mg butanone oxime/kg-bw per day, based on histopathological effects in the spleen and liver of adult rats observed in both a one-generation and a two-generation reproduction study (and in the kidney in the one-generation study) (Tyl et al. 1996; Japan MHW 1998) and based on signs of anemia in adult female rabbits observed in a range-finding developmental study (Springborn Laboratories 1990b; Derelanko et al. 2003). For acute exposures, an oral lowest-observed-effect level (LOEL) of 300 mg/kg-bw was determined based on transient neurotoxic effects in rats (Schulze and Derelanko 1993), and a dermal LOAEL of 180 mg/kg-bw was determined based on methemoglobin production and splenic erythrophagocytosis in a 24-hour rabbit study (Allied Corporation 1984b; US EPA 1986).

As stated under “Exposure Assessment”, due to the lack of empirical data on concentrations in several media, estimates of daily intake for the general population were not derived. Thus, margins of exposure could not be derived for comparisons between critical effect levels based on repeated daily exposures to butanone oxime and upper-bounding estimates of daily intake.

Exposure to butanone oxime is most likely to occur through use of consumer products. Based on product scenario modelling using ConsExpo, the highest air concentrations resulted from inhalation during use of alkyd paints and coatings, resulting in a range of 73–223 mg/m³. Using the Wall Paint Exposure Assessment Model, an 8-hour average air concentration of 195 mg/m³was derived for alkyd paints. Comparison of these conservative air concentrations with the acute to short-term critical effect levels for inhalation exposure (107–190 mg/m³) results in margins of exposure of 0.5–2.6. A limited number of studies measured air concentrations ranging from 6.0 to 18 mg/m³under various simulated paint scenarios using products with lower concentrations of butanone oxime (0.2 – 0.6%). Resulting margins of exposures from these scenarios range from 6 to 30.

Acute dermal exposures during use of alkyd paints and coatings were estimated to be 0.0226–1.06 mg/kg-bw. These estimates were compared to a dermal critical effect level of 180 mg/kg-bw, which leads to margins of exposure ranging from 170 to 8000.

In light of the uncertainties in the databases on exposure and effects, it is considered that the derived margins of exposure for these consumer product scenarios (all estimated margins of exposure based on inhalation exposure, and the lower margins of exposure based on dermal exposure) may not be adequately protective of human health for non-cancer effects.

Uncertainties in Evaluation of Risk to Human Health

This screening assessment does not include a full analysis of the mode of induction of effects, including cancer, of butanone oxime. In addition, only limited information is available concerning the potential toxicity of butanone oxime following oral and dermal exposure and for reproductive toxicity, developmental toxicity and genotoxicity studies based on inhalation exposures. Thus, critical effect levels determined in this screening assessment are limited by the toxicity database and by uncertainties in the interpretation of the biological significance of effects, including uncertainties in the interpretation of intraspecies and interspecies variation.

Uncertainty in exposure to butanone oxime from the environmental media and food in Canada is high, as no empirical data were available with which to derive exposure estimates. While empirical data is absent, food is not expected to be a source of exposure to butanone oxime. While the most likely source of exposure of the general population to butanone oxime is expected to be alkyd paint products, uncertainty is associated with the use of default assumptions. However, the concentrations of butanone oxime in the selected products used for modelling consumer product exposure scenarios are based on Canadian-specific information.

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Conclusion

Based on the information presented in this screening assessment, it is concluded that butanone oxime 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.

On the basis of the potential inadequacy of the margins between estimated exposures to butanone oxime and critical effect levels, it is concluded that butanone oxime is a substance that may be 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 butanone oxime meets one or more of the criteria set out in section 64 of CEPA 1999. Additionally, butanone oxime meets the criteria for persistence but does not meet the criteria for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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 and, where appropriate, the performance of potential control measures identified during the risk management phase.

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[OECD] Organisation for Economic Co-operation and Development. 2003. SIDS [Screening Information Data Set] Initial Assessment Profile for 2-Butanone oxime (MEKO) (CAS No. 96-29-7). SIAM [SIDS Initial Assessment Meeting] 17, 11-14 November 2003. Available from: http://cs3-hq.oecd.org/scripts/hpv/index.asp
 
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Appendix 1: Upper-bounding estimates of exposure to butanone oxime in consumer products

Dermal acute (internal) dose: 0.147 mg/kg-bw

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Appendix 2: Summary of health effects information for butanone oxime

Footnote

^[1] (No. of pups born/no. of implantations) × 100.

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2-Butanone, oxime
(Butanone oxime)

Chemical Abstracts Service Registry Number
96-29-7

Environment Canada
Health Canada

March 2010

(PDF Version - 299 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 1: Upper-bounding estimates of exposure to butanone oxime in consumer products
15. Appendix 2: Summary of health effects information for butanone oxime

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-butanone, oxime (butanone oxime), Chemical Abstracts Service Registry Number 96-29-7. This substance was identified in the categorization of the Domestic Substances List as a high priority for action under the Ministerial Challenge. Butanone oxime was identified as a high priority as it was considered to pose greatest potential for exposure of individuals in Canada and had been classified by the European Commission on the basis of carcinogenicity. Although butanone oxime met the ecological categorization criteria for persistence, it did not meet the criteria for bioaccumulation potential or inherent toxicity to aquatic organisms. Therefore, the focus of this assessment of 2-butanone, oxime relates primarily to human health risks.

Butanone oxime is widely used as an anti-skinning agent in the formulation of alkyd paints, varnishes, stains and coatings for both industrial and consumer use. In Canada , the substance has also been reported in a number of pesticide products, namely wood preservatives and antifouling marine paints, as well as in some adhesives, silicone sealants and printing inks. Furthermore, butanone oxime is used as a corrosion inhibitor in industrial boilers and water treatment systems and serves as a blocking agent in the manufacturing process of urethane polymers.

According to the information submitted under section 71 of CEPA 1999, butanone oxime was not manufactured by any company in Canada in the 2006 calendar year. However, approximately 500 000 kg of the substance was imported in 2006, and nearly 120 000 kg was used in the same reporting year. There are few data on the release and fate of butanone oxime in environmental media in Canada or elsewhere. Butanone oxime is not a naturally occurring substance; thus, releases of the substance to the environment are expected to result directly from anthropogenic activities. Considering the quantity of butanone oxime in commerce in Canada and its use in a variety of consumer products, exposure of the general population to the substance is expected to be moderate.

As butanone oxime was classified on the basis of carcinogenicity by the European Commission, carcinogenicity was a key focus for this screening assessment. Increased incidences of liver tumours were observed in rat and mouse lifetime studies, and there was also an increased incidence of mammary gland tumours in female rats; however, this was seen only at moderate and/or high concentrations of butanone oxime. Consideration of the available information regarding genotoxicity indicates that butanone oxime 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 nasal cavity of rats and/or mice in inhalation studies of short-term through to chronic exposure duration. Also, repeated-dose studies based on oral exposure showed effects in the spleen, liver and kidney of rats as well as hematological effects in both rats and rabbits. Based on comparison of estimated exposures to butanone oxime in Canada with the critical effect levels, and taking into account the uncertainties in the databases on exposure and effects, it is considered that the resulting margins of exposure, particularly for consumer exposure from products containing the substance, may not be adequately protective of human health for non-cancer effects.

On the basis of the potential inadequacy of the margins between estimated exposures to butanone oxime and critical effect levels, it is concluded that butanone oxime is a substance that may be 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 ecological hazard and estimated releases of butanone oxime, 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. Butanone oxime does meet the criteria for persistence but does not meet the criteria for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations.

Based on the information available, it is concluded that butanone oxime meets one or more 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 and, where appropriate, the performance of potential control measures identified during the risk management phase.

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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; 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-butanone, oxime (butanone oxime) was identified as a high priority for assessment of human health risk because it was considered to present GPE and had been classified by another agency on the basis of carcinogenicity.

The Challenge for butanone oxime 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 were received.

Although butanone oxime was determined to be a high priority for assessment with respect to human health and met the ecological categorization criteria for persistence, it did not meet the criteria for bioaccumulation or inherent toxicity to aquatic organisms. Therefore, this assessment focuses principally on information relevant to the evaluation of risks to human health.

Screening assessments examine scientific information and develop conclusions by incorporating a weight of evidence approach and precaution.

This 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 and stakeholder research reports and from recent literature searches, up to November 2008 for the human health sections and May 2009 for the ecological sections. 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) of 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 prioritizing 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 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 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. Both the human health and ecological 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. Michael Jayjock (The LifeLine Group) and Dr. Glenn Talaska (University of Cincinnati). Additionally, the draft of this screening assessment was subject to a 60-day 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 assessment is based are summarized below.

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Substance Identity

2-Butanone, oxime is also commonly known as methyl ethyl ketoxime (MEKO). However, for the purposes of this document, this substance will be referred to as butanone oxime, based on the European Inventory of Existing Commercial Chemical Substances (EINECS) name. Information on the identity of butanone oxime is summarized in Table 1.

Table 1. Substance identity for butanone oxime

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Physical and Chemical Properties

Table 2 contains experimental and modelled physical and chemical properties of butanone oxime that are relevant to its environmental fate. When experimental data were not available, the property was estimated using models, as indicated in Table 2. Although butanone oxime is a weak acid and will dissociate, it does so only at very high pH (>12). Therefore, it is in the neutral form at environmentally relevant pH values (6–9), and the neutral form of butanone oxime was used for model estimation.

Table 2. Physical and chemical properties for butanone oxime

Although two geometrical isomers are possible for butanone oxime, the trans isomer predominates (>99%) (OECD 2003).

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Sources

Butanone oxime is an anthropogenic substance and is considered to be a high production volume chemical by the Organisation for Economic Co-operation and Development (OECD 2004), the US Environmental Protection Agency (US EPA 2006) and the European Commission (ESIS 2006). Worldwide production of butanone oxime is estimated at between 10 000 and 20 000 tonnes per year (OECD 2003). According to the information submitted under section 71 of CEPA 1999, butanone oxime was not manufactured by any company in Canada in the 2006 calendar year. However, imports of the substance into Canada above the reporting threshold of 100 kg were approximately 500 000 kg in the same year (Environment Canada 2009a).

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Uses

The most prevalent use of butanone oxime is as an anti-skinning agent in the formulation of alkyd paints, primers, varnishes and stains, to prevent oxidative drying and the formation of hard, gelatinous films on the surface of the paint product in the container. According to the information submitted under section 71 of CEPA 1999, nearly 120 000 kg of butanone oxime was used in Canada in 2006 (Environment Canada 2009a). The majority of these uses were in the manufacture of alkyd paint products for both industrial and consumer applications. Based on available information, the concentration of butanone oxime in alkyd paint products in Canada is =1% by weight (w/w), while a typical concentration ranges from 0.02 to 0.5% w/w (2009 personal communication from Canadian Paints and Coatings Assocation Working Group to Environment Canada; unreferenced). According to the section 71 responses, butanone oxime is also present in colorants or pigments used in alkyd paints or printing inks at concentrations of 0.1% and 0.2% w/w, respectively (Environment Canada 2009a).

The substance is also present as a formulant in several pesticide products, namely wood preservatives and antifouling marine paints, in use in Canada (2009 personal communication from Pest Management Regulatory Agency, Health Canada, to Risk Management Bureau, Health Canada; unreferenced). In addition, it is a minor component of some sealants and adhesives manufactured in Canada and, to a lesser degree, of some fillers and artists’ paint and printing materials (Environment Canada 2009a).

Butanone oxime is also used as a corrosion inhibitor in industrial boilers (Rumpf 1993) and water treatment systems (Newton et al. 2001; Derelanko et al. 2003) and as a blocking agent in the manufacturing process of urethane polymers (Subramani et al. 2004). According to the information submitted under section 71 of CEPA 1999, butanone oxime is used as a corrosion inhibitor and as a blocking agent in the manufacture of urethane polymers in Canada (Environment Canada 2009a).

No current use of butanone oxime in cosmetics has been notified in Canada . Internationally, the use of butanone oxime in cosmetics is prohibited in Denmark (Danish Ministry of the Environment 2004) and in the United Kingdom (U.K. Secretary of State 2008) in accordance with an amendment to Directive 76/768/EEC of the European Commission (European Commission 2004). Butanone oxime is found in some printing inks used in the manufacture of food packaging materials, but there is no direct contact of butanone oxime with food.

Releases to the Environment

According to the information submitted under section 71 of CEPA 1999, butanone oxime was not manufactured by any company in Canada in 2006. In addition, there were no reports of any significant industrial releases of butanone oxime in the same calendar year in the section 71 responses (Environment Canada 2009a). The Canadian Chemical Producers’ Association (CCPA 2009) reported the release of 356 kg of butanone oxime to the environment in 2007. The reporting of industrial releases of butanone oxime to the National Pollutant Release Inventory (NPRI 2007) is not required. The total industrial releases of butanone oxime are expected to be low, and the most significant releases of butanone oxime are expected to take place at the consumer use stage.

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Environmental Fate

Based on its physical and chemical properties (Table 2), butanone oxime is characterized by high water solubility (100 000 mg/L), moderate vapour pressure (350 Pa), low log Kow (0.65), and low Henry’s Law constant (0.30 Pa·m³/mol). Half-lives in air (modelled as 7.21 days, see Table 4b) and in water (measured as 18 days based on the hydrolysis rate, see Table 4a) are used in Level III fugacity modelling. The results are summarized in Table 3 and suggest that butanone oxime will reside largely or predominantly in the compartment to which it is released. There is somewhat moderate partitioning in water and soil, when the substance is released to air; and moderate partitioning in water if released to soil.

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

Butanone oxime is considered to be a non-ionizing compound due to its high acid dissociation constant (pK_a >12); thus, it will be in the neutral form at environmentally relevant pHs (6–9).

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Persistence and Bioaccumulation Potential

Environmental Persistence

Table 4a presents the empirical biodegradation and hydrolysis data for butanone oxime in water. This substance may hydrolyse, depending on the pH. At 20°C, butanone oxime is hydrolytically unstable at pH 4, whereas no hydrolysis occurs at pH 9. At pH 7, 14% of the substance was hydrolysed after 4 days (Environment Canada 2009b), which translates to a half-life of 18 days based on hydrolysis in the aquatic environment. Therefore, at neutral to acidic environmental conditions, hydrolysis may be an important degradation pathway for this substance. Hydrolysis products are 2-butanone (CAS RN 78-93-3) and hydroxylamine (CAS RN 7803-49-8) (ECB 2000a and 2000b).

The inherent biodegradation study (MITI 1992) suggests that this substance undergoes primary biodegradation, but that ultimate biodegradation is, at best, slow (Table 4a).

Table 4a. Empirical data for degradation ofbutanone oxime

The European Chemicals Bureau (ECB) published a datasheet on butanone oxime, reporting degradation studies with alternative OECD approved tests with conclusions of inherent, primary and ultimate biodegradability (2000a). Studies report 70% degradation related to dissolved organic carbon (DOC) in 14 days, while only ~25% degradation related to biological oxygen demand (BOD).

In addition to experimental data on the degradation of butanone oxime as above, a quantitative structure–activity relationship (QSAR)-based weight of evidence approach (Environment Canada 2007) was applied using the degradation models shown in Table 4b.

Table 4b. Modelled data for degradation of butanone oxime

 The BIOWIN (2008) aerobic biodegradation models (BIOWIN submodels 3, 4, 5 and 6) suggest that butanone oxime biodegrades rapidly. The BIOWIN submodels 5 and 6 probability results are both greater than 0.3, the cut-off suggested by Aronson et al. (2006) to identify substances as having a half-life <60 days (based on the MITI probability models). However TOPKAT predicts that the substance may not biodegrade rapidly in water, while CATABOL suggests that the substance is just between the cut-offs for ‘biodegrades slowly’ (BOD < 20%) and ‘may biodegrade fast’ (BOD > 21%). Given the existence of experimental data, more weight is given to the empirical measures, the results of which are also supported by aerobic BIOWIN submodels 3, 4, 5 and 6. There is sufficient confidence, based on the experimental data, when taken together with the BIOWIN model predictions, to expect that there is significant biodegradation with a half-life that is likely well below 182 days.

Although little butanone oxime is expected to partition to sediment, it may remain in soil if released to this environmental compartment (see Table 3). Since BIOWIN (2008) biodegradation prediction is expected to be fast, along with a moderate potential for hydrolysis, these data suggest that the degradation half-life in water is likely = 90 days, thus the degradation half-lives for soil and sediments extrapolated using Boethling et al.’s (1995) factors (t_{½ water} : t_{½ soil} : t_{½ sediment} = 1:1:4), are = 180 days and = 365 days, respectively.

Based on the empirical and modelled data (see Tables 4a and 4b above), it is concluded that butanone oxime meets the persistence criterion in air (half-life in air ³2 days), but does not meet the criteria for water, soil or sediment (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).

The long-range transport potential (LRTP) of this substance was predicted using two models: the Transport and Persistence Level III Model (TaPL3 v.3.00) and the OECD Pov and LRTP Screening Tool. Results are presented in Table 4c.

Table 4c. Model predictions and level of concern of the long-range transport potential of butanone oxime

The TaPL3 model provides an estimate of the characteristic travel distance (CTD) only for the substance, defined as the maximum distance travelled by 63% of the substance, of 1376 km. Beyer et al. (2000) proposed characteristic travel distances of > 2000 km as representing high long-range transport potential, 700–2000 km as moderate and < 700 km as low. Based on the modelled result from TaPL3, this substance is expected to have a moderate long-range transport potential.

The LRTP of butanone oxime was also assessed using the OECD tool, based on a combination of overall environmental persistence (P_ov) and CTD or transfer efficiency (TE). P_ov has been introduced as a concept to weigh half-lives according to partitioning behaviour and is a kind of average of all the half-lives in air, water, sediment and soil (Mackay 2006). This parameter is found to closely link to the potential for long-range transport, but is not currently used for decision making in hazard assessment as most regulatory authorities rely on the single-media half-life approach. TE is a measure, expressed as percentage, for the extent of the deposition of a substance onto the surface media of a target area after being transported away from the region of release (Klasmeier et al. 2006). Based on the level of concern rating system (Scheringer et al. 2006), the long-range transport potential of butanone oxime is expected to be moderate as well.

Potential for Bioaccumulation

Experimental log K_ow values (0.59-0.65) for butanone oxime (see Table 2 above) suggest that this chemical has low potential to bioaccumulate in biota. Experimentally derived bioconcentration factors (BCF) of 0.5–5.8 for carp (Cyprinus carpio) and Japanese medaka (Oryzias latipes) (MITI 1992; ECB 2000a) indicate that butanone oxime is not bioaccumulative. This conclusion is also supported by modelled BCF and bioaccumulation factor (BAF) values (Table 5) using the default of no metabolism, which were used in a weight of evidence approach (Environment Canada 2007) for evaluating the bioaccumulation potential of this substance.

Table 5. Fish BAF and BCF predictions for butanone oxime with default of no metabolism

Furthermore, log K_ow values for the hydrolysis products 2-butanone and hydroxylamine are very low (ECB 2000; OECD 2008), indicating that the hydrolytic products of butanone oxime also have low potentials to bioaccumulate.

Based on the available empirical and kinetic-based modelled values, it is concluded that butanone oxime does not meet the bioaccumulation criteria (BAF or BCF =5000) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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Potential to Cause Ecological Harm

The approach taken in this assessment was to examine the available scientific 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 site-specific aquatic risk quotient calculations as well as information on the persistence, bioaccumulation, inherent toxicity, sources and fate of the substance.

As described previously, butanone oxime is persistent in air, but not in water, soil or sediment compartments. It is also expected to have a low bioaccumulation potential. The most sensitive experimental ecological effects data for a range of species, as well as modelled data, are summarized in Table 6. Robust study summaries were not prepared for the empirical studies, as the studies were not available. However, the lowest value of all ecotoxicity data (6.1 mg/L) collected was used as a conservative estimate of the critical toxicity value (CTV) to characterize the potential for effects on sensitive species. The modelled data generally support the empirical results.

Table 6. Empirical and modelled data for aquatic toxicity of butanone oxime

The toxicity data indicate that butanone oxime has a moderate potential to be toxic to algae and a low potential for most other aquatic organisms. Furthermore, considering the toxicity of the hydrolysis products (2-butanone and hydroxylamine) to sensitive aquatic species, as well as the comparatively low rate of hydrolysis (14% in 4 days) under environmental conditions, the risk due to the hydrolysis products of butanone oxime is not expected to be significantly higher than that of the compound itself (ECB 2000b; OECD 2008).

Toxicity data were not found for the organisms in the soil or sediment compartments.

The high importation volume of butanone oxime into Canada , together with information on its uses, indicates potential for widespread release of this substance into the Canadian environment. If released to water, butanone oxime is expected to remain in water (>99%; see Table 3). In this screening assessment, site-specific aquatic exposure scenarios were developed to estimate releases into the aquatic environment from industrial operations and resulting aquatic concentrations.

Two sewage treatment plants (STPs) were identified as having the highest releases of butanone oxime, as determined from information obtained through the section 71 survey (Environment Canada 2009a). Each site includes discharges from a certain number of industrial users of butanone oxime. One site releases to a relatively large receiving water body, whereas the other site releases to a considerably smaller one. The predicted environmental concentrations (PECs) for both sites were estimated based on the quantity of butanone oxime used by all facilities served by each STP, the fraction estimated to be discharged to the STP, the STP removal rate, the STP effluent flow and the dilution capacity of the receiving water. The key value in the PEC estimate is the fraction of the substance discharged to the STP. This fraction is 0.3%, resulting from the cleaning of semi-bulk containers or totes that are used for the transportation of the substance, and is assumed by default (Great Western Containers 2005). The higher calculated PEC for the two sites was 0.010 mg/L.

A predicted no-effect concentration (PNEC) was derived from the chronic algal toxicity value of 6.1 mg/L for Pseudokirchneriella subcapitata (see Table 6). An assessment factor of 100 was applied to account for uncertainties related to interspecies and intraspecies variability in sensitivity and extrapolation from a laboratory EC₅₀ to a no-effect value in the field. This yielded a PNEC of 0.06 mg/L. The highest resulting risk quotient, calculated as the ratio of the PEC to PNEC, was 0.17, indicating that the substance is not anticipated to harm aquatic organisms.

Butanone oxime is thus considered unlikely to be causing ecological harm in Canada . Considering the comparatively low hydrolysis rate of butanone oxime, the hydrolysis products are not expected to pose a threat either.

It should be noted that this conclusion was reached despite the conservative assumptions that were made in response to uncertainties encountered in the assessment. A key uncertainty relates to the lack of empirical data on environmental concentrations in Canada , which was addressed by predicting realistic worst-case concentrations in water using an industrial exposure model. There is also uncertainty associated with the PNECused in the risk quotient calculation, because details of the study were not available. However, the CTV used is considered to be conservative, as it is the lowest empirical value observed and is at least one order of magnitude lower than the next lowest toxicity value. In addition, an assessment factor of 100 was applied to the CTV to derive the PNEC.

Also, regarding ecotoxicity, based on the predicted partitioning behaviour of this chemical, the significance of soil and sediments as important media of exposure is not well addressed by the effects data available. However, exposures near industrial point sources are expected to be highest in the aquatic compartment.

Uncertainties also exist with the conclusion for persistence. Very limited empirical data were available, and some model results were contradictory. These data were nevertheless used to estimate approximate half-lives for water, soil and sediment. However, the weight of evidence, considering both the empirical and modelled data, indicates that this substance does not meet the persistence criteria for water, soil or sediment.

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Potential to Cause Harm to Human Health

Exposure Assessment

Environmental Media and Food

No measured concentrations of butanone oxime in environmental media in Canada or elsewhere were identified. Based on its high vapour pressure and half-life in air, butanone oxime is expected to exist primarily as a vapour and to persist in ambient air. However, as no significant industrial releases of butanone oxime to the air were reported in 2006, the concentration of butanone oxime in ambient air is expected to be low. Modelled estimates based on current information also predict that the concentration of butanone oxime in air is low, at approximately 1.79 ng/m³(ChemCAN 2003). Similarly, the predicted concentrations for water and soil are very low (0.550 ng/L and 7.08 × 10^-4 ng/g, respectively).

No measured concentrations of butanone oxime in food in Canada or elsewhere were identified. Based on the uses of butanone oxime in Canada , food is unlikely to be a source of exposure. Given that the experimental log K_ow values for butanone oxime are low, the substance is not expected to bioaccumulate in biota, and accumulation of butanone oxime in the food chain is not considered likely.

Due to the lack of empirical data on concentrations in environmental media and food, upper-bounding daily intake estimates for the general population were not derived.

Consumer Products

With regard to consumer products, butanone oxime is most prevalent in alkyd paints, stains, varnishes and coatings, according to information submitted under section 71 of CEPA 1999. Butanone oxime is also present in a few sealants, adhesives and fillers that are used mainly by industry, but which may also be available to the general population for home maintenance and do-it-yourself applications. Accordingly, use of alkyd paint containing butanone oxime was the primary scenario used to characterize exposure from products.

A limited number of studies report concentrations of butanone oxime during manufacture and use of products such as alkyd paints. A US study of consumer exposure to butanone oxime (Chang 1998) predicted a maximum concentration of butanone oxime in indoor air of 18 mg/m³ based on the use of alkyd paint containing 0.293% w/w butanone oxime, the highest level of butanone oxime that was present in the products tested. A limited unpublished study measured butanone oxime concentrations of up to 9.9 ppm (30 mg/m³) during a simulation using an indoor painting scenario with an alkyd paint containing approximately 0.2% butanome oxime (unpublished study submitted to Environment Canada, 2009b; unreferenced).

However, as butanone oxime content of alkyd paints used in Canada can be higher (up to 1% (2009 personal communication from Canadian Paints and Coatings Association to Environment Canada; unreferenced)) potential exposure at this level was modelled.

Exposure estimates were therefore derived using ConsExpo v. 4.1 software (ConsExpo 2007). Resulting estimated air concentrations and dermal exposure (external) are summarized in Table 7. The inputs and assumptions used in ConsExpo v. 4.1 modelling of each of the consumer product scenarios are provided in Appendix 1, where both external and internal exposure estimates during use of these products are presented. There were no identified data on absorption of butanone oxime following inhalation exposure. While dermal absorption have been reported to range between 13% and 29% in a study conducted in rats (Burka et al. 1998), the estimates of internal exposure were derived using 100% uptake for inhalation and dermal absorption.

Table 7. Summary of estimated air concentrations and dermal external applied dose of butanone oxime during use of consumer products

The US EPA’s Wall Paint Exposure Assessment Model v. 3.2 (WPEM 2001) predicted a maximum indoor air concentration of butanone oxime of 227 mg/m³ for the alkyd paints and an 8-hour average concentration of 195 mg/m³.

Based on the available information, the most likely route of exposure to butanone oxime for the general population is likely from inhalation during use of alkyd paints and coatings, based on the maximum mean event concentration. However, in light of the limited data available on concentrations in environmental media, confidence in this estimate is very low.

Health Effects Assessment

Appendix 2 contains a summary of the available health effects information for butanone oxime.

The European Commission has classified butanone oxime as Category 3 for carcinogenicity (causes concern for humans owing to possible carcinogenic effects) (European Commission 2000, 2001). In chronic lifetime studies in both rats and mice exposed by inhalation to butanone oxime, there was an increased incidence of liver tumours (adenomas and carcinomas) in both species at all tested exposure concentrations. However, statistically significant increases in incidence were observed only at 267 and 1333 mg/m³ for liver adenomas in male rats and at 1333 mg/m³ for liver carcinomas in male rats and mice. A statistically significant increased incidence of mammary gland fibroadenomas was also observed in female rats at 1333 mg/m³. Non-neoplastic effects observed in rats included histopathological effects in the spleen (congestion, increased pigmentation in the reticuloendothelial cells and extramedullary hematopoiesis) and in the nasal turbinates (degeneration of the olfactory epithelium) at all exposure concentrations, in the liver (increased incidences of basophilic foci and hepatocyte vacuoles) at 267 and 1333 mg/m³, changes in blood parameters at 1333 mg/m³ and enlarged testes in males at 267 and 1333 mg/m³. Non-neoplastic effects observed in mice included dose-related increases in liver hypertrophy and necrosis as well as in olfactory epithelium degeneration in the nasal turbinates at all exposure concentrations, changes in blood parameters at 267 and 1333 mg/m³ and changes in serum chemistry parameters at 1333 mg/m³. The lowest-observed-adverse-effect concentration (LOAEC) for non-neoplastic effects was 53 mg/m³ (15 ppm), based on effects in the spleen and nasal turbinates of rats and effects in the liver and nasal turbinates of mice (Newton et al. 2001). Long-term oral or dermal studies using butanone oxime were not identified.

Butanone oxime was not mutagenic in the majority of bacterial mutation assays using Salmonella typhimurium, but it was positive in a mouse lymphoma cell mutation assay with and without activation (Allied Corporation 1983b; Rogers-Back et al. 1988; JETOC 1999; NTP 1999). In vitro assays for chromosomal aberration in Chinese hamster ovary and lung cells, for sister chromatid exchange in Chinese hamster ovary cells and for unscheduled deoxyribonucleic acid (DNA) synthesis in rat hepatocytes all showed negative responses (Allied Corporation 1983a; IHF Inc. 1995; JETOC 1999; NTP 1999). In vivoassays for micronuclei were both negative for bone marrow cells in rats and for peripheral blood cells in mice; rats and mice were dosed orally (Microbiological Associates Inc. 1990; NTP 1999). In an in vivo assay in rats exposed by inhalation, butanone oxime was negative for DNA adducts but positive for ribonucleic acid (RNA) adducts in rat liver cells (Honeywell International Inc. 2000).

Fully elucidated modes of action analysis for induction of the observed tumours have not been identified. The European Commission (2000) considered that a possible mechanism for the increased incidences of liver tumours in male rats and mice was the metabolism of butanone oxime to a carcinogenic agent, mediated by sulfotransferase. The sex and organ specificity of tumour formation correlated with the typically higher activity of this enzyme in male rodents. Völkel et al. (1999) showed that the incubation of liver microsomes from mice, rats and humans with butanone oxime resulted in the formation of nitronates, but that the rates of formation did not correlate with sex and species differences in liver tumour response; they concluded that “other mechanisms of tumourigenicity not related to nitronate mutagenicity and DNA-damage may thus be operative.” The European Commission (2000) did not comment on whether the mode of action for liver tumours in rats was due to threshold mechanisms. However, the in vitro and in vivo genotoxicity results for butanone oxime were mostly negative, including an in vivo study that utilized inhalation exposure and was found to be negative for DNA adducts in rat liver cells. Therefore, based on the available data, butanone oxime appears to lack mutagenic potential. This lack of mutagenic potential may also explain why the European Commission (2000) did not comment on whether the mode of action for mammary gland tumours in rats was due to threshold mechanisms.

In a mouse inhalation study with exposures to butanone oxime for 1, 2 or 4 weeks, degeneration of the olfactory epithelium in the nasal cavity was observed in males at concentrations of 107 and 356 mg/m³ (incidence and severity increased with increasing exposure concentration) (Newton et al. 2002). In 13-week inhalation studies, degeneration of the olfactory epithelium in the nasal cavity was observed in male mice at concentrations of 36–356 mg/m³ (incidence and severity increased with increasing exposure concentration), whereas increased relative liver weights were observed in male rats at 267 and 1333 mg/m³ (Newton et al. 2001, 2002). The LOAEC for subchronic exposure was 36 mg/m³, based on degeneration of the olfactory epithelium in the nasal cavity of mice.

In a 4-week oral rat study, changes in hematological parameters (increase in reticulocytes, platelets and red blood cells) and increased relative spleen weight with accompanying histopathological abnormalities (increases in congestion, extramedullary hematopoiesis and hemosiderin granules) were observed in both sexes at 20 and 100 mg/kg body weight (kg-bw) per day, whereas hemosiderin granules in the liver were observed in females at the same doses (Japan MHW 1996; JETOC 1999). Butanone oxime was administered via drinking water in a 13-week rat study. Relative liver weights were increased in males at doses of 25–280 mg/kg-bw per day (NTP 1999). In another 13-week rat study, in which butanone oxime was administered via gavage, changes in liver and spleen weights, hemosiderosis of spleen and hematological effects were observed in both sexes at doses of 25–225 mg/kg-bw per day (Allied Signal Inc. 1977). The lowest-observed-adverse-effect level (LOAEL) for short-term and subchronic oral exposure was 20 mg/kg-bw per day, based on changes in hematological parameters, increased relative spleen weight with accompanying histopathological abnormalities, and hemosiderin granules in the liver observed in the 4-week rat study.

In a one-generation oral rat study, the LOAEL for reproductive toxicity was 100 mg/kg-bw per day, the highest dose, based on a statistically significant decrease in female delivery index (%) ^[1](Japan MHW 1998), whereas no treatment-related effects on reproductive parameters were observed in a two-generation study in which rats were dosed by gavage at 0–200 mg/kg-bw per day (Tyl et al. 1996). In both the one-generation and two-generation rat studies, a parental LOAEL of 10 mg/kg-bw per day, the lowest dose tested, was established, based on histopathological effects in the spleen and liver (and in the kidney in the one-generation study).

Teratogenicity was not observed in pregnant rats and rabbits dosed orally with butanone oxime during gestation (Springborn Laboratories 1990a, b; Mercieca et al. 1991; Derelanko et al. 2003). The lowest oral LOAEL for developmental toxicity was 40 mg/kg-bw per day, the highest dose, based on abortions in 3 of 10 adult females in pregnant rabbits dosed by gavage during gestation (Springborn Laboratories 1990b; Derelanko et al. 2003). The lowest oral LOAEL for maternal toxicity was 10 mg/kg-bw per day, based on signs of anemia (increased reticulocytes and methemoglobin) in rabbits dosed at 0–80 mg/kg-bw per day in a range-finding developmental study (Springborn Laboratories 1990b; Derelanko et al. 2003).

Studies designed to determine median lethal dose or concentration (LD₅₀ or LC₅₀) values were also able to determine lowest effect levels based on acute exposure. The lowest LOAEC for inhalation exposure was 190 mg/m³, based on decreased body weight gain in the observation period (7 or 14 days) after 4 hours of inhalation exposure in rats (Allied Corporation 1984b). The lowest LOAEL for dermal exposure was 180 mg/kg-bw, based on methemoglobin production and splenic erythrophagocytosis in a 24-hour dermal rabbit study (Allied Corporation 1984a; US EPA 1986).

Toxicokinetic studies on butanone oxime in mice and rats show that it is rapidly absorbed from the gastrointestinal tract, undergoes widespread uptake, distributes over the entire body, is extensively metabolized and does not accumulate in tissues. Excretion of butanone oxime and its metabolites occurs in the urine and bile or as volatiles in expired air (ICCA MEKO 2003). In single-dose studies in rats, significantly greater amounts of volatiles were excreted following dermal administration than after gavage or intravenous administration (NTP 1999). However, no toxicokinetic data based on repeated dosing via the oral, inhalation, nor dermal pathways were identified. The toxicokinetic studies of butanone oxime demonstrated the existence of two metabolic pathways and the possibility of a third one (based on acute oral, dermal and intravenous doses only). The major pathway is the hydrolysis of butanone oxime to 2-butanone (methyl ethyl ketone), and the second pathway is the oxidation of butanone oxime to butane 2-nitronate by microsomal monooxygenases, but this occurs at very low rates (ICCA MEKO 2003). ICCA MEKO (2003) reported that “With respect to the three [metabolic] pathways, there were no quantitative differences in the extent of MEKO [butanone oxime] metabolism between male and female rats.”

The confidence in the toxicity database for butanone oxime is considered to be low to moderate, as adequate information is available to address effects that may be of concern and identify critical endpoints based on inhalation exposures of acute to long-term duration. However, there was a lack of reproductive and developmental toxicity studies based on inhalation exposure; and limited studies via the dermal route.

Characterization of Risk to Human Health

Carcinogenicity was considered in the health effects assessment for butanone oxime, as the substance had been classified as carcinogenic by the European Commission (2000, 2001). As shown under the “Health Effects Assessment” section, increased incidences of liver tumours were observed in rat and mouse lifetime studies, and there was also an increased incidence of mammary gland tumours in female rats. However, these were seen only at mid- and/or high concentrations of butanone oxime. Consideration of the available information on genotoxicity indicates that butanone oxime 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.

With respect to non-cancer effects, the lowest inhalation LOAEC for chronic exposures was 53 mg/m³, based on degeneration of the olfactory epithelium in the nasal cavities of both mice and rats, liver cell hypertrophy and necrosis in mice, and histopathological effects in the spleen of rats observed in lifetime studies with these species. For subchronic exposures, the lowest inhalation LOAEC was 36 mg/m³, based on degeneration of the olfactory epithelium in the nasal cavity of mice observed in a 13-week inhalation study. Likewise, for short-term exposures, the lowest inhalation LOAEC was 107 mg/m³, based on degeneration of the olfactory epithelium of the nasal cavity of mice exposed to a butanone oxime exposure regime of 6 hours/day, 5 days/week, for 1, 2 or 4 weeks. The occurrence of toxicological sequelae following five exposures (30 total hours of exposure) is relevant for the acute exposure risk assessment. For acute exposures, an inhalation LOAEC of 190 mg/m³ was determined based on decreased body weight gain in rats in a 4-hour inhalation study. The changes in body weight gain were not noted at critical effect levels in short-term inhalation studies. However, an analysis of the change in the dose–response curve over time (190 mg/m³ acutely, 107 mg/m³ after 5 days and 36 mg/m³ after subchronic exposure) suggests that the body weight gain deficits occur in the appropriate dose range following acute exposure.

The lowest oral LOAEL for short-term and subchronic exposures was 10 mg butanone oxime/kg-bw per day, based on histopathological effects in the spleen and liver of adult rats observed in both a one-generation and a two-generation reproduction study (and in the kidney in the one-generation study) (Tyl et al. 1996; Japan MHW 1998) and based on signs of anemia in adult female rabbits observed in a range-finding developmental study (Springborn Laboratories 1990b; Derelanko et al. 2003). For acute exposures, an oral lowest-observed-effect level (LOEL) of 300 mg/kg-bw was determined based on transient neurotoxic effects in rats (Schulze and Derelanko 1993), and a dermal LOAEL of 180 mg/kg-bw was determined based on methemoglobin production and splenic erythrophagocytosis in a 24-hour rabbit study (Allied Corporation 1984b; US EPA 1986).

As stated under “Exposure Assessment”, due to the lack of empirical data on concentrations in several media, estimates of daily intake for the general population were not derived. Thus, margins of exposure could not be derived for comparisons between critical effect levels based on repeated daily exposures to butanone oxime and upper-bounding estimates of daily intake.

Exposure to butanone oxime is most likely to occur through use of consumer products. Based on product scenario modelling using ConsExpo, the highest air concentrations resulted from inhalation during use of alkyd paints and coatings, resulting in a range of 73–223 mg/m³. Using the Wall Paint Exposure Assessment Model, an 8-hour average air concentration of 195 mg/m³was derived for alkyd paints. Comparison of these conservative air concentrations with the acute to short-term critical effect levels for inhalation exposure (107–190 mg/m³) results in margins of exposure of 0.5–2.6. A limited number of studies measured air concentrations ranging from 6.0 to 18 mg/m³under various simulated paint scenarios using products with lower concentrations of butanone oxime (0.2 – 0.6%). Resulting margins of exposures from these scenarios range from 6 to 30.

Acute dermal exposures during use of alkyd paints and coatings were estimated to be 0.0226–1.06 mg/kg-bw. These estimates were compared to a dermal critical effect level of 180 mg/kg-bw, which leads to margins of exposure ranging from 170 to 8000.

In light of the uncertainties in the databases on exposure and effects, it is considered that the derived margins of exposure for these consumer product scenarios (all estimated margins of exposure based on inhalation exposure, and the lower margins of exposure based on dermal exposure) may not be adequately protective of human health for non-cancer effects.

Uncertainties in Evaluation of Risk to Human Health

This screening assessment does not include a full analysis of the mode of induction of effects, including cancer, of butanone oxime. In addition, only limited information is available concerning the potential toxicity of butanone oxime following oral and dermal exposure and for reproductive toxicity, developmental toxicity and genotoxicity studies based on inhalation exposures. Thus, critical effect levels determined in this screening assessment are limited by the toxicity database and by uncertainties in the interpretation of the biological significance of effects, including uncertainties in the interpretation of intraspecies and interspecies variation.

Uncertainty in exposure to butanone oxime from the environmental media and food in Canada is high, as no empirical data were available with which to derive exposure estimates. While empirical data is absent, food is not expected to be a source of exposure to butanone oxime. While the most likely source of exposure of the general population to butanone oxime is expected to be alkyd paint products, uncertainty is associated with the use of default assumptions. However, the concentrations of butanone oxime in the selected products used for modelling consumer product exposure scenarios are based on Canadian-specific information.

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Conclusion

Based on the information presented in this screening assessment, it is concluded that butanone oxime 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.

On the basis of the potential inadequacy of the margins between estimated exposures to butanone oxime and critical effect levels, it is concluded that butanone oxime is a substance that may be 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 butanone oxime meets one or more of the criteria set out in section 64 of CEPA 1999. Additionally, butanone oxime meets the criteria for persistence but does not meet the criteria for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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 and, where appropriate, the performance of potential control measures identified during the risk management phase.

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Appendix 1: Upper-bounding estimates of exposure to butanone oxime in consumer products

 Dermal acute (internal) dose: 0.147 mg/kg-bw 

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Appendix 2: Summary of health effects information for butanone oxime

Footnote

^[1] (No. of pups born/no. of implantations) × 100.

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