Screening Assessment for the Challenge Hexane (2024)

Environment Canada
Health Canada

August 2009

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. Conclusion
13. References
14. Appendix 1a: Upper-bounding estimates of daily intake of n-hexane by the various age groups of the general population in Canada (µg/kg-bw per day)
15. Appendix 1b: Upper-bounding estimates of daily intake of n-hexane from foods based on the level of residual n-hexane typically found in refined vegetable oils (0.8 ppm)
16. Appendix 2: Summary of health effects information for n-hexane

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 n-hexane, Chemical Abstracts Service Registry Number 110-54-3. This substance was identified in the categorization of the Domestic Substances List as a high priority for action under the Challenge, as it was considered to pose greatest potential for exposure to individuals in Canada and had been classified by the European Commission on the basis of reproductive toxicity. The substance did not meet the ecological categorization criteria for persistence or bioaccumulation potential. Therefore, the focus of this assessment of n-hexane relates to human health risks.

n-Hexane is a naturally occurring component of crude oil and natural gas and is present in refined petroleum products such as motor fuels. According to data submitted in CEPA 1999 section 71 responses, over 5 billion kilograms of n-hexane were manufactured and 10 -100 million kilograms of n-hexane were imported into Canada in 2006. Although the section 71 survey did not apply to activities of n-hexane in fuel, both reported quantities included activities related to fuel.

The physical and chemical properties of n-hexane make this substance ideal for many uses and applications. It is used as a solvent, a formulation component, a chemical intermediate, a processing aid, and a dispersant in various chemical processes. Another major use of n-hexane besides its use in petroleum is in food processing as a solvent for extraction of vegetable oils. A wide variety of products known to contain n-hexane in Canada include adhesives, sealants, binders, fillers, lubricants, paints and coatings, rubber and rubber cements, brake cleaners, and degreasers.

n-Hexane has been measured in ambient and indoor air in Canada and the major route of exposure to n-hexane by the general population of Canada is expected to be inhalation. Exposure from other media (drinking water, soil) and food was estimated to not contribute significantly to total exposures.

Products containing n-hexane are used primarily for professional purposes and exposure to n-hexane by the general population from these sources is expected to be minimal and infrequent.

The critical effect level for repeated-dose toxicity via inhalation was based not only on nervous system effects in a 24-week rat inhalation study but also on increased number of resorptions in a mouse developmental toxicity study. The margin of exposure between the critical effect level for inhalation and the upper-bounding exposure estimate for n-hexane is considered to be adequately protective.

The critical effect level for repeated-dose toxicity via the oral route was based on adverse effects in heart muscle and related parameters in a 30-day rat study. Comparison of the critical effect level for repeated dose effects via the oral route and the upper-bounding estimate of daily intake of n-hexane by the general population in Canada, yields a margin of exposure that is considered to be adequately protective.

Based on the available information on its potential to cause harm to human health and the resulting margins of exposure for repeated-dose effects, it is concluded that n-hexane is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

On the basis of ecological hazard and reported releases of n-hexane, it is concluded that this 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. n-Hexane does not meet the criteria for persistence or bioaccumulation as set out in the Persistence and Bioaccumulation Regulations.

This substance will be included in the upcoming Domestic Substances List (DSL) inventory update initiative. In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessment.

Based on the information available, it is concluded that n-hexane does not meet any of the criteria set out in section 64 of CEPA 1999.

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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 human health. Based on the results of a screening assessment, the Ministers can propose to take no further action with respect to the substance, to add the substance to the Priority Substances List (PSL) for further assessment, or to recommend that the substance be added to the List of Toxic Substances in Schedule 1 of the Act and, where applicable, the implementation of virtual elimination.

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), that 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 n-hexane 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 reproductive toxicity.

The Challenge for n-hexane was published in the Canada Gazette on November 17, 2007 (Canada 2007). 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 n-hexane was determined to be a high priority for assessment with respect to human health, it did not meet the ecological criteria for potential for persistence or bioaccumulation potential. Therefore, this assessment focuses principally on information relevant to the evaluation of risks to human health.

Under CEPA 1999, screening assessments focus on information critical to determining whether a substance meets the criteria for defining a chemical as toxic as set out in section 64 of the Act, where

"64. [...] a substance is toxic if it is entering or may enter the environment in a quantity or concentration or under conditions that

1. have or may have an immediate or long-term harmful effect on the environment or its biological diversity;
2. constitute or may constitute a danger to the environment on which life depends; or
3. constitute or may constitute a danger in Canada to human life or 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, stakeholder research reports and from recent literature searches, up to August 2008. 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 prioritization of the substance). Decisions for human health are based on the nature of the critical effect and/or margins between conservative effect levels and estimates of exposure, taking into account confidence in the completeness of the identified databases on both exposure and effects, within a screening context. The 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. The human health portions of this assessment have undergone external written peer review/consultation. Comments on the technical portions relevant to human health were received from scientific experts selected and directed by Toxicology Excellence for Risk Assessment (TERA), including Susan Griffin (US EPA), Donna Vorhees (Science Collaborative - North Shore), and Joan Strawson (TERA). The ecological portions of the assessment have also undergone external written peer review/consultation. Additionally, the draft of this assessment was subject to a 60-day public comment period. Although 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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n-Hexane is a straight-chain saturated aliphatic hydrocarbon with 6 carbon atoms with the molecular formula of C₆H₁₄. At standard temperature and pressure, it is a colourless flammable liquid with high volatility and gasoline-like odour (IPCS 1991, NIOSH 1994, O'Neil 2001). It is poorly soluble in water but soluble in most organic solvents (IPCS 1991, NIOSH 1977). It can be easily analyzed by gas chromatography coupled with flame ionization detection or mass spectrometry^{Footnote 1} (IPCS 1991).

Basic information on the identity of n-hexane is summarized in Table 1.

For the purpose of this assessment, the substance is referred to as n-hexane (rather than its DSL name "hexane") throughout this report in order to avoid potential ambiguity associated with the term "hexane" which may commonly refer to both n-hexane and hexanes. While n-hexane is a substance of specific molecular structure, hexanes contain n-hexane and other hexane isomers, which are branched hydrocarbons of the same molecular formula (C₆H₁₄), namely, 2-methylpentane (isohexane), 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

In a laboratory or under a research setting, n-hexane with high purity (also commonly referred to as analytical grade hexane) is used as a solvent or a reagent, and may contain from 0.5 to 5% of other hexane isomers (Baker and Rickert 1981, IPCS 1991, Sandmeyer 1981). It may also contain other less volatile impurities, such as benzene, which has been detected at a trace level of 0.05% (Baker and Rickert 1981). Technical grade hexane has a lesser purity and consists of approximately 50% n-hexane and 50% isohexane and cyclohexane, and contains impurities such as benzene (0.001%) and other aromatics (0.01%) (Verschueren 2001).

Commercial hexane, on the other hand, may refer to a wide range of solvent mixtures that consist of hexane isomers including n-hexane and related 6-carbon compounds (such as cyclohexane and methyl cyclopentane), and possibly small quantities of C₅ and C₇ hydrocarbons (Eastman and Mears 2000). Concentration of n-hexane in commercial hexane may range anywhere from 20 to 80% (IPCS 1991). Low levels of pentane and heptane isomers, acetone, methyl ethyl ketone, dichloromethane, and trichloroethylene may also be included, as well as other less volatile impurities, up to 0.04 % (IPCS 1991).

While commercial hexane is expected to be most commonly used in industrial or commercial settings, this assessment was conducted specifically on n-hexane (CAS RN 110-54-3). In cases where this assessment is to be extended to address hexanes as well as other organic solvents, significant consideration should be given to the specific situation of its use.

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n-Hexane is a highly volatile, naturally occurring component of the paraffin (also referred to as alkane or aliphatic) fraction of crude oil and natural gas. It is a constituent of heating and motor fuels refined from petroleum produced from crude oil and natural gas (ASTDR 1999). n-Hexane has been identified as a High Production Volume (HPV) chemical by OECD (OECD 2004) and the

According to the responses to the section 71 survey of CEPA 1999 received before May 22, 2009, over five billion kilograms (5 × 10⁹kg) or 5 million tonnes ofn-hexane were manufactured in Canada in 2006 (Environment Canada 2007b). The total quantity imported into Canada in the same calendar year was reported to be in the range of 10 -100 million kilograms (Environment Canada 2007b). This survey did not apply to any person who manufactured, imported, or used hexane in fuel, however, a significant portion of the submissions reported activities related to fuels (Environment Canada 2007b).

According to Statistics Canada, total crude oil and equivalent petroleum products in Canada in 2006 amounted to 104 million cubic meters (104 × 10⁶ m³), out of which 98 million cubic meters (98 × 10⁶ m³) belonged to light and heavy crude oil (Statistics Canada 2006). Crude bitumen and other condensates accounted for the remaining amount. Hexanes have been reported to comprise 1.3 - 10.74% in light and 1.09 - 7.91% in heavy crude oils with mean compositions of 4.87% and 4.11% by volume, respectively (Crude Quality 2009a,b). Applying the maximum hexane composition of 10.74%, the maximum possible quantity of n-hexane in crude oil in Canada in 2006 can be estimated to be 10.5 × 10⁶ m³ or approximately 6 900 tonnes.

The net production of petroleum products from refinery production of crude oil and equivalents in 2006 was reported to be 120 × 10⁶ m³, of which 42 × 10⁶ m³ is comprised of motor gasoline (Statistic Canada 2006). In Canada , the maximum concentration of n-hexane in gasoline is found to be 5% with an average concentration of 2.69% (Personal communication from Risk Management Bureau, Health Canada to Risk Assessment Bureau, Health Canada , dated 2008-10-09; unreferenced). Based on the net production volume of motor gasoline in Canada in 2006 (42 × 10⁶ m³), the maximum amount of n-hexane in motor gasoline in the specified year can then be estimated to be 2.1 × 10⁶ m³ or 1.4 × 10⁶kg

Commercial hexane is manufactured via two-tower distillation of a suitable hydrocarbon feedstock, which may be straight-run gasoline distilled from crude oil or natural gas liquids. It can also be obtained from the remains of catalytic reformates after the removal of aromatic compounds. n-Hexane can be purified from hexane mixtures using molecular sieves (IPCS 1991).

Other minor sources of n-hexane have been recognized as biogenic production by fungi in ducts and insulation materials in homes and office buildings (Ahearn et al. 1996), marine phytoplankton (McKay et al. 1996), and terrestrial plants (Rinnan et al. 2005).

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A major global use of n-hexane is as a component in fuels and other petroleum products (NLM 2005). Although use of n-hexane in fuels was exempted from section 71 data collection under CEPA 1999, a significant portion of the submissions reported activities related to fuels (Environment Canada 2007b). End-use fuels such as motor vehicle gasoline and liquefied petroleum gas formulated with n-hexane is not a primary focus of this assessment. It will be addressed separately under the petroleum Sector Stream Approach of the Chemicals Management Plan.

High solubility of n-hexane in oil, its low boiling point and narrow boiling point range, and relatively low cost make this substance ideal for many applications besides its use in petroleum products (Eastman and Mears 2000).

Food processing is another major global application of n-hexane, where it is used as a solvent for extraction of vegetable oils from various seeds and crops (ATSDR 1999, Mears and Eastman 2005, O'Neil 2001, ICPS 1991). It is also used in the production of defatted products such as defatted soy flour (ATSDR 1999; IPCS 1991) and food grade silicone (Jet-Lube of Canada Ltd. 2007).

In Canada, hexane is listed as a food additive permitted for use as a carrier or extraction solvent (Canada 1978). The permitted maximum residue limits of hexane in food are; 10 parts per million (ppm) in vegetable fats, oils, and oil seed meals, 25 ppm in spice extracts or natural extractives, 2.2% in the solvent used for hop extract, and 1.5 ppm in pre-isomerized hop extract (Canada 1978). The Controlled Products Regulations established under the Hazardous Products Act requires n-hexane to be disclosed on the Material Safety Data Sheet that must accompany workplace chemicals when it is present at a concentration of 1% or greater as specified on the Ingredient Disclosure List (Canada 1988a,b).

n-Hexane is also used as a defoaming agent and/or a raw material in the manufacturing of polyolefins, elastomers, synthetic rubbers and some pharmaceuticals (Mears and Eastman 2005, NLM 2005, IPCS 1991). In Canada, n-hexane has been used as a defoaming agent in the manufacture of coating and adhesives for polyolefin films and polystyrene resins. Solvent residues may be found in the formulations of coating and adhesives used in food packaging at ppm levels. Another food related use of n-hexane is as a propellant for aerosols in the formulation of lubricants and cleaners. Lubricants have no direct food contact and cleaners are used then followed by a water rinse after the treatment to remove any residues. Considering its physical and chemical properties and its use under well-ventilated conditions in food plants, none of the uses are expected to cause any indirect exposure to n-hexane from food (Personal communication from Food Packaging Materials and Incidental Additives Sections, Health Canada to Risk Assessment Bureau, Health Canada, dated 2008-08-11; unreferenced).

Other uses of n-hexane in Canada include as a solvent, a formulation component, a chemical intermediate, a processing aid, and a dispersant in various chemical processing (Environment Canada 2007b). A wide range of its uses lead to a variety of end products including adhesives, sealants, binders, fillers, lubricants, paints and coatings, rubber and rubber cements, break cleaners, and degreasers, all of which are recognized globally (ATSDR 1999, IPCS 1991, Mears and Eastman 2005, NLM 2005). n-Hexane is also a common laboratory reagent and solvent (Environment Canada 2007b).

Cosmetic products which were notified to Health Canada to contain n-hexane include manicure preparation products (one polish thinner, one resin activator, and one speed cure), one skin moisturizer, and one animal hair styling aerosol product (CNS 2008).

n-Hexane is also found as a component of mineral spirits in 15 insecticide products at a concentration of less than 0.1% (Personal communication from Pest Management Regulatory Agency, Health Canada to Risk Assessment Bureau, Health Canada, dated 2008-09-22; unreferenced).

n-Hexane is widely used in the manufacture of veterinary medicinal ingredients (active ingredients) as well as some veterinary drugs as marketed products. It is not used as a medicinal or non-medicinal ingredient. All marketed products are required to meet international standards for residual solvents to be authorized for sale in Canada and the maximum residual limit for n-hexane is 290 ppm (Personal communication from Veterinary Drugs Directorate, Health Canada to Risk Assessment Bureau, Health Canada, dated 2008-08-22; unreferenced).

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Information reported under section 71 of CEPA 1999 indicated that the total release of n-hexane to the environment in 2006 was 1 000 - 5 000 tonnes (1 - 5 million kilograms), of which the majority was released to the atmospheric compartment at approximately 99.7% of the total quantity of reported releases. Only 0.25% and 0.05% releases were reported to water and to land, respectively (Environment Canada 2007b). The environmental releases reported under the National Pollutant Release Inventory (NPRI) indicated 4 438 tonnes (4.438 million kilograms) of n-hexane were released to air, while releases of 0.855 tonnes to water and 1.2 tonnes to land were reported in 2006 (NPRI 2008).

The majority of n-hexane release to the environment is considered through the manufacture, use, and disposal of various products associated with the petroleum industry (Bingham et al. 2001). Indeed the summary of top 50 industries' reported emissions under NPRI 2006 indicated that the petroleum sector comprised 68% of the total number of reporting facilities in Canada. In terms of released quantity to air, petroleum and agricultural-food sectors comprised approximately 80% of the total release quantity to air, followed by the rubber and chemical manufacturing sector and the textile sector.

As a component of petroleum products, the release of n-hexane to environmental media by the use of heating and motor fuels is expected to contribute to the total ambient air concentration where most of the demand for gasoline involves transportation. While in most cases n-hexane in gasoline is consumed during its combustion in engines, gasoline use and handling could result in emissions during refuelling, evaporation during storage, and exhaust releases when there is incomplete combustion of fuels (US EPA 1994).

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If released to water, n-hexane is not expected to adsorb to suspended solids and sediment based upon the estimated log K_oc. Volatilzation from water surfaces is expected to be an important fate process based on the estimated Henry's Law constant and limited water solubility. The solubility of n-hexane in water is increased by the presence of methanol (Groves 1988).

If released to soil at depth, n-hexane is expected to have a relatively high mobility based on the estimated K_oc value of 150. Volatilization from moist soil surfaces is expected to be an important fate process based on the estimated Henry's Law constant (1.82 × 10⁵ Pa·m³/mol) and low water solubility. n-Hexane may volatilize from dry soil surfaces as well due to its high vapour pressure. n-Hexane will undergo biodegradation in soil and water but volatilization is expected to be the predominant process in the environment (Solano-Serena et al. 2000).

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In the atmosphere, the main degradation pathway of vapour-phase n-hexane is by reaction with photochemically-produced hydroxyl radicals. The experimental reaction rate of 5.61 × 10^-12 cm³/mol·sec (Atkinson 1989) equates to a half-life of 1.91days, assuming first order kinetics, a 12hourday, and the hydroxyl radical concentration of 1.5 ×10⁶OH radicals/cm³ (Table 4a). Empirical data for biodegradation in water indicated 100% biodegradation over 28days in a ready-biodegradation test for n-hexane (NITE 2002), leading to the half-life of n-hexane in water of much less than 182days.

Despite its relatively short half-life (1.9 days) for photooxidation (Tables 4a and 4b), atmospheric n-hexane is one of the least photochemically reactive hydrocarbons (Katagiri and Ohashi 1975). While similar hydrocarbons such as n-pentane and methyl pentane undergo photochemical conversion to smog containing peroxyacethylnitrate and ozone, n-hexane is not expected to have a pronounced effect on the physical properties of the atmosphere, to participate in the depletion of the ozone layer, or to alter precipitation patterns (CIIT 1977).

Because few experimental data on the degradation of n-hexane are available, a QSAR-based weight-of-evidence approach (Environment Canada 2007a) was applied using the degradation models shown in Table 4b. The modelled data support the conclusions based on empirical data as they predict this substance to degrade relatively fast in air and water.

The results in Table 4b indicate that all the aerobic degradation models (BIOWIN 3, 4,5,6, TOPKAT and CATABOL) suggest this substance biodegrades rapidly. Moreover, the probability model results are greater than 0.5, the cut-off suggested by Aronson et al. (2006) that identifies substances as having "fast" biodegradation (based on the MITI probability models). The overall conclusion from BIOWIN is "ready biodegradable", however, this substance may not degrade rapidly under anaerobic conditions.

Other ultimate degradation models, CATABOL and TOPKAT, suggest that n-hexane undergoes mineralization in a 28 day time frame with a predicted high probability or high extent of biodegradation. TOPKAT, which simulates the MITI 28 day biodegradation test, produced a probability of 0.98 which is higher than the suggested threshold for non-persistent substances in this model (greater than 0.7) (TOPKAT 2004). CATABOL predicted 98% biodegradation based on the OECD 301 ready biodegradation test (%BOD), which has been suggested to indicate "not persistent" (Aronson and Howard 1999) with a half-life in water of less than 182 days. Assuming a first order rate kinetics, the calculated half-life from CATABOL is 5 days. n-Hexane was considered to be within the model domain of CATABOL, and the estimated reliability was high at 1.0.

Considering the results of the BIOWIN probability models as well as its overall conclusion and the results of the other ultimate degradation models, there is a strong consensus suggesting that the biodegradation half-life in water is < 182 days. This conclusion supports the empirical data while being consistent with its physical and chemical properties of this substance.

Using an extrapolation ratio of 1:1:4 for a water:soil:sediment biodegradation half-life (Boethling et al. 1995), the half-life in soil is also less than 182 days and the half-life in sediment is less than 365 days. This indicates that n-hexane is not expected to be persistent in soil and sediment.

Based on the empirical and modelled data described above (Tables 4a and 4b), n-hexane does not meet any of the persistence criteria (half-life in air greater than or equal to2 days, half-lives in soil and water greater than or equal to182 days, and half-life in sediment greater than or equal to365 days) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

The modified Gobas BAF middle trophic-level model for fish predicted a BAF of 575 L/kg, without consideration of biotransformation, indicating that n-hexane does not have the potential to bioconcentrate nor biomagnify in the environment. The results of BCF model calculations provide additional evidence supporting the low bioconcentration potential of this substance.

In addition, experimental bioconcentration data were available for two analogous substances, cyclohexane (CAS RN 110-82-7) and octane (CAS RN 540-84-1), through the Japanese National Institute of Technology and Evaluation database (NITE 2002). These substances are reported to have maximum BCF values of 129 and 540, respectively.

Based on the available empirical and kinetic-based modelled values and BCF data for analogous substances, n-hexane does not meet the bioaccumulation criterion (BCF or BAF greater than or equal to 5000) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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A - In the Aquatic Compartment

There is modelled and experimental evidence that n-hexane causes harm to aquatic organisms at low to moderate concentrations. These data are summarized in tables 6a and 6b.

A study conducted for the Dutch Government investigated the toxicity of numerous substances that are transported by ship in order to categorize their potential hazard to the environment (TNO 1987). Three species were involved in the testing: Chaetogammarus marinus, Mysidopsis bahia, and Daphnia magna. Test solutions were prepared by adding an amount in excess of the water solubility, stirring for 24 hours and allowing separation for an additional 24 hours. Tests were conducted in closed glass vessels and the test medium was replaced every 24 hours. Concentrations were measured by gas chromatography. Results show borderline high toxicity to the saltwater invertebrate species C. marinus and M. bahia.

In addition, from the U.S. EPA ecotoxicology database (ECOTOX 2007) nine studies are available that report median acute aquatic toxicity to fish and invertebrates due to exposures ranging from 1,5 to 3300mg/L.

A range of aquatic toxicity predictions were also obtained from the various QSAR models considered. Table 6b lists those predictions that were considered reliable and that were used in the QSAR weight-of-evidence approach for aquatic toxicity (Environment Canada 2007a).

These results indicate that n-hexane is, in general, moderately hazardous to aquatic organisms (i.e., acute LC₅₀ or EC₅₀ values were mostly greater than1.0mg/L and less than 100mg/L), though it potentially could be highly toxic to some taxa (e.g., two acute values were less than1.0mg/L).

Available empirical data indicate that n-hexane could cause harm to sensitive aquatic organisms at relatively low concentrations in water. The modelled results support the empirical data, indicating high to moderate toxicity to aquatic organisms.

n-Hexane is naturally produced in the environment, but is also manufactured, imported and used in large volumes in Canada (i.e., millions of kilograms per year). The many activities reported in Canada during the calendar year 1986 for the DSL and the section 71 survey (Environment Canada 2007b) for 2006 show that uses of this substance in Canada are widespread. The NPRI listed more than 300 facilities that reported releases of n-hexane to the environment in 2006 (NPRI 2008). Submissions were also received as a result of the section 71 survey of CEPA 1999, which included reported releases to the environment (Environment Canada 2007b).

Given the data submitted under section 71 of CEPA 1999 (Environment Canada 2007b) and the NPRI release data (NPRI 2008), n-hexane is expected to be introduced to the environment in Canada mostly through point and disperse atmospheric emissions. Environment Canada's National Air Pollution Surveillance (NAPS) network (NAPS 2000 - 2008) has recorded n-hexane concentrations in the atmosphere. In more than 20 000 measurements taken across the country for the years 2000-2008, n-hexane concentrations did not exceed 282 mg/m³ (0.08 ppm).

n-Hexane has been detected, but not quantified, in Lake Erie and Lake Ontario (GLWQB 1983) and in drinking water in the United States (Kool et al. 1982). Water samples taken from the Gulf of Mexico contained n-hexane at an average concentration of 4.6 ng/L (Sauer et al. 1978). No more recent monitoring data pertaining to the presence of this substance in Canadian surface waters have been identified.

Since a proportion of n-hexane may be released to water, a generic scenario was used to estimate a realistic worst case concentration of n-hexane resulting from an industrial discharge using Environment Canada's Industrial Generic Exposure Tool - Aquatic (IGETA). A facility located in Montréal, Québec, reported the release of less than 1 tonne to the aquatic environment and accounted for the majority of the reported releases to water. Therefore, the release of 1 tonne of n-hexane was assumed, spread over 250days per year and with approximately 20% removal during sewage treatment. This scenario (involving application of a ten-fold dilution factor to the estimated concentration in sewage treatment plant effluent) provides a conservative predicted environmental concentration (PEC) of 0.0001mg/L. Details regarding the inputs used to estimate this concentration and the output of the model are described in Environment Canada (2009b).

The approach taken in this ecological screening assessment was to examine available scientific information and develop conclusions based on a weight-of-evidence approach and precaution as required under CEPA 1999.

A risk quotient (RQ) analysis, integrating potential exposures with potential adverse ecological effects, was performed for aquatic ecosystems. A conservative predicted no-effect concentration (PNEC) was derived by selecting the lowest experimental toxicity value (see Table 6a), and dividing it by a conservative application factor of 100. The use of this application factor is to account for the uncertainties associated with potential differences in species sensitivities and to extrapolate from a laboratory-based measure of acute effects to a predicted chronic no-effect concentration in the field. The PNEC calculated for n-hexane was 0.004mg/L L based on tests with the invertebrate species C. marinus and M. bahia. A conservative scenario of industrial releases to water estimates that the resulting risk quotient (PEC/PNEC) for n-hexane is 0.03. In addition, the measured atmospheric concentrations are many orders of magnitude below levels reported to cause acute toxicity in mice via inhalation.

Based on the information available, n-hexane is unlikely to be causing ecological harm in Canada .

For n-hexane, there were a limited number of experimental data for degradation, and no experimental data for bioaccumulation identified during this evaluation. Estimation of these properties relied primarily on QSARs. While there are uncertainties associated with the use of QSAR models to estimate chemical and biological characteristics, approaches used provided for meaningful interpretation of the information and identification of substances that are priorities for further actions. While there were numerous ecotoxicological studies available for n-hexane, the volatility of the substance makes it difficult to produce accurate results. Several of the reported toxicity values were well above the reported water solubility of the substance.

It is also noted that, with regard to ecotoxicity, evaluation primarily focused on the toxicity to organisms in the pelagic aquatic environment. The release and partitioning behaviour of this substance can result in the exposure of organisms living in other media (air, soil). Limited data on potential effects to such organisms have been identified.

Given the large quantity and widespread use of n-hexane in commerce, it is likely that releases to the Canadian environment are substantially higher than those derived solely from the NPRI reporting. Some releases of n-hexane to water are expected, but the substance is quite volatile. Therefore, conservative assumptions were made when using models to estimate concentrations of n-hexane in receiving water bodies. A key uncertainty relates to the lack of empirical data on environmental concentrations in Canada , which was addressed by using a conservative exposure model to calculate a PEC. There is also uncertainty associated with the PNEC used in the risk quotient calculation, because of limited amount of empirical toxicity data available. This was addressed by dividing the critical toxicity value by an assessment factor of 100.

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Upper-bounding estimates of daily intake of n-hexane for all age groups are summarized in Appendix 1a. The estimates ranged from 32 microgram per kilogram body weight (µg/kg-bw) per day for seniors (greater than 60 years old) to 95 µg/kg-bw per day for children (6 months to 4 years old).

The maximum concentrations of n-hexane reported in ambient and indoor air in Canada were used for the estimation. Indoor air represented the predominant contribution to the total estimated daily intake for all age groups, ranging from 24 to 73 µg/kg-bw per day, followed by ambient air ranging from 7 to 21 µg/kg-bw per day. Together, air is estimated to be the major source of exposure to n-hexane by the general population of Canada .

n-Hexane concentration ranges in ambient and indoor air reported in Canada among the selected critical studies are presented in Table 7.

While the highest concentration of n-hexane in ambient air reported in Canada between 2000 and 2008 was 282µg/m³ at a NAPS station in a residential area in Windsor, Ontario in 2002 (NAPS 2002), the summary of NAPS data indicates that the mean concentration of n-hexane falls in the range of 0.15 to 1.5 mg/m³s (NAPS 2000 - 2008). The mean concentration of n-hexane in other studies also falls in the range of 0.15 - 8.2 mg/m³(AENV 2004; Gouvernement du Québec 2002; OMEE 2000; Ville de Montréal 2002; Health Canada 2008; OMOE 2005). Comparison of the highest concentration to the mean concentration range reported among all critical studies clearly shows that the total upper-bounding estimate of daily intake of n-hexane based on the maximum reported value of 282µg/m³is a conservative estimate.

Similarly, the highest concentration of n-hexane in indoor air in the critical data set (Canadian studies in the 1990s-2000s) was 138µg/m³ from a study conducted in Windsor, Ontario in 2006 (Health Canada 2008). This study was performed over a two year period in 2005 and 2006, and the mean concentration of n-hexane ranged from 2.3 to 8.0 µg/m³. In other studies, the mean concentration of n-hexane ranged from 1.2 to 8.0 mg/m³ (Bell et al. 1991; Davis and Otson 1996; Fellin et al 1992; Fellin and Otson 1997; Otson and Zhu 1997). Therefore, the indoor air contribution to the total upper-bounding estimate of daily intake of n-hexane based on the maximum reported value of 138µg/m³ is also considered as a conservative estimate.

One localized source of n-hexane where the general population of Canada would be exposed is at gas stations during filling up of a motor vehicle gas tank. Potential exposure to n-hexane vapour from motor gasoline was reported in Canada in 1985-1986 (PACE 1987, 1989). This study was conducted in two phases (summer 1985 and winter 1986) at 50 service stations in five cities across Canada (Halifax, Montreal, Toronto, Calgary, and Vancouver) to assess exposure of service station attendants (long-term) and self-serve customers (short-term) to gasoline vapours during normal activities. The short-term study was conducted using a personal sampler for 10 - 15 minutes to represent the time during fill-up of a gas tank by a customer. The study was done for regular leaded gasoline, regular unleaded gasoline and super unleaded gasoline. The mean concentration of n-hexane among all short-term studies (114 samples in summer; 119 samples in winter) was 16 800 mg/m³ (maximum 185 000 mg/m³) in summer, and 24 700 mg/m³(maximum 329 000 mg/m³) in winter. Maximum composition of n-hexane in each type of gasoline ranged from 6.06 % (super unleaded) to 12.47% (leaded) in summer and from 3.67 (super unleaded) to 7.21% (leaded) in winter. The current level of n-hexane in the air at gas station is expected to be lower than the reported values in this study, as the current average composition of n-hexane in gasoline (2.69% as stated in the "Sources" section) is lower than the reported composition in mid 1980s (PACE 1987, 1989),

A similar study was conducted more recently in Belgium in 1997 where concentrations of n-hexane vapour, during filling up of a gas tank, were measured for 120 samples (CONCAWE 1997). The mean concentration of n-hexane vapour measured was 2 250 mg/m³ (maximum 7 300 mg/m³). In this study, the average sampling time was only 1 minute and 38 seconds, which is significantly shorter than the Canadian study in 1985-1986 (PACE 1987, 1989).

Emissions of n-hexane at gas stations would contribute to higher localized ambient air concentrations of n-hexane at stations across the county. However, the exposure during gasoline fill-ups at gas stations is not considered critical based on the short exposure time and based on the health effects assessment (refer to the following "Health Effects Assessment" section), which indicated that critical nervous system effects were not observed for short-term exposures of n-hexane in robust toxicity studies.

No Canadian data were available in water and soil. Concentrations in drinking water and soil were modelled using ChemCAN 6.0 (ChemCAN 2003), based on the release information to air in 2006 reported under NPRI (NPRI 2008). The modelled contribution to the total estimated daily intake values from water and soil for all age groups resulted in negligible levels (less than 1 × 10^-7 µg/kg-bw per day) compared to air.

Several non-Canadian studies were identified to report the presence of n-hexane in food. It has been reported in extra-virgin olive oil at levels of 19.1 - 95.3 mg/L (Overton and Manura 1995). Maximum mean residue concentrations in peanut oil and sunflower oil have been reported at 0.9 mg/kg and 1.5 mg/kg, respectively (Hautfenne et al. 1987). It has also been detected in headspace analysis of roasted filberts (Kinlin et al. 1972), and chickpea seed (Rembold et al. 1989), as well as in soy protein products (Honing et al. 1979).

As the dataset was poor for food, the estimates from food sources were determined according to the most recent information on residual levels in foods summarized in Appendix 1b. Based on the levels of residual n-hexane typically found in refined vegetable oils of 0.8 ppm, the highest daily intake of n-hexane from foods is estimated to be 1.45 mg/kg-bw per day for the 6 - 8 year old age group (Appendix 1b; Personal communication from Chemical Health Hazard Assessment Division, Health Canada to Risk Assessment Bureau, Health Canada, dated 2008-10-15; unreferenced). This estimate indicates that the contribution from food sources at the worst case is 1.95% of the estimated total daily intake. Therefore, this percentage was incorporated to all age groups for a conservative estimate of the total daily intake of n-hexane from environmental media and food.

The contribution from food sources is considered an overestimate due to following factors. An n-hexane residue level of 0.8 ppm was assumed for the oil component of all processed foods containing vegetable oil as an ingredient. This is the maximum level of n-hexane found in commercial grade hexane. However, processed foods that contain vegetable oil are in many instances exposed to processing temperatures that far exceed the boiling point of n-hexane (68.7 °C). It is therefore expected that n-hexane residues in the oil component of processed foods would be further reduced during the cooking process. In addition, all food categories containing vegetable oil as an ingredient were considered including oils extracted without the use of hexane, such as virgin oils and cold-pressed oils, since there was no way of distinguishing them from oils extracted using hexane only (Personal communication from Chemical Health Hazard Assessment Division, Health Canada to Risk Assessment Bureau, Health Canada, dated 2008-09-26; unreferenced).

Confidence in the upper-bounding estimate of exposure to n-hexane via environmental media and food is considered to be high as recent Canadian data were available for both ambient and indoor air which represented the predominant source of exposure. No Canadian data were identified in other media (drinking water, soil) and food, however, these media were estimated not to contribute significantly to the total daily intake, which agrees with its physical and chemical properties (high volatility and low water solubility). The total upper-bounding estimate of exposure to n-hexane is considered to be a conservative estimate.

Based on the information submitted under the section 71 survey of CEPA 1999, the major use categories of n-hexane in consumer products were identified as adhesives, lubricant, paints, and automotive parts cleaners and degreasers (Environment Canada 2007b). For some of these products including lubricant (less than 60%), brake parts cleaner and degreaser (less than100%), automobile parts cleaning products (i.e., tire shine, less than 60%), and contact cleaner (less than 90%), concentrations of n-hexane in the products are relatively high as indicated by the percentages in brackets (Environment Canada 2007b). Many of these products are for automobile care/maintenance products and considered primarily for professional use. Although it may also be used by the general population, these products are considered to be used outdoors and/or infrequently. Under such circ*mstances, exposure via inhalation during the use of these products is expected to be minimal.

Other products where interior use (i.e., basem*nts, garages) may be expected include construction adhesive, gasket sealant, spray paint, weatherstrip adhesive, weatherstrip cement, and spray adhesive. Maximum concentrations of n-hexane for each type of products according to the submitted and publically available information are summarized in Table 8 together with use conditions based on consumer product exposure model parameters (frequency of use and exposure duration) (RIVM 2006, US EPA 1986).

The model suggests that the use of these products presented in Table 8 results in exposure duration of 5 to 240 min. Exposure estimates during short-term use of consumer products were not developed for this substance based on the following reasons.

The use of these products is considered primarily for professional use and is expected to be infrequent by the general population. In addition, any potential contribution of consumer products to total exposure of the general population is captured in indoor and ambient air levels, for which empirical data were available from recent Canadian studies. Finally, based on the health effects assessment (refer to the following "Health Effects Assessment" section), critical nervous system effects were not observed for short-term exposures of n-hexane in robust toxicity studies.

Similar considerations were taken for a small number of cosmetic products containing n-hexane notified to Health Canada (CNS 2008, refer to "Uses" section) and exposure estimates were not derived for these products in this assessment.

Appendix 2 contains a summary of the available health effects information for n-hexane.

The European Commission has classified n-hexane as Category 3 (causes concern for human reproduction) Risk phrase R62 (possible risk of impaired fertility) for reproductive toxicity. This classification was based on effects observed in male rat following inhalation or oral exposure to n-hexane or its metabolite 2,5-hexanedione in male reproductive toxicity studies (European Commission 1997, 2004). Effects observed include histological changes in the testes and epididymis as well as changes in sperm parameters, and are described in more detail below.

Male rats were were exposed to n-hexane at 3524 mg/m³ (1000 ppm) for 61 days. At 2 weeks and 10 months after cessation of exposure, testicular damage was observed in the form of decreased size and weight of testes, atrophy of seminiferous tubules and loss of nerve growth factor-immunoreactive cell population. Total loss of germ cell line occurred in a few animals up to 14 months post-exposure (Nylén et al 1989).

In an inhalation testes morphology study in male rats lasting from 1 day up to 6 weeks, focal degeneration of spermatocytes and mild exfoliation of elongated spermatids were observed at 17622 mg/m³ (5000 ppm) (De Martino et al. 1987). The effects were first observed after 24 hours of treatment. Other effects observed at various time intervals after cessation of exposure included the presence of degenerating germ cells and inflammatory cells in the seminiferous tubules. The severity of the lesions in the seminiferous tubules increased with the duration of exposure, and extended treatment resulted in reduction in diameter and collapse of the tubules, including aplastic tubules.The testes and/or epididymides of all rats were affected after 3 weeks in groups exposed up to 6 weeks.

When administered orally in a 6-month comparative toxicity study in male rats, atrophy of the testicular germinal epithelium was observed at the highest dose of 4000 mg/kg-bw/day (Krasavage et al. 1980). In another oral reproductive study in male rats, there were no treatment-related effects on sperm or reproductive organs at the tested doses of 10000 mg/kg-bw/day for 5 days or 20000 mg/kg-bw for 1 day (Linder et al. 1992).

In an inhalation developmental toxicity study in mice, an increase in resorptions was observed at 705 mg/m³ (200 ppm) and higher (early and late resorptions significantly increased at 705 mg/m³ and late resorptions significantly increased at 17622 mg/m³) (Mast et al. 1988a).

When administered orally to mice in a developmental study, decreased average maternal weight gain was observed at 2200 mg/kg-bw/day and 2170 mg/kg-bw/day, but not at higher doses up to 9900 mg/kg-bw/day. Decreased foetal weight was observed at 7920 mg/kg-bw/day and above. Maternal deaths were observed at 2830 mg/kg-bw/day and above. (Marks et al. 1980). There was no evidence of teratogenicity in both inhalation and oral developmental studies in rats and mice (Bus et al. 1979; Marks et al. 1980; Mast 1987; Mast et al. 1988a; Stoltenburg-Didinger et al. 1990).

No guideline cancer studies were identified using n-hexane only. In a subchronic lung morphology study conducted in male rabbits exposed by whole body inhalation for 24 weeks, papillary tumours in terminal bronchioles and alveolar ducts were observed at the only tested concentration of 10573 mg/m³ (3000 ppm) (Lungarella et al. 1984). Multiple short-term genotoxicity assays have been conducted in vitro, most of which were negative. In vivo studies for chromosome aberrations tests in bone marrow cells of rats and mice were positive (Hazleton Labs 1992, Shelby and Witt 1995, NTP 1991), whereas those for micronuclei and sister chromatid exchange and dominant lethal assays were all negative (Litton Bionetics 1980, Mast et al.1988c, NTP 1991, Shelby and Witt 1995).

No chronic animal studies using pure n-hexane have been identified. However, neurotoxicity is identified as the most sensitive endpoint based on numerous subchronic animal studies. The lowest-observed-effect-concentration (LOEC) for inhalation exposure was 705 mg/m³ (200 ppm) based on decreased distal latency, motor nerve conduction velocity and mixed nerve conduction velocity (distal and, distal plus proximal combined) in male rats in a 24-week study (12 hrs/day). No clinical signs of neurotoxicity were observed at any concentration (Ono et al. 1982).

In a 16-week study in which male rats were exposed to n-hexane by inhalation at higher concentrations, similar effects were observed, including a dose-dependent reduction in motor nerve conduction velocity at 4230 and 10574 mg/m³ (Huang et al. 1989). Paranodal swelling and clinical signs of neuropathy (marked reduction in grip strength, slowness of motion) were also present at these concentrations. The LOEC for this study was 1762 mg/m³ based on a dose-related decrease in the nervous system-specific protein, ß-S-100.

Other inhalation studies suggest that when daily exposure was of shorter duration, effects on the nervous system may be less severe, or first appear at higher doses. In a 13-week inhalation study in rats, early stage paranodal swellings of the tibial nerve were evident in 1/5 and 4/5 male rats at 22907 and 35243 mg/m³ (6500 and 10000ppm) respectively. No clinical signs of neuropathy were observed (Cavender et al. 1984). In a 13-week inhalation study in mice, paranodal swellings of the tibial nerve were observed in both sexes, and decreased locomotor activity was observed in females at 35243 mg/m³ (10000ppm). Non-neurotoxic effects included a dose-related increase in lesions of the nasal turbinates in males and in females at 35243mg/m³ (10000ppm) (NTP 1991).

The lowest-observed-effect-level (LOEL) for exposure via the oral route was 189mg/kg-bw/day based on adverse effects in heart muscle and related parameters (reduction in ventricular fibrillation threshold, decreased levels of myocardial magnesium and potassium, changes in the ultrastructure of the myocardium) in male rats exposed to 0 or 189mg/kg/day for 30days through gavage (Khedun et al. 1996). In a 90-day oral rat study (males only), signs of neurotoxicity (severe hindlimb weakness or paralysis with dragging of at least one hind foot, morphologic changes in nerve tissue), were observed at the highest dose of 4000mg/kg bw/day (Krasavage et al. 1980).

There are a considerable number of human studies which measured nervous system effects. Three of the more pertinent studies are described in Appendix 2 and summarized below.

Male workers from a tungsten carbide alloys producing factory were evaluated to assess the effects of low levels of n-hexane on the peripheral nervous system. They were exposed to an average n-hexane concentration of 204mg/m³ (58 ppm) in the breathing zone over an average period of 6.2 years. However, there was also co-exposure to acetone. Compared to controls, exposed workers showed an increased frequency of headache, dysthesia in limbs and muscle weakness, decreases in muscle strength, in vibration sensation of the radial processes [as stated in original paper], and in maximal MCV and residual latency of motor nerve conduction in the posterior tibial nerve (Sanagi et al. 1980).

Mutti et al. (1982) observed both clinical and electrophysiological signs of neuropathy in shoe factory workers exposed to a mixture of hydrocarbons, including n-hexane over a 9-year period. Based on time-weighted average concentrations for n-hexane, sleepiness, dizziness, weakness in limbs, hypoesthesia and paraesthesia were more frequent in all exposed workers. Motor action potential (MAP) was reduced in median, ulnar and peroneal nerves in both mild (243mg/m³) and high (474mg/m³) exposure groups, while in the high exposure group, motor nerve conduction velocity (MCV) was decreased in the median and peroneal nerves.

In an offset printing factory, mean background TWA of n-hexane was 222 mg/m³ (63 ppm) and mean personal air concentration of n-hexane for offset machine workers was 465 mg/m³ (132 ppm). Subjects worked at this facility for an average of 2.6 years (range one month to 12 years), and in the trade for an average of 6.4 years (range one month to 30 years) While other solvents (i.e. toluene) were present in cleaning solutions used by the workers, n-hexane was predominant. The exposed workers were divided into three groups according to signs of peripheral neuropathy: healthy workers, subclinical (showing abnormalities in nerve conduction parameters), and symptomatic (showing both clinical and electrophysiological evidence of peripheral neuropathy), and compared to a control group. In healthy workers, sensory action potential (SAP) in nerves was decreased compared to controls. In the subclinical group, SAP, SAP amplitude and MCV were decreased, as well as a mild reduction in MAP amplitude and mild prolongation in mean distal latency (DL). In the symptomatic group, further reduction in SAP, MAP amplitudes and MCV, including an obvious prolongation in mean DL, and clinical signs of peripheral neuropathy were observed (numbness, paraesthesia, and pain and weakness in extremities). This study showed how degradation of electrophysiological parameters was related to clinical signs of neuropathy in humans (Chang et al. 1993).

Humans may recover from n-hexane induced neuropathy within 1-3 years after termination of exposure but deterioration of muscle strength and sensory deficits commonly worsen within 2-5 months of the cessation of exposure before slow recovery begins. However, certain neurotoxic effects may persist in cases of very high exposures. The mechanism of continued progression of effects after termination of exposure is not clear (Huang 2008).

Several toxico*kinetic studies have been conducted in laboratory animals but only a few in humans. In a 4-hr inhalation study in male volunteers, 22-24% of n-hexane was absorbed across the lungs and the average half-life for n-hexane in blood was 1.5-2 hrs (Veulemans et al. 1982). It is principally metabolized in the liver to various metabolites that are then distributed in the blood to various organs and tissues. No oral absorption studies were identified, although a single oral exposure study in human volunteers identified 2,5-hexanedione as the main metabolite in urine (Baelum et al. 1998). In occupational exposure studies where there was exposure to other substances in addition to n-hexane, metabolites identified in urine included 2,5-hexanedione, 2,5-dimethylfuran, 2-hexanol, -valerolactone, and 4,5-dihydroxy-2-hexanone. The major metabolite of n-hexane in laboratory animals is 2-hexanol. No toxico*kinetic studies based on dermal exposure were identified (US EPA 2005).

Level of confidence in the toxicity database is moderate to high as there is sufficient information to address the endpoint of concern (neurotoxicity) based on inhalation exposure, including human studies which measured neurotoxicity, and adequate information on acute, short-term, subchronic and genotoxicity endpoints. Animal studies measuring reproductive and developmental endpoints were limited and chronic toxicity data were lacking, although some carcinogenicity data were provided via a 24-wk inhalation study in rabbits.

Although a thorough analysis of the mode of action of n-hexane is beyond the scope of this screening assessment, it is recognized that the neurotoxicity observed following n-hexane exposure is likely caused by its metabolite 2,5-hexanedione. This -diketone appears to have the ability to interact with specific proteins on neurofilaments, via pyrrole formation, which eventually results in neuropathy. Structural analogues, such as n-heptane and pentane, do not have the ability to form -diketone metabolites (US EPA 2005).

Based principally on the classification from the European Commission, an important effect of hexane is impaired fertility. However, the US EPA (2005) and the ATSDR (1999) identified the nervous system as the target organ for n-hexane exposures. Neurotoxic effects due to hexane exposure were observed at concentrations lower than those observed for impaired fertility effects.

Several human studies suggested neurotoxic effects at inhalation levels lower than those identified from animal toxicity studies. However, the human epidemiology studies are not as robust as the animal studies because effects from co-exposure to several other substances could not be separated from effects due to n-hexane exposure and due to other confounding factors inherent in epidemiology studies. Thus, the critical effect level for repeated-dose toxicity via inhalation is considered to be 705 mg/m³, based on decreases in nerve conduction parameters in a 24-week rat study, and increased number of resorptions in a mouse developmental toxicity study.

The principal source of exposure to hexane is expected to be through inhalation (ambient and indoor air). A comparison between the lowest LOEC for repeated dose toxicity (705mg/m³) and measured ambient and indoor air concentrations of 282µg/m³ and 138µg/m³, respectively, resulted in margins of exposure (MOEs) of approximately 2500 (ambient air) and 5100 (indoor air), which were considered to be adequately protective.

The critical effect level for repeated-dose toxicity via the oral route (189mg/kg-bw/day) was based on adverse effects in heart muscle and related parameters in a 30-day rat study. Comparison of the critical effect level for repeated dose effects via the oral route and the upper-bounding estimate of daily intake of n-hexane by the general population in Canada (95µg/kg-bw/day) for children (0.5-4 years old), resulted in a margin of exposure (MOE) of approximately 2000, which is considered to be adequately protective.

MOEs were not established for consumer products containing n-hexane as the use of these products are considered specialized and/or infrequent by the general population, and critical nervous system effects were not observed for short-term exposures in robust toxicity studies. In addition, many products considered are for outdoor use and exposure via inhalation is expected to be minimal. Finally, the empirical data on n-hexane concentration in air from recent Canadian studies account for exposures associated with the use of consumer products.

There was insufficient information to assess the carcinogenicity of n-hexane. No chronic studies were available; however, evidence of lung tumours at a high n-hexane concentration (10,573mg/m³) was observed in a 24-wk rabbit study.

The scope of this screening assessment does not take into consideration a full analysis of the mechanism of action of n-hexane, and it does not take into account possible differences between humans and experimental animals in sensitivity to effects induced by this substance or in metabolism of the substance. There is uncertainty surrounding the relevance to humans of the reproductive effects observed in male rats. Lack of chronic studies leads to uncertainty regarding long-term and carcinogenic effects.

Although n-hexane is often present in co-occurrence with other substances, the exposure from n-hexane through its commercial mixture formulation was not considered in this report.

The level of uncertainty in quantification of population exposure to n-hexane in the general environment is low based on the fact that there were sufficient recent Canadian studies that examined the concentration of this substance in the critical environmental media, ambient and indoor air. Although the concentration of n-hexane in other environmental media (water and soil) and food were not available, these media were estimated not to play significant roles in exposure estimates for the general population, which is in agreement with its physical and chemical properties.

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Based on the information presented in this screening assessment, it is concluded that n-hexane is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term effect on the environment or its biological diversity, or that constitute or may constitute a danger to the environment on which life depends. Additionally, n-hexane does not meet the criteria for persistence or bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

Based upon the potential adequacy of the margins of exposure between conservative estimates of exposure to n-hexane via environmental media and critical effect levels for inhalation exposures, it is concluded that hexane be considered as a substance that is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

It is therefore concluded that hexane does not meet the criteria in paragraphs 64(a), 64(b) or 64(c) of CEPA 1999. Additionally, hexane does not meet the criteria for persistence or bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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• Percentage of n-hexane in commercial hexanes can range from 20-80% (IPCS 1991). Therefore, daily intake estimates for n-hexane are based on 80% of the level of residual hexanes typically found in refined vegetable oils, as indicated by the Institute of Shortening and Edible Oils (1 ppm).
• The age groups listed above are the specific child and adult age groups with the highest consumption of vegetable fats and oils relative to other age groups.
• While hexane is listed in the Food and Drug Regulation (FDR) for use in hop extract, the Brewers Association of Canada has indicated that hexane has not been used as an extraction solvent for hops since 2000. It has been replaced mainly by carbon dioxide. In addition, the Association has indicated that all inventories of hop extracts that would have used hexane are likely no longer on the market.
• Hexane is listed in the FDR for use in spice extracts, natural extractives and vegetable oil seed meals. While no consumption data were available for these food ingredients, their contribution to the total diet is considered negligible in comparison to vegetable fats and oils. In addition, the Canadian Spice Association has stated that hexane residues in spice extracts are typically in the 5-15 ppm range and spice extracts themselves are typically found in the final food as consumed in the 0.01-0.05% range. Based on these usage levels, typical hexane residues in the final food would be less than 0.0015 ppm, significantly less than the 1 ppm level that may be found in refined vegetable oils.
• The FDR lists several alternate extraction solvents in addition to hexane that may be used in or upon spice extracts, natural extractives and vegetable oil seed meals.

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