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Screening Assessment for the Challenge

Hexanoic acid, 2-ethyl-

Chemical Abstracts Service Registry Number
149-57-5

Environment Canada
Health Canada

September 2011


(PDF Version - 511 KB)

Table of Contents

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 hexanoic acid, 2-ethyl- (or 2-ethylhexanoic acid), Chemical Abstracts Service Registry Number 149-57-5[1]. This substance was identified in the categorization of the Domestic Substances List as a high priority for action under the Challenge initiative under the Chemicals Management Plan Challenge. 2-Ethylhexanoic acid (2-EHA) was identified as a high priority as it was considered to pose greatest potential for exposure (GPE) of individuals in Canada and is classified by the European Commission on the basis of developmental toxicity. The substance did not meet the ecological categorization criteria for persistence, bioaccumulation potential, or inherent toxicity to aquatic organisms.

According to information reported under section 71 of CEPA 1999, 2-EHA was not manufactured in Canada in 2006 above the reporting threshold of 100 kg but was imported into the country in a total quantity ranging from 100 000 to 1 000 000 kg in 2006. The major use of 2-EHA is in the preparation of metal salts used in various applications including as drying agents in paint and inks. 2-EHA is also used to produce an ester used as a plasticizer. 2-EHA is primarily an industrial intermediate whereby the resulting derivatives are contained in the finished products.

Data were identified for 2-EHA concentrations in the Canadian environment (water and sediment), as well as concentrations in influents, effluents, and biosolids from a number of municipal wastewater treatment plants in Québec, Canada. In 2006, the majority of 2-EHA in Canada was sent to non-hazardous, off-site waste management facilities. Limited data were available regarding concentrations of 2-EHA in food.

The critical human health effect associated with exposure to 2-EHA is developmental toxicity, based on observations in experimental animals. In addition, effects on the liver and stomach and reduced body-weight gain were observed following repeated-dose exposures to 2-EHA and 2-ethylhexanol, which is metabolized extensively to 2-EHA. The margins between upper-bounding estimates of exposure from environmental media and food and consumer products (alkyd paint) and critical effect levels in experimental animals are considered adequate to address uncertainties in the health effects and exposure databases.

On the basis of the adequacy of the margins between upper-bounding estimates of exposure to 2-EHA and critical effect levels, it is concluded that 2-EHA is a substance that is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

2-Ethylhaxanoic acid is a highly soluble substance that primarily exists in its ionized (negatively charged) form in water at environmentally relevant pHs. Empirical and modelled data demonstrate that 2-EHA biodegrades quickly in the environment and has a low potential to accumulate in the lipid tissues of organisms. Acute and chronic toxicity values indicate that the substance is moderately toxic to aquatic organisms (acute LC50 or EC50 >1.0 mg/L and <100 mg/L). Realistic estimates of exposure were determined for site-specific industrial releases and consumer releases to water. The predicted environmental concentrations in water of this substance (as well as actual concentrations measured in Canadian river water and effluents) are estimated to be below the predicted no-effect concentration for sensitive aquatic organisms, resulting in risk quotients lower than 1.

On the basis of its low ecological hazard and conservatively estimated releases of 2-EHA, 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. 2-EHA does not meet the criteria for persistence or bioaccumulation as set out in the Persistence and Bioaccumulation Regulations.

Based on the information available, it is concluded that 2-EHA does not meet any of the criteria set out in section 64 of CEPA 1999.

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

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Introduction

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

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

The Ministers therefore published a notice of intent in theCanada 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 hexanoic acid, 2-ethyl- (or 2-ethylhexanoic acid) was identified as a high priority for assessment of human health risk because it was considered to present GPE and had been classified by other agencies on the basis of developmental toxicity. The Challenge for this substance was published in theCanada Gazette on September 26, 2009 (Canada 2009a, 2009b). A substance profile was released at the same time. The substance profile presented the technical information available prior to December 2005 that formed the basis for categorization of this substance. As a result of the Challenge, submissions of information pertaining to the substance were received.

Although 2-ethylhexanoic acid (2-EHA) was determined to be a high priority for assessment with respect to human health, it did not meet the categorization criteria for persistence, bioaccumulation or inherent toxicity to aquatic organisms.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of CEPA 1999. Screening assessments examine scientific information and develop conclusions by incorporating a weight-of-evidence approach and precaution.[2]

This final screening assessment includes consideration of information on chemical properties, hazards, uses, and exposure, including the additional information submitted under the Challenge. Data relevant to the screening assessment of this substance were identified in original literature, review and assessment documents, stakeholder research reports and from recent literature searches, up to June 2010for the ecological and human health sections. Key studies were critically evaluated; modelling results have also 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 final screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents a summary of the critical information upon which the conclusion is based.

This final screening assessment was prepared by staff in the Existing Substances Programs at Health Canada and Environment Canada and incorporates input from other programs within these departments.

The ecological and human health portions of this assessment have undergone external, written peer review/consultation. Comments on the technical portions relevant to human health were received from scientific experts selected and directed by Toxicology Excellence for Risk Assessment (TERA), including Joan Strawson (Toxicology Excellence for Risk Assessment [TERA]), Dr. Michael Jayjock (The Lifeline Group) and Dr. Chris Bevans (CJB Consulting). Additionally, the draft of this screening 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 assessment remain the responsibility of Health Canada and Environment Canada. Approaches used in the screening assessments under the Challenge have been reviewed by an independent Challenge Advisory Panel.

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

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Substance Identity

Substance Name

For the purposes of this document, this substance will be referred to as 2-EHA, which has been derived from the inventory name hexanoic acid, 2-ethyl. Information on the identity of 2-EHA is summarized in Table 1.

Table 1. Substance identity for 2-EHA

Chemical Abstracts Service Registry Number (CAS RN)149-57-5
DSL nameHexanoic acid, 2-ethyl-
National Chemical Inventories (NCI) names[a]

Hexanoic acid, 2-ethyl- (AICS, ASIA-PAC, ENCS, PICCS, SWISS, NZIoC, TSCA)

2-ethylhexanoic acid (EINECS, ECL, PICCS)

Ethyl hexanoic acid, 2- (PICCS)

2-ethylhexanoic acid (EHA) (PICCS)

Other names(±)-2-Ethylhexanoic acid; α-Ethylcaproic acid; α-Ethylhexanoic acid; 2-Butylbutanoic acid; 2-Ethyl hexanoic acid; 2-Ethyl-1-hexanoic acid; 2-Ethylcaproic acid; 2-Ethylhexoic acid; 3; Heptanecarboxylic acid; Butylethylacetic acid; Caproic acid, α-ethyl-; Ethylhexanoic acid; NSC 8881; Octylic acid

Chemical group

(DSL Stream)

Discrete organics
Major chemical class or useOrganic – acids / esters
Major chemical sub-classNot available
Chemical formulaC8H16O2
Chemical structure Chemical structure 149-57-5
SMILES[b]O=C(O)C(CCCC)CC
Molecular mass142.212 g/mol
[a] National Chemical Inventories (NCI) 2007: AICS (Australian Inventory of Chemical Substances); ASIA-PAC (Asia-Pacific Substances Lists); ECL (Korean Existing Chemicals List); EINECS (European Inventory of Existing Commercial Chemical Substances); ENCS (Japanese Existing and New Chemical Substances); NZIoC (New Zealand Inventory of Chemicals); PICCS (Philippine Inventory of Chemicals and Chemical Substances); SWISS (SWISS Giftliste 1 and Inventory of Notified New Substances); and TSCA (Toxic Substances Control Act Chemical Substance Inventory).
[b] Simplified Molecular Input Line Entry System

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Physical and Chemical Properties

Experimental and estimated physical and chemical properties of 2-EHA that are relevant to its environmental fate are presented in Table 2.

Models based on quantitative structure–activity relationships (QSARs) were used to generate data for some of the physical and chemical properties of 2-EHA. These models are mainly based on fragment addition methods (i.e., they rely on the structure of the chemical) (except for WSKOW 2008). Most of the models accept only the neutral (i.e., un-ionized) form of a chemical as input (in SMILES form). However, this substance is ionic with an estimated pKa of 4.82, which means that at environmentally relevant pHs (6 to 9) it will exist largely to entirely in the ionized form (94 to 100%, respectively) as a result of giving up the proton from the hydroxyl group. The log D and water solubility values predicted using the ACD/PhysChem Suite (2009) are dependent on pH, thus accounting for the ionizing characteristics of this substance. The experimental log Kow value agrees well with the log Dow value at pH 3, where the neutral form predominates. At pH 6–8, the ionized (negatively charged) form predominates and, thus, the log Dow values are lower. All other physical and chemical property values in Table 2 refer to the neutral form of this substance and the influence of its ionic nature on these properties is further discussed in the section on Environmental Fate.

Table 2. Physical and chemical properties for the neutral form of 2-EHA (unless otherwise indicated)

PropertyTypeValue[a]Temperature °CReference
Physical formColourless to yellow liquidBASF 2009; Eastman 2010
Melting point

(°C)
Experimental-60[*], -118.4 European Commission 2000; US EPA 2001, 2010; BASF 2009
Modelled38 MPBPVP 2008 (mean value)
Boiling point

(°C)
Experimental[*]223–229 European Commission 2000; US EPA 2002, 2010; Eastman 2010
Modelled234 MPBPVP 2008
Density

(kg/m3)
Experimental905–910

(0.905–0.91 g/cm3)
20European Commission 2000; US EPA 2010
Vapour pressure

(Pa)
Experimental[*]1.33–<1020European Commission 2000; US EPA 2001, 2010
Modelled12.825MPBPVP 2008

(mean value)
Henry’s Law constant

(Pa·m3/mol)
Experimental[*]0.2920EPIsuite 2008
Modelled[b]0.30, 0.37

(bond versus group)
25HENRYWIN 2008
Log Kow

(octanol-water partition coefficient)

(dimensionless)
Experimental[c]2.6–2.7[*]25European Commission 2000
Modelled2.96 KOWWIN 2008
Log Koc

(organic carbon-water partition coefficient)

(dimensionless)
Modelled[d]1.4–1.7 KOCWIN 2008
Log D[e]

(distribution coefficient) (dimensionless)
Modelled

(Log Dow; octanol-water)
2.6, 1.4,

0.4, -0.5

(pH 3, 6, 7, 8, respectively)
 ACD/PhysChem Suite 2009
Modelled

(Log Doc; Organic carbon-water)
2.8, 1.6,

0.6, 0

(pH 3, 6, 7, 8, respectively)
 ACD/PhysChem Suite 2009
Water solubility (mg/L)Experimental[f]1400

(pH ca. 3.3)
20–25BASF 2009; HSDB 1983– ; US EPA 2010
2000*–2500

(0.2–0.25% by weight; pH ca. 3.3)
20–25HSDB 1983– ; Kyowa Hakko 2009; US EPA 2010
Modelled[g]286525WSKOW 2008
2350,

37 240,

1 000 000

(pH 3, 6, 7.5, respectively)
 ACD/PhysChem Suite 2009
Other solubilitiesSoluble in ethyl ether, carbon tetrachloride; slightly soluble in ethanol HSDB 1983–
pKa

(acid dissociation constant) (dimensionless)
Modelled4.8225ACD/PhysChem Suite 2009
[*] Values used in modelling with EPIsuite (2008); including boiling point of 226°C and vapour pressure of 4 Pa.
[a] Values in parentheses represent the original ones as reported by the authors or as estimated by the models.
[b] Henry’s Law constant is calculated using experimental values for vapour pressure and water solubility of 0.03 mmHg and 2000 mg/L (HENRYWIN 2008).
[c] The partition coefficient was determined using the OECD guideline 107 partition coefficient (n-octanol/water) flask-shaking method. According to the method, measurements should be made on ionizable substances only in their non-ionized form (free acid or free base) produced by the use of an appropriate buffer.
[d] As noted by the model, Koc may be sensitive to pH and includes fragment corrections for organic acid.
[e] Log D – distribution coefficient taking into account the presence of the ionic species; represents a net amount of the neutral and ionic forms expected to partition into the lipid or organic carbon phases at a given pH.
[f] All references for water solubility values include note that it is strongly acidic or give pH ca. 3.3. At this pH, the substance is almost entirely in its neutral form (97%, according to ACD/PhysChem Suite 2009). BASF (2009) noted that it is immiscible in water. USEPA (2010) includes information submitted to HPVIS program. The value of 2000 mg/L is used to model other properties.
[g] WSKOW (2008) uses the experimental values for log Kow (2.6) and melting point (-60 C). The ACD/PhysChem Suite (2009) water solubility predictions are dependent on pH, taking into account the ionizing characteristics of this substance.

In addition, the substance 2-EHA is a chiral molecule, which means it is non-super imposable on its mirror image (enantiomers). Therefore, the two enantiomers of this substance may have different biological effects.

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Sources

2-EHA does not occur naturally in the environment and in North America it is produced from n-butanal (Bizzari et al. 2009). Aldol condensation of two molecules of n-butyraldehyde produces 2-ethyl-2-hexenal; upon reduction of the alkene, 2-ethylhexanal is produced. 2-Ethylhexanal is a versatile intermediate: reduction of the aldehyde produces 2-ethylhexanol, a component of plasticizers such as diethylhexylphthalate (DEHP) and diethylhexyl adipate (DEHA) and oxidation of the aldehyde produces the substance 2-EHA; see Figure 1 for details (HSDB 1983–; Billig 2003; Bizzari et al. 2009).

Figure 1. Synthesis of 2-EHA - 2-EHA does not occur naturally in the environment and in North America it is produced from n-butanal (Bizzari et al. 2009). Aldol condensation of two molecules of n-butyraldehyde produces 2-ethyl-2-hexenal; upon reduction of the alkene, 2-ethylhexanal is produced. 2-Ethylhexanal is a versatile intermediate: reduction of the aldehyde produces 2-ethylhexanol, a component of plasticizers such as diethylhexylphthalate (DEHP) and diethylhexyl adipate (DEHA) and oxidation of the aldehyde produces the substance 2-EHA; see Figure 1 for details (HSDB 1983–; Billig 2003; Bizzari et al. 2009).

Figure 1. Synthesis of 2-EHA

Detection of 2-EHA in environmental media, foods and consumer products may also be due to leaching and/or transformation of other chemicals in finished products. For example, 2-EHA can be released from 2-ethylhexanoate salts and esters, owing to dissociation of the ions and ester hydrolysis, respectively. 2-EHA can also come from degradation of 2-ethylhexanol containing esters, which can occur in the environment as well as in humans (Figure 2).

Figure 2. Sources of 2-EHA from environmental media, foods, and the use of finished products - Detection of 2-EHA in environmental media, foods and consumer products may also be due to leaching and/or transformation of other chemicals in finished products. For example, 2-EHA can be released from 2-ethylhexanoate salts and esters, owing to dissociation of the ions and ester hydrolysis, respectively. 2-EHA can also come from degradation of 2-ethylhexanol containing esters, which can occur in the environment as well as in humans

Figure 2. Sources of 2-EHA from environmental media, foods, and the use of finished products

Based on a survey conducted under section 71 of CEPA, 1999, no Canadian companies reported manufacturing 2-EHA above the 100 kg/year threshold in 2006 (Environment Canada 2010a). Results from the same survey indicated that a total quantity between 100 000 and 1 000 000 kg of this substance was imported into Canada in 2006 (Environment Canada 2010a). Many companies submitting 2006 information also reported importing or using 2-EHA above thresholds in 2008 (Environment Canada 2010a). According to Bizzari et al. (2009), Canadian imports of 2-EHA were 500 000 kg in 2007 and 400 000 kg in 2008, primarily from the USA. 2-EHA is a high production volume (HPV) chemical in the United States (US EPA 2010) and in the European Union (ESIS c1995–2010).

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Uses

The primary use of 2-EHA is in the preparation of metal salts that are used as drying agents in paints, inks, varnishes, lacquers, and enamels, and are gelling agents for hydrocarbons (CCOHS 1997; Cragg 2001; Billig 2003; Bizzari et al. 2009). The most common metal salts produced from 2-EHA in the USA are those containing cobalt, manganese, zirconium, calcium, and zinc (Bizzari et al. 2009). The lead, cobalt, manganese, and zinc salts (soluble in hydrocarbons) serve as drying agents for lacquers and enamels. The iron, nickel, and cobalt salts are used as stabilizers for silicones. The copper salt is a fungicide for marine and other applications. On contact with water these salts are expected to dissociate into free metal and free acid moieties (US EPA 2002).

2-EHA is also used to produce esters (e.g., 2-ethylhexanoate ester) that are used in the production of plasticizers, in particular for polyvinyl butyral (PVB) resins, which are used in automotive windshields, architectural applications and vinyl products, including resilient vinyl flooring. PVB resins are also used in the production of polyvinyl chloride (PVC) (CCOHS 1997; Bizzari et al. 2009). The neopolyol esters of 2-EHA are used in the manufacture of synthetic lubricants, which are used in residential and commercial refrigerators and air conditioners with minor amounts being used in automotive applications (Bizzari et al. 2009).

2-EHA may also be used: as an oxidation catalyst during the manufacture of propylene oxide/styrene from ethylbenzene; as a catalyst promoter in the production of various polyester products including low-density polyethylene; as a catalyst in polyurethane foam; as a corrosion inhibitor in antifreeze; and in wetting agents, gel thickeners, emulsifiers, and fungicides (CCOHS 1997; Bizzari et al. 2009).

2-EHA is of particular importance in the production of alkyd resins used for baking enamels because of their exceptional stability (even at temperatures over 200°C), as well as their good weathering and aging stability. The acid and its derivatives are also used in the manufacture of lubricants, detergents, flotation aids, and corrosion inhibitors, as catalysts for polyurethane foaming, for solvent extraction, and for dye granulation(HSDB 1983–). In addition, 2-EHA may be used as a chemical intermediate in pharmaceuticals, dyes, flavourings, and fragrances (BASF 2007; Dow 2008; Eastman 2008).

According to submissions made under section 71 of CEPA 1999, approximately 386 000 kg of 2-EHA were used in Canada in 2006 (Environment Canada 2010a). Reported uses in Canada in 2006 included: as a viscosity adjustor in industrial coatings, to control ash-clogging in incinerator boilers, in mill and temper rolling oils, in flotation reagents, in industrial cleaners, lubricants and sealants, as a neutralizing agent in polyol resins ultimately used in foams, and in various other industrial applications (Environment Canada 2010a). 2-EHA was also reported as being used in products that may be available to the general public including as an ingredient in paint driers, in liquid and spray paints, and as an additive to antifreeze. In addition, 2-EHA was identified as an impurity in unsaturated polyester resins (Environment Canada 2010a).

In Canada, 2-EHA is a List 2 formulant that can be found in seven non-food pesticide products, five of which are discontinued and whose registrations will expire over the next 2 years. Four of these are antimicrobial tree dressings and one is a siding stain and preservative. One of the remaining products is approved to manufacture products only destined for export (2010 emails from Pest Management Regulatory Agency to Risk Management Bureau, Health Canada; unreferenced). According to the Canadian Cosmetic Notification System, 2-EHA is listed as an ingredient in two temporary tattoo products (CNS 2010). 2-EHA is not listed on Health Canada’s Cosmetic Ingredient Hotlist, a list of substances that are restricted or prohibited in cosmetics (Health Canada 2010).

In Canada, stannous 2-ethylhexanoate (CAS RN 301-10-0) may be used as a starting material for components that could possibly be found in coatings for cans and polystyrene trays, and zirconium 2-ethylhexanoate (CAS RN 22464-99-9) may be used as a starting material for components that could possibly be found in coatings, paint driers, and inks (2010 emails from Foods Directorate Health Canada to Risk Management Bureau, Health Canada; unreferenced). It should also be noted that according to the Food and Drug Regulations, no person shall sell any food in a package that has been manufactured from a polyvinyl chloride formulation containing an octyltin chemical (Canada 1978).

Releases to the Environment

Information reported under section 71 of CEPA 1999 indicated that for 2-EHA, approximately 1500 kg of this substance were released into the environment in 2006, primarily to air. Responses to the section 71 notice also reported a transfer of between 100 and 1 000 kg of 2-EHA as hazardous or recycled waste and approximately 23 000 kg as non-hazardous waste to off-site waste management facilities in 2006 (Environment Canada 2010a). Potential releases to water from both industrial and consumer use of products containing 2-EHA are further discussed in the Ecological Exposure Assessment section later in this report.

2-EHA may also be released from the biodegradation of plasticizers such as DEHP and DEHA (see Figure 2). Soil microbes readily oxidize 2-ethylhexanol to 2-EHA; however, the branched acid is degraded less readily (Nalli et al. 2002, 2006).

Information on the release and disposal of 2-EHA in Canada has not been reported through the National Pollutant Release Inventory (NPRI) to be above the reporting thresholds (Environment Canada 2008).

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Environmental Fate

Based on its physical and chemical properties (Table 2), its ionic characteristics and varied uses, 2-EHA is expected to be found primarily in water as a result of releases to the environment. Sediment and soil would tend not to be sinks for 2-EHA if it was released to water or soil (Staples 2001).

If released to the aquatic environment, 2-EHA is expected to remain in the water column owing to its high water solubility and low estimated log Koc. In addition, this substance is almost completely ionized at environmentally relevant pHs. The estimated acid dissociation constant (pKa) of 4.82 indicates that this substance primarily exists in its ionized (base or anionic) form in water, by giving up the proton from the hydroxyl group. The proportion of base form is greater than 94%, at a pH range of 6–9 (Environment Canada 2010b). Adsorption characteristics would be influenced by its ionic nature, and thus this substance would have limited affinity for suspended solids and would not tend to accumulate in bed sediments.

Similarly, if released to soil, this substance would have limited affinity for organic matter (which generally has a net negative charge) but could bind to some degree to positively charged soil particles (e.g., nitrogen containing complexes, metals). As a result, 2-EHA is expected to be moderately to highly mobile in soils.

When released to air, 2-EHA is not expected to remain in this compartment, and given its physical-chemical properties as an ionic substance, removal can occur due to both rain and photo-oxidation reactions. The air-water distribution is influenced by ambient pHs and 2-EHA’s pKa and would effectively result in negligible transfer of this substance into the air phase from other compartments at an environmentally relevant pH range. The low experimental Henry's Law constant suggests that the neutral form of 2-EHA would have low volatility from water and moist soil surfaces. The substance's Henry's law constant would be anticipated to be much lower than that of the neutral form under typical ambient pH conditions, given the expected predominance of the ionized form in the environment. However, its experimental vapour pressure for the neutral form is moderate suggesting that this form may volatilize to some degree from dry acidic soil surfaces.

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Persistence and Bioaccumulation Potential

Environmental Persistence

Tables 3a and 3b present the available biodegradation data, which indicate the half-life of 2-EHA in water, soil and sediment is likely to be much shorter than 182 days (6 months) and that the substance is not likely to persist in those environmental compartments.

Based on the available experimental data (Table 3a), the aerobic biodegradation of 2-EHA in water and sediment appears to occur fairly quickly. Model results were consistent and also predicted that this substance would biodegrade quickly in water (Table 3b). Decreases of 4 to 50% in initial 2-EHA concentrations ranging from 5.1 mg/L to 67.8 mg/L were observed after 21 days incubation in an aerobic mixed bacterial culture obtained from trench leachate at two waste disposal sites (Francis 1982). Waggy (1994) reported an aerobic biodegradation value of 83% (theoretical biochemical oxygen demand or ThBOD at 20 days) in an activated sludge (non-acclimated) after 20 days, with concentrations of 2-EHA of 3, 7, and 10 mg/L used. Companies reporting to the European Commission (2000) also indicated that this substance is rapidly degraded, with >95 to 100% ultimate degradation reported over 3 to 5 days in an activated sludge. In all of these cases, the original studies were not obtainable and data are presented as cited in other reports.

Table 3a. Empirical degradation data for 2-EHA

MediumFate processDegradation valueDegradation endpointReference
Aerobic
WaterPrimary biodegradation

(mixed bacterial culture from trench leachate)[a]
4% degradation;

21 days

(5.1 mg/L 2-EHA)
Francis 1982
WaterPrimary biodegradation

(mixed bacterial culture from trench leachate)[b]
16, 24% degradation;

21 days

(67.8 mg/L 2-EHA; nitrogen amended)
Francis 1982
WaterPrimary biodegradation

(mixed bacterial culture from trench leachate)[b]
50% degradation;

21 days

(with acclimation, 59.5 mg/L 2-EHA)
Francis 1982
WaterUltimate biodegradation

(activated, non-acclimated

sludge)[c]
60, 76, 83%ThBOD5,10,20 days[d]

(2.44 g O2/g 2-EHA)
Waggy 1994
WaterUltimate biodegradation (activated sludge)>95,

100
% degradation;

5 days (COD[e]) and Zahn-Wellens test,

3 days (TOD)
European Commission 2000
Anaerobic
WaterUltimate biodegradation

(anaerobic digester sludge)
92.3%COD average removal; 15 days

(8200 mg/L 2-EHA)
Yap et al. 1992
WaterUltimate biodegradation

(anaerobic digester sludge)
98% removal; 2 days; chemical analysis

(1 mg/L 2-EHA)
Chua and Chen 1995
WaterUltimate

biodegradation

(various digested sludge)
~100% mineralization; 12 days;

(36 g 2-EHA)
Mosche 2004
SedimentUltimate biodegradation

(soft clay, deep river sediment)
>98% removal; 15 days;

chemical analysis

(2.3 g/L 2-EHA)
Chua et al. 1998, 2001
[a] At a low-level radioactive waste disposal site in Maxey Flats, Kentucky; as cited in Syracuse Research Corporation’s biodegradation file; measured concentrations, pH 7, 28°C.
[b] At a low-level radioactive waste disposal site in West Valley, New York; as cited in Syracuse Research Corporation’s biodegradation file; measured concentrations, pH 7, 28°C.
[c] As cited in USEPA (2001, 2010); similar to OECD Guideline 301D; concentrations of 3, 7, and 10 mg/L used.
[d] ThBOD = theoretical biochemical oxygen demand
[e] COD = chemical oxygen demand

2-EHA also completely degrades in anaerobic systems (Chua and Chen 1995; Chua et al. 1995, 1998, 2001; Yap et al. 1992). Yap et al. (1992) designed an anaerobic biofilter to degrade a high strength simulated pharmaceutical wastewater containing 2-EHA (8200 mg/L initial concentration). The optimal performance of the biofilter was attained at 1.1 days hydraulic retention time (HRT), where the average chemical oxygen demand (COD) removal efficiency over 15 days was 92.3%. Periodic chemical analyses often showed less than 70 mg/L 2-EHA in the effluent. Chua and Chen (1995) developed a novel adsorption-anaerobiosis column system that effectively removed a concentration of 1000 mg/L of 2-EHA from contaminated water at an HRT of 2 days. In studying the degradation of surfactants, Mosche (2004) demonstrated almost complete anaerobic mineralization of 2-EHA using different inocula (digested sewage sludge, digested organic waste, and biofilm). 2-EHA (36 g) was added to biomass suspensions and concentrations were monitored. The substance disappeared after 12 days, and after a second addition of 36 g of the substance at this time, the added 2-EHA disappeared within the subsequent 5 days. The ultimate degradation of 2-EHA in anaerobic sediment of the Pearl River, southern China was studied in vitro with enrichment shake-flask cultures (Chua et al. 1998, 2001). Over the course of 15 days, almost all of the initial concentration of 2-EHA (2300 mg/L) was degraded, which was determined using theoretical values from chemical reaction stoichiometry. Chemical concentrations, methane and carbon dioxide levels were measured. The anaerobic degradation pathway of 2-EHA has been elucidated by Chua et al. (1995, 1996).

In other studies, various wastewater treatment systems have demonstrated the removal of 2-EHA, but such results may not necessarily be attributable to biodegradation, depending on the processes used and retention times. Also, some plasticizers present in the influents may also degrade to this substance over the course of these processes. The process streams and residues of a sewage treatment plant (STP) in Montreal, Québec, were investigated by Barnabé et al. (2008). Given the relatively short retention period of this treatment facility, which incorporates primary and physicochemical treatment steps, 2-EHA declined by 59% compared with influent concentrations and was still detected in the effluent at a concentration of 0.0148 mg/L. In another study, six other sewage treatment plants in Québec (equipped with various biological treatment systems) were studied and 2-EHA was measured in almost all sampled influents, effluents and sludge (Barnabé et al., unpublished data; see the Ecological Exposure Assessment section of this document for a summary). Ng et al. (1989) treated pharmaceutical wastewaters containing 2-EHA using a two-stage batch system, which effectively reduced this substance to non-detectable levels in less than 6 days. Finally, a combination of anaerobic treatment followed by aerobic treatment of tannery wastewater resulted in the complete removal of short-chain carboxylic acids, which included 2-EHA in the untreated wastewater at concentrations between 0.1 to 1 mg/L (Reemtsma and Jekel 1997).

Although experimental data on the degradation of 2-EHA are available, a QSAR-based weight-of-evidence approach (Environment Canada 2007) was also applied with the degradation models shown in Table 3b. Model results are generally consistent with the empirical information, indicating relatively rapid primary and ultimate biodegradation of 2-EHA.

Table 3b. Modelled degradation data for 2-EHA

Fate processModel and model basisModel result and predictionExtrapolated half-life (days)
Air
Atmospheric oxidationAOPWIN 2008[a]t 1/2 ~ 16 hours<2
Ozone reactionAOPWIN 2008[a]n/a[b] 
Water
HydrolysisHYDROWIN 2008[a]n/a[b] 
Primary biodegradation
Biodegradation (aerobic)BIOWIN 2008[a]

Sub-model 4: Expert Survey

(qualitative results)
4.3[c]

“biodegrades fast”
<182
Ultimate biodegradation
Biodegradation (aerobic)BIOWIN 2008[a]

Sub-model 3: Expert Survey

(qualitative results)
3.5[c]

“biodegrades fast”
<182
Biodegradation (aerobic)BIOWIN 2008[a]

Sub-model 5:

MITI linear probability
0.6[d]

“biodegrades fast”
<182
Biodegradation (aerobic)BIOWIN 2008[a]

Sub-model 6:

MITI non-linear probability
0.8[d]

“biodegrades fast”
<182
Biodegradation (aerobic)TOPKAT 2004

Probability
1[d]

“biodegrades very fast”
<182
Biodegradation (aerobic)CATABOL c2004–2008

% BOD

(biological oxygen demand)
% BOD = 59

“biodegrades fast”
<182
[a] EPIsuite (2008) using SMILES notation in Table 1.
[b] n/a: not available. Model does not provide an estimate for this type of structure.
[c] Output is a numerical score from 0 to 5.
[d] Output is a probability score.

When an extrapolation ratio of 1:1:4 for a water : soil : sediment biodegradation half-life (Boethling et al. 1995) is used, the ultimate degradation half-life in soil is also <182 days and the half-life in sediments is <365 days (based on an ultimate degradation half-life in water that is expected to be <90 days). This indicates that 2-EHA is not persistent in soil or sediment.

Abiotic degradation of 2-EHA, including indirect photolysis and hydrolysis, will not play a significant role in the environmental fate of this substance. Although this substance is not expected to reside in air, if released to air, the substance will react with hydroxyl radicals, with an estimated degradation half-life of 16 hours (Table 3b). The substance is not expected to react appreciably with other photo-oxidative species in the atmosphere (such as O3), nor is it likely to degrade via direct photolysis as predicted from the models in Table 3b and because that the substance does not contain chromophores that absorb at wavelengths greater than 290 nm (HSDB 1983–). The substance does not contain functional groups expected to undergo hydrolysis. Based on its short degradation half-life by reaction with hydroxyl radicals this substance is not considered to be persistent in air.

Based on the good agreement between empirical and modelled data (Tables 3a and 3b), there is a consistent line of evidence to suggest that 2-EHA does not meet the persistence criteria in air, soil, water, or sediment (half-life in air ≥ 2 days, half-lives in soil and water ≥ 182 days and half-life in sediment ≥ 365 days) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

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Potential for Bioaccumulation

Experimental log Kow values for 2-EHA suggest that this chemical has a low potential to bioaccumulate (see Table 2).

No experimental bioaccumulation factor (BAF) and/or bioconcentration factor (BCF) data for 2-EHA were available, so a predictive approach was applied with available BAF and BCF models as shown in Table 4. According to the Persistence and Bioaccumulation Regulations (Canada 2000), a substance is bioaccumulative if its BCF or BAF is ≥ 5000; however, measures of BAF are the preferred metric for assessing bioaccumulation potential of substances. BCFs may not adequately account for the bioaccumulation potential of substances via the diet, which predominates for substances with log Kow greater than ~4.0 (Arnot and Gobas 2003). The log Kow for 2-EHA is ~2.7. Kinetic mass-balance modelling is in principle considered to provide the most reliable prediction method for determining the bioaccumulation potential because it allows for correction for metabolic transformation as long as the log Kow of the substance is within the log Kow domain of the model.

BCF and BAF estimates for the neutral form of the substance, corrected for potential biotransformation or not, were generated with the BCFBAF model. This represents a worst-case condition for this substance (EPIsuite 2008) since it is expected to be present mainly in the less bioavailable, ionized form in the environment. Metabolic rate constants (kM) were derived by means of structure activity relationships described further in Arnot et al. (2008a, 2008b, 2009). Since metabolic potential can be related to body weight and temperature (Hu and Layton 2001; Nichols et al. 2007), the BCFBAF model further normalizes thekM for a 10-g fish at 15°C to the body weight of a fish in the middle trophic level fish in the Arnot-Gobas model (184 g) (Arnot et al. 2008b). The middle trophic level fish was used to represent overall model output as suggested by the model developer and is most representative of fish weight likely to be consumed by an avian or terrestrial piscivore. ThekM calculated with the BCFBAF QSAR for a 10-g fish at 15°C is ~1.3, which suggests a substantial rate of whole-body biotransformation even when further normalized to a 184-g fish (kM = 0.6 days-1); this is consistent with the chemical structure.

Table 4. Modelled bioaccumulation data for 2-EHA

Test organismEndpointWet weight value (L/kg)Reference
FishBAF

(neutral form)
31.3

(with metabolism)
Arnot and Gobas 2003 (Arnot-Gobas middle

trophic level)
50.7

(no metabolism)
FishBCF

(neutral form)
31.3

(with metabolism)
Arnot and Gobas 2003

(Arnot-Gobas

middle trophic level)
47.5

(no metabolism)
FishBCF

(corrected for metabolism)
135CPOPs 2008
FishBCF[a]

(ionizable organics)
1.12Fu et al. 2009
FishBCF

(accounts for ionization potential)
3.2BCFBAF 2008
[a] The regression equation for strong acids (pH 6) is log BCF = 0.34 logDow + 0.65; log Dow at pH 6 = 1.37.

All estimated BCFs and the BAF are much less than the 5000 threshold. The lowest BCFs were approximately 1 to 3 L/kg. These BCF values, which were estimated to account for ionization potential, were also much lower than those BCF or BAF values estimated for the neutral form of the substance. The available modelled evidence thus indicates that 2-EHA has a low bioaccumulation potential, which is consistent with 1) its low experimental log Kow value of 2.7 (for the neutral form), 2) the almost complete ionization of this substance in water at ambient pHs and 3) its expected fast rate of metabolism in fish.

Based on the available information, 2-EHA does not meet the bioaccumulation criterion (BCF or BAF ≥ 5000) as set out in thePersistence and Bioaccumulation Regulations (Canada 2000).

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Potential to Cause Ecological Harm

The acute and chronic toxicity of 2-EHA has been tested in five species of fish (including one test on embryos), an amphibian, an invertebrate, a green alga, a marine hydroid, a freshwater polyp, and bacteria. A summary of the experimental ecological effects is presented in Table 5.

Table 5. Empirical aquatic toxicity data for 2-EHA

Test organismTest typeEndpointValue (mg/L unless indicated otherwise)Reference
Fish
Fathead minnow

Pimephales promelas
Acute

(96 hours, static)
LC50[a]70

(pH 5.3–5.5)[b]
US EPA 2001, 2010
Chronic

(7 days)
IC25

(decreased body weight)
23.0

(12–25)
Horn et al. 2004
Carp

Cyprinus carpio
Acute

(45 hours)
NOEL>117

mg/kg-bw[c]

(no effects)
European Commission 2000
Rainbow trout

Oncorhynchus mykiss
Acute

(96 hours)
LC50150

(110–220)
Horn et al. 2004
Acute

(48–96 hours, static)
LC501801

(nominal)
European Commission 2000
Pumpkinseed

Lepomis gibbosus
Acute

(48–96 hours, static)
LC50270

(nominal)
European Commission 2000
Zebrafish

Brachydanio rerio, embryos
Chronic[d]

(31 hours)
MATC[e]8.65[*]Herrmann 1993
Amphibians
African clawed frog

Xenopus laevis, embryos
Acute

(96 hours, renewal)
EC50

(teratogenesis)
47.5

(44–51)
Dawson 1991
Acute

(96 hours, renewal)
LC50645.5

(496–759)
Dawson et al. 1996
Invertebrates
Water flea

Daphnia magna
Acute

(48 hours)
EC50[f]

(immobilization)
85.4

(79.8–91.4)

(nominal; 31.25–500 mg/L tested)
US EPA 2001, 2010
Acute

( 48 hours)
LC50120

(0–430)
Horn et al. 2004
Acute

(24–48 hours)
EC50

(immobilization)
85.4–116.6European Commission 2000
Chronic

(21 days)
NOEC25BASF 2009
Algae
Green alga

Scenedesmus subspicatus
Chronic

(72 hours)
EC50[b]

(biomass and growth rate)
49–61US EPA 2001, 2010
Chronic

(96 hours)
EC50[b]

(biomass and growth rate)
41–44US EPA 2001, 2010
Other animals
Marine hydroid HydractiniaAcute

(48 hours)
MATC

(embryogenesis)
57.7Berking 1991
Acute

(24 hours)
EC50

(metamorphosis)
1000Berking 1991
Freshwater polyp

Hydra
Acute

(2 days)
EC50

(head regeneration)
10.8Berking 1991
Microrganisms
Microtox assayAcute

(5 minutes)
EC50

(light generation)
43Nalli et al. 2002
Pseudomonas putidaChronic

(17 hours)
EC50

(respiration inhibition)
110European Commission 2000
Chronic

(30 minutes)
EC50

(respiration inhibition)
670European Commission 2000
Activated sludgeChronic

(30 minutes)
EC20

(respiration inhibition)
650European Commission 2000
Rhodococcus rhodochrousChronic

(200 hours)
EC50

(growth, reproduction)
>288.4

No effects
Nalli et al. 2006
[*] Value used to calculate the predicted no effects concentration.
[a] LC50 – The concentration of a substance that is estimated to be lethal to 50% of the test organisms.
[b] Test solutions were not buffered.
[c] Carp were force-fed doses of 88, 109, 117 mg/kg·bw of 2-EHA.
[d] This study was designated as a chronic endpoint because the embryo phase of zebra fish, and particularly its early stages, are short-lived. Zebra fish embryos hatch in 3 to 4 days, with most organs being developed within the first day. Treatment was started at stage 14 (there are 23 stages identified, with the early stage lasting about 20 minutes and the late stages – stages 19 to 23 – occurring from 17 to 28 hours). The animals were scored for retardation of development on day 2 whenever the control group had reached stage 23.
[e] MATC – The maximum allowable toxicant concentration, generally presented as the range between the NOEC(L) and LOEC(L) or as the geometric mean of the two measures.
[f] EC50 - The concentration of a substance that is estimated to cause some effect on 50% of the test organisms.

These experimental results are relatively consistent amongst all organisms tested, and the majority of acute and chronic effect concentrations spanned less than two orders of magnitude (8.65–670 mg/L; with the exception of the effect at 1000 mg/L). The lowest effect concentration was reported for zebrafish embryos (Herrmann 1993) where 2-EHA exposure led to a concentration-dependent retardation of embryonic development and a maximum allowable toxicant concentation (MATC) of 8.65 mg/L. This chronic value was used to derive the predicted no-effects concentration (PNEC) as described later in this report.

Daphnia magna and rainbow trout were exposed to serial dilutions (100, 50, 25, 12.5, and 6.25% by volume) of a solution of 1700 mg/L 2-EHA (Horn et al. 2004). The LC50 was determined after a 48-hour period for D. magna (120 mg/L) and a 96-hour period for rainbow trout (180 mg/L). In the same study, fathead minnows were exposed to serial dilutions (100, 50, 25, 12.5, and 6.25% by volume) of a solution of 86 mg/L 2-EHA. At a concentration of 23 mg/L, a 25% decline in body weight of fathead minnows was reported for the 7-day study.

The effect of 2-EHA alone or in combination with other carboxylic acids was investigated on Xenopus laevis embryo development (Dawson 1991). The single chemical and chemical mixtures were tested on three occasions in embryos from a different breeding pair for each of the three tests. Each treatment included five concentrations and a control, each with 25 embryos. The concentrations of 2-EHA tested were 0, 22, 44, 55, 66, and 88 mg/L. After an exposure period of 96 hours (with solution renewal every 24 hours), the embryos were fixed and the types of malformations were recorded. As found in previous investigations, the effect of carboxylic acids on total malformation induction was concentration-additive and the mixture of carboxylic acids (with 2-EHA) resulted in an EC50 value (5.7 mg/L) an order of magnitude lower than that obtained for 2-EHA tested alone (47.5 mg/L). At the highest concentration of 2-EHA tested (88 mg/L), malformations were observed in 80% of the embryos exposed, and microcephaly and abnormal gut coiling were the most commonly observed. The incidence of multiple defects was 42%.

Berking (1991) investigated the effects of 2-EHA (among other substances) on the developmental processes in hydroids, including the freshwater polyp Hydra and the marine hydroidHydractinia. Results showed that 2-EHA interfered with embryogenesis and metamorphosis in Hydractinia and caused head regeneration in Hydra.

Nalli et al. (2002) reported the acute toxicity of this substance based on the 5 minute Microtox assay, which involves the short-term incubation of 2-EHA with the luminescent marine bacterium Photobacterium phosphoreum. A concentration of 43 mg/L caused a 50% decrease in light output.

Modelled predictions for aquatic toxicity were also performed for 2-EHA. ECOSAR (2008) results for neutral organics (predicted values were multiplied by a factor of 10 owing to the existence of an acid moiety in the structure) included: fish (96-hour LC50), 159 mg/L; daphnid (48-hour LC50), 103 mg/L; and green alga (96-h EC50), 74 mg/L. Chronic toxicity values included: fish (30-day) 18 mg/L, daphnid 14 mg/L, and green algae 33 mg/L. TOPKAT results were deemed unreliable overall. Results from CPOPs (2008) included: D. magna(48-hour LC50), ≤10.7 mg/L; and fathead minnow (BCFmax LC50), ≤19.1 mg/L. The CPOPs model recognizes that reactive groups exist and that the substance may be more toxic than is the predicted baseline narcosis (i.e., the “less than value” is added to results). These predictions are consistent with the empirical data as discussed.

No ecological effects studies were found for 2-EHA in media other than water.

The majority of these results indicate that 2-EHA is moderately toxic to aquatic organisms (acute LC50s or EC50s > 1.0 mg/L and < 100 mg/L).

Ecological Exposure Assessment

Data concerning concentrations of 2-EHA in the Canadian environment and elsewhere have been identified (Table 6).

Table 6. Concentrations of 2-EHA in the environment

MediumLocation; yearConcentrationReference
Water/Effluent (mg/L)
Melted snowMontreal, Québec; 20040.0067Horn et al. 2004
River waterMontreal, Québec; 20040.0032
Creek waterMontreal, Québec; 20040.0012
Influent; wastewater treatment plants[a]Montreal, Québec; 20050.036Barnabé et al. 2008
Quebec City, Québec; 20050.004Barnabé et al. (unpublished data)
Gatineau, Québec0.068
Drummondville, Québec0.014
Granby, Québec0.013
Victoriaville, Québec0.009
Thetford Mines, Québec0.014
Effluent; wastewater treatment plants[a]Montreal, Québec; 20050.015Barnabé et al. 2008
Quebec City, Québec; 20050.039Barnabé et al. (unpublished data)
Gatineau, Québec0.044
Drummondville, Québec0.005
Granby, Québec0.007
Victoriaville, QuébecNot detected
Thetford Mines, QuébecNot detected
Sediment/Sludge (mg/kg)
River sedimentMontreal, Québec; 20040.110Horn et al. 2004
Homogenized sludge

(or primary)
Montreal, Québec; 200520.7Barnabé et al. 2008
Press-filtered sludge (or dewatered)Montreal, Québec; 200514.6
Primary sludgeQuébec; 2005

(three WWTPs)[b]
20–228Beauchesne et al. 2008
Secondary sludgeQuébec; 2005

(four WWTPs)
5–65Beauchesne et al. 2008
Thickened sludgeQuébec; 2005

(three WWTPs)
11–19Beauchesne et al. 2008
Digested sludgeQuébec; 2005

(three WWTPs)
5–30Beauchesne et al. 2008
Dewatered sludgeQuébec; 2005

(five WWTPs)
2–64Beauchesne et al. 2008
[a] Listed in decreasing order of population served.
[b] WWTP: wastewater treatment plant

2-EHA has been detected in precipitation, surface waters and river sediment in eastern Canada (Horn et al. 2004), along with common plasticizers such as di(2-ethylhexyl) adipate or DEHA. River sediments had the highest concentration of 2-EHA (0.110 mg/kg) but this substance was not observed in samples of a landfill leachate (which may be attributed to the anaerobic conditions of the landfill, as suggested by the authors). These authors suggest that the source of 2-EHA in these environmental samples is most likely from the biodegradation of the plasticizers DEHA and di(2-ethylhexyl) phthalate or DEHP.

In addition, 2-EHA has been measured in the influents, effluents and sludges of wastewater treatment plants (Barnabé et al. 2008; Barnabé et al. 2008 unpublished data; Beauchesne et al. 2008). Following primary and physico-chemical treatment at a sewage treatment plant in Montreal (Barnabé et al. 2008), about 43% of 2-EHA inputs were discharged in the effluent going into receiving surface waters (i.e., the St. Lawrence River), and about 5% was found in the dewatered sludge (which was subsequently incinerated). This substance was also found in the sludges from several WWTPs in Québec, in which measured concentrations ranged from 2–228 mg/kg in primary, secondary, digested, and dewatered sludges (Beauchesne et al. 2008).

Concentrations of 2-EHA were measured in the influent, effluent and sludge of six other WWTPs in Québec (Barnabé et al. unpublished data). The industrial contribution to influent was determined to be < 5% (for Québec City, Gatineau, and Victoriaville), 49% (Granby), and 60% (Drummondville). Concentrations ranged from 0.004 to 0.068 mg/L (influents), not detected to 0.044 mg/L (effluents), 0.005 to 0.019 mg/kg (untreated sludge; 4 plants), 0.005 to 0.03 mg/kg (digested sludge; 3 plants), and 0.002 to 0.064 mg/kg (dewatered sludge; 4 plants) (Barnabé et al., unpublished data; Beauchesne et al. 2008).

Industrial Release

The aquatic exposure of 2-EHA resulting from industrial activities is expected if the substance is released from industrial use to a WWTP and the treatment plant subsequently discharges its effluent to a receiving water body. The concentration of the substance in the receiving water near the discharge point of the WWTP is used as the predicted environmental concentration (PEC) in evaluating the aquatic risk of the substance. It can be calculated with the equation

Cwater-ind = [1000 × Q × L × (1 - R)] / [N × F × D]

where:

Cwater-ind is aquatic concentration resulting from industrial releases, mg/L
Q is total substance quantity used annually at an industrial site, kg/year
L is loss to wastewater, fraction
R is wastewater treatment plant removal rate, fraction
N is number of annual release days, days/year
F is wastewater treatment plant effluent flow, m3/day
D is receiving water dilution factor, dimensionless

A site-specific exposure analysis was conducted for the aquatic compartment at the five industrial sites reporting the highest industrial use quantities of 2-EHA. These sites were identified from the 29 companies who responded to the CEPA section 71 survey (Environment Canada 2010a). The uses of this substance varied amongst these sites and included either use as a lubricant and lubricant additive, an intermediate in an anti-tack agent, a gelling agent, a metal-working lubricant, a metal carboxylate (salt), an antifreeze additive, a substance to control ash clog in incinerator boilers, a dryer to promote polymerization, or in paint formulations. These top five industrial users each reported an annual use quantity of 2-EHA in the range of 10 000 to 1 000 000 kg/year. The selection of these sites is based on a general assumption that the quantity released is proportional to the quantity used and that these sites would represent a realistic worst-case scenario in Canada.

In this site-specific exposure analysis (Environment Canada 2010c), each site includes one facility, one WWTP, and one receiving water body. The PEC in the receiving water was estimated based on the concentration in the wastewater treatment effluent and by applying a dilution factor of up to 10. The concentration in the wastewater treatment effluent was estimated based on a fraction of the substance lost from the facility to a local municipal wastewater treatment plant, a wastewater treatment plant removal rate, and its effluent flow. The loss fraction was conservatively estimated to be in the range of 2.3 to 5% resulting from the chemical container handling operations and the industrial processes relevant to the facilities under consideration. This range is expected to represent the upper bound of the losses to wastewater, and the release from an actual facility is expected to be below this upper bound. The removal rate by a local WWTP is assumed to be zero in the case of unknown treatment and estimated by a computer model (Simple Treat 1997) to be 4.4% for primary treatment and 77.4% for secondary treatment. The effluent flow of a local WWTP is proportional to the population served and is in the range of 32 000 to 2 000 000 m3/day for the sites considered.

Based on the above assumptions, the PECs are estimated to be in the range of 0.23–16 µg/L for the top five industrial users of 2-EHA. An assumption for the frequency of release was also used in the estimation which is 250 days/year for the industrial users (small or medium sized facilities).

Consumer Release

As 2-EHA can be found in consumer and commercial products and is reported to be released to water, Mega Flush, Environment Canada’s spreadsheet tool, was employed to estimate the substance concentration in multiple water bodies receiving sewage treatment plant effluents to which consumer and commercial products containing the substance may have been released (Environment Canada 2009). The spreadsheet tool provides these estimates for approximately 1000 release sites across Canada based on the following assumptions:

The PEC of 2-EHA in the receiving water bodies was estimated to be in the range of 0.018–0.11 mg/L. The estimate is based on the expectation that a total of ~29 000 kg/year of the substance is used by residential and commercial consumers (i.e., the total quantity related to use in a consumer or commercial product, which does not include quantities used as an intermediate based on the assumption that the substance is no longer available). The equation and inputs used to calculate the PEC are described in Environment Canada (2010d).

Characterization of Ecological Risk

The approach taken in this ecological screening assessment was to examine various supporting 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 conservative risk quotient calculations, as well as information on persistence, bioaccumulation, toxicity, sources, and fate of the substance.

2-EHA is not expected to be persistent in air, water, soil or sediment. It is also expected to have a low bioaccumulation potential. The high importation volumes of 2-EHA into Canada, along with information on its uses and presence in wastewater effluents, indicate potential for widespread and continual release into the Canadian environment. Once released into the environment, it will be found mainly in water. It also has moderate potential for toxicity to aquatic organisms.

A predicted no-effect concentration (PNEC) was derived by dividing the chronic toxicity value of 8.65 mg/L (the most sensitive valid experimental value) for zebrafish embryos by an assessment factor of 100 (to account for interspecies and intraspecies variability in sensitivity, to estimate a long-term no-effects concentration, and to extrapolate from lab to field studies). The resulting PNEC value is 0.08 mg/L.

A risk quotient analysis, integrating conservative estimates of exposure in Canada with toxicity information (calculated as PEC/PNEC), was performed for the aquatic medium to determine whether there is potential for ecological harm in Canada. Measured concentrations of 2-EHA in river water, creek water, and snow near Montreal, Québec, compared with the PNEC, resulted in risk quotients of less than 0.1. PECs were calculated using the measured concentration of 2-EHA in effluents at a number of WWTPs in Québec, with a dilution factor of 10 applied to estimate the concentration in the receiving water (similar to the approach used in the site-specific industrial release scenarios). These analyses also resulted in risk quotients of much less than 1. The site-specific industrial scenarios presented (which considered the actual receiving water bodies) yielded PECs of 0.23–16 µg/L (Environment Canada 2010c). The resulting risk quotients for the five industrial sites evaluated ranged from 0.008 to 0.2. Therefore, harm to aquatic organisms is unlikely at these sites. Using a similar PEC/PNEC approach, the consumer release scenario tool predicted that PECs for 2-EHA would not exceed the PNEC in any water bodies receiving wastewater across Canada under low (10th percentile) flow conditions (Environment Canada 2010d).

This information suggests that 2-EHA is not causing harm to ecosystems in Canada.

Uncertainties in Evaluation of Ecological Risk

In assessing the persistence of this substance in the environment, some of the empirical data on primary aerobic biodegradation were contradictory, although complete details were not available to further evaluate these studies. The experimental data for ultimate aerobic and anaerobic biodegradation were however consistent and indicated the fast biodegradation of this substance by activated sludge. Model results were consistent and also predicted that this substance would biodegrade quickly in water.

The bioaccumulation assessment for 2-EHA is limited by the absence of experimental bioaccumulation data. This situation necessitated the use of models to generate predicted BCF and BAF values. Although all predictions have some degree of error, generally these models are relatively accurate and the metabolism-corrected model outputs confirmed that 2-EHA can be expected to have a low bioaccumulative potential.

There is the potential for this substance to partition to a limited extent to sediments and wastewater sludge (and hence potentially end up being applied to soil as biosolids), as indicated by the concentration data available. However, the effects data available apply only to aquatic organisms, and it is not feasible to calculate a PNEC for soil or sediment based on equilibrium partitioning theory as this substance ionizes. In addition, it is important to note that this substance is acidic, and depending on the quantity added to soil and the buffering capacity of the soil, could influence the acidity of the soil under moist conditions.

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Potential to Cause Harm to Human Health

Exposure Assessment

As 2-EHA is primarily an industrial intermediate (Bizzari et al. 2009), it is unlikely that measured concentrations of 2-EHA in environmental media and foods are due to uses of 2-EHA itself (CAS RN 149-57-5). 2-EHA is a breakdown product and/or metabolite of several high volume plasticizers, including DEHP and DEHA. For example, these plasticizers may undergo biodegradation to release 2-EHA in wastewater treatment plants. The substance is also released from products containing metal salts of 2-EHA.

Environmental Media and Foods

2-EHA was identified but not quantified in one ambient air study that collected five samples from three sites along the Niagara River (Hoff and Chan 1987). Based on the physical and chemical properties of 2-EHA and the release information reported under the section 71 survey, concentrations in air are not expected to be significant.

One report of 2-EHA measured in tap water in Montreal, Québec was identified; a single sample was collected and determined to contain 0.050 µg/L 2-EHA (Horn et al. 2004). The authors also reported concentrations of the substance in natural waters, snow and river sediment; the concentrations are presented in Table 6. A more recent publication from the group reports the concentration of 2-EHA in wastewater treatment plant influents (25.6–48.0 µg/L) and effluents (14.8 µg/L) (Barnabé et al. 2008). The tap water concentration was considered the most relevant value and was used to estimate intake of this substance by Canadians. Intake of 2-EHA is estimated to range from 0.0003 µg/kg-bw per day to 0.0053 µg/kg-bw per day for individual 12–19 years of age and formula-fed infants, respectively (see Appendix 1).

Reports of 2-EHA in terrestrial soil or house dust were not identified; one measurement of the substance in river sediment was identified (Table 6). This was not considered an appropriate surrogate because the low estimated Henry’s Law constant suggests the substance will have low volatility from moist soil while the moderate experimental vapour pressure suggests it will volatilize from dry soil.

No Canadian data on the presence of 2-EHA in foods were identified. There are two reports on levels of 2-EHA found in baby food and fruit juice packaged in glass jars sealed with metal lids on the European market (Elss et al. 2004; Ežerkis et al. 2007). The authors suggest that the substance migrates from the plastic seal, as 2-EHA salts are used as heat stabilizers in plastics. No association was observed between the concentration of 2-EHA measured and the composition (fat or water content) of the food product. An association between supplier and concentration was noted and the authors indicated that migration is most strongly influenced by technological processes such as thermal sterilization (Ežerkis et al. 2007). In 2004, the German Federal Institute for Risk Assessment (BfR) estimated the intake of 2-EHA by infants (weighing 7.5 kg) to range from 0.06 to 0.3 mg/kg-bw per day based on the results of Elss et al. (BfR 2004). In the Elss et al. (2004) report, 34 of 35 samples contained less than 0.6 mg/kg of 2-EHA, and one sample contained 3.2 mg/kg of 2-EHA in the food product. These values represent the intake range reported by BfR (2004); it is assumed that the entire 700 g/day diet contains these concentrations. In 2007, Ežerkis and coworkers reported measurements of 2-EHA in baby food from 13 European countries; in this study 53 of 63 samples (84%) contained <0.6 mg/kg of 2-EHA in the food product and the maximum concentration was 3.4 mg/kg ( Ežerkis et al. 2007). Generally these results are consistent with that of Elss et al. (2004); the increased incidence of concentrations greater than 0.6 mg/kg of 2-EHA in food products was primarily associated with a single supplier. Based on these data, exposure estimates were developed with 0.6 and 3.4 mg/kg of 2-EHA in food products representing 89% of samples and the maximum concentration reported, respectively. The highest exposure group is non-formula-fed infants 0–6 months of age with an estimated intake ranging from 19 to 107 µg/kg-bw per day, followed by the 0.5–4-year and 20–59- year age groups at 3.5–20 and 1.5–8 µg/kg-bw per day, respectively (see Appendix 1). These estimates were derived assuming the substance was only present in foods likely packaged in glass jars sealed with metal lids (e.g., baby food, fruit juice, condiments, jam, etc.).

Confidence in the characterization of exposure to 2-EHA via environmental media (air, water and soil) is low because neither air nor soil concentrations were identified and although the substance was measured in river sediment, this was not considered an appropriate surrogate. One measurement of the substance in tap water was identified, and while the data were from Canada, only one sample was taken. Confidence in the exposure via food is low because no Canadian values were identified, and only two publications describing concentrations of 2-EHA in European baby foods were identified. Confidence is high that the numerical intake estimate of exposure for the highest exposure group, non-formula-fed infants 0–6 months old, is conservative because the upper end of the intake estimate is based on the maximum concentration reported.

Consumer Products

Release of 2-EHA from products containing salts, esters and 2-ethylhexanol-based plasticizers is considered to be a source of general population exposure.

In Europe, the Danish Ministry of the Environment has measured the release of 2-EHA from a number of consumer products. 2-EHA was extracted by saliva stimulant from the surface of one wooden toy at a very low concentration, 3.2 µg of 2-EHA per gram surface material (Hansen and Pedersen 2005). It was also identified but not quantified in one brand of marker pen intended for children (Hansen et al. 2008). 2-EHAacid was reported to volatilize from several products containing polyvinyl chloride (PVC) such as clay when heated (Pors and Fuhlendorff 2002), household voltage converters (Malmgren-Hansen et al. 2003), artificial turf (Nilsson et al. 2008), and adult toys (Nilsson et al. 2006). Nilsson et al. (2006) reported that upper-bounding estimates of exposure for use of adult toys was up to 0.1 mg/kg-bw per day.

Consistent with these findings other groups have reported 2-EHA emissions from household products such as PVC-containing floor tiles and wall papers (Karpe et al. 1995; Kirchner and Karpe 1996), as well as lacquers and foils for furniture coating (Salthammer 1997). These studies did not provide sufficient information to form the basis of an exposure scenario.

Based on information submitted through the section 71 survey and on information in the literature, 2-EHA may be present in the following products available to the general public: alkyd paints, spray paints, paint driers, stains and antifreeze (HPD 2009a, 2009b; Environment Canada 2010a). Concentrations of 2-EHA were reported to range from 0.01% to <1% in liquid and spray paint products (Environment Canada 2010a). According to the Household Products Database (HPD) (2009a), 2-EHA concentrations ranged from <0.04% in a translucent stain (arts and crafts)to 1–5% in a paint drying product, and 1–8% in antifreeze.

Estimates of dermal and inhalation exposure to 2-EHA for adults (aged 20–59 years old) who used alkyd paint and spray paint were derived with the ConsExpo model (ConsExpo 2006) and are presented in Appendix 2. In addition to the use of ConsExpo (ConsExpo 2006), the U.S. Environmental Protection Agency’s Wall Paint Exposure Model (WPEM) software (US EPA 2001) was used to model consumer exposure from use of alkyd paint. The WPEM results were consistently lower; therefore, the ConsExpo model outputs were considered to provide a more conservative estimate of exposure. A range of potential 2-EHA concentrations (from 0.01 to 1%) in paint was used to provide a lower and upper estimate of exposure. Modelled estimates of dermal exposure to 2-EHA from use of alkyd paint ranged from 0.005 to 0.5 mg/kg-bw per event for paint containing 0.01 and 1% 2-EHA, respectively. Modelled estimates of dermally applied doses of 2-EHA from the use of spray paint ranged from 0.002 to 0.2 mg/kg-bw per event for paint containing 0.01% and 1% 2-EHA respectively. Modelled air concentrations (mean event) ranged from 0.08 to 8.2 mg/m3 from use of akyld paint, and from 0.03 to 3.4 mg/m3 from use of spray paint. Estimates of exposures from use of paint dryers, stains, and antifreeze were not derived because of a lack of available model parameters; however, the estimates presented for alkyd and spray paints are considered sufficient to account for acute exposures from these other potential consumer products.

According to the Cosmetic Notification System, 2-EHA is an ingredient in two temporary tattoos. The concentration of 2-EHA, mineral spirits, and 2-ethylhexanoate combined, ranged from 0.3 to 1% in one product and from 3 to 10% in the other (CNS 2010). Exposure estimates from the use of these products could not be derived because of the lack of 2-EHA specific concentration data in the products and the lack of model parameters.

Confidence in the modelled estimates is moderate as some data on specific Canadian products containing 2-EHA and the concentrations in the final products were identified; however, some scenarios could not be derived because of a lack of model parameters. Confidence is high that actual exposures from use of consumer products do not exceed the upper-bounding exposure estimates presented for paint products. Confidence is also high that exposure to 2-EHA from the use of CAS RN 149-57-5 in consumer products is low; however, confidence in the exposure to the 2-EHA moiety from sources such as 2-EHA salts is low as this assessment did not thoroughly investigate these substances. Several of these salts have been categorized as organic metal salts and will be assessed separately.

Health Effects Assessment

A summary of the available health effects information for 2-EHA is presented in Appendix 3. In view of the limited available database on 2-EHA, data on 2-ethylhexanol was also taken into consideration. Data on 2-ethylhexanol was considered relevant to the assessment of 2-EHA because 2-ethyhexanol is rapidly and extensively metabolized to 2-EHA via oxidation in vivo and subsequently undergoes biotransformation via the same metabolic pathway as 2-EHA (Albro 1975; Deisinger et al. 1994; BG Chemie 1999).

The European Commission has classified 2-EHA as Category 3 for developmental toxicity (causes concern for humans owing to possible developmental toxic effects) (European Commission 1995, 1996; ESIS c1995-2010). This classification was based on observed developmental effects, such as skeletal variations (wavy ribs, reduced ossification) and skeletal malformations (club foot) in rats following oral doses of 2-EHA given on days 6-19 of gestation. The studies are described below and are also presented in Appendix 3.

In an oral developmental toxicity study in which pregnant rats were exposed to 2-EHA at 0, 100, 300, or 600 mg/kg-bw per day via drinking water during days 6-19 of gestation, skeletal variations, such as wavy ribs and reduced cranial ossification, were observed in the absence of maternal toxicity at the lowest dose in fetuses. A dose-dependent increase in skeletal malformations (club foot) was also observed in fetuses (statistically significant at the highest and intermediate dose). The lowest-observed-adverse-effect level (LOAEL) for maternal toxicity in this study was 600 mg/kg-bw per day based on decreased maternal body weight gain (Pennanen et al. 1992). In another study, pregnant rats were administered 2-EHA by gavage during days 6 to 15 of gestation and exhibited skeletal variations (reduced ossification) at 250 mg/kg-bw per day in fetuses. Maternal toxicity (lethargy, ataxia, respiratory distress, and increased absolute and relative liver weight) was noted at 500 mg/kg-bw per day. In the range-finding study in rats done by the same authors, a LOAEL of 500 mg/kg-bw per day was identified based on reduction in fetal body weight and significant decrease in the percentage of living fetuses, and a LOAEL for maternal toxicity of 1000 mg/kg-bw per day based on mortality of seven out of eight (7/8) rats between days 7 and 9 of gestation was observed (Bushy Run 1988a; Hendrickx et al. 1993). In pregnant rats exposed to high dose levels, fetal malformations and early fetal deaths were also observed at 900 mg/kg-bw per day and higher. Although no effects in the dams were noted in one study, maternal deaths were observed at 1200 mg/kg-bw per day in the second study (Ritter et al. 1987; Narotsky et al. 1994). Rabbits appear less sensitive to developmental effects of 2-EHA. When New Zealand white rabbits were exposed to 2-EHA by gavage to 0, 25, 125, or 250 mg/kg-bw per day during gestation days 6 to 18, no developmental effects in fetuses were observed. However, the treatment-related death of 1/15 dams and the abortion by 1/15 dams was observed at 125 mg/kg-bw per day. Death of 1/15 dams and clinical signs of toxicity in surviving dams (lethargy, ataxia, respiratory distress and significant reduced body weight gain) were observed at 250 mg/kg-bw per day. In the range-finding study in rabbits, maternal toxicity was noted at 500 mg/kg-bw per day and higher, based on high mortality (Bushy Run 1988b; Hendrickx et al. 1993).

In addition, when pregnant rats and mice were exposed to 2-ethylhexanol by the oral route, similar developmental effects were observed. However, developmental effects were only seen at levels causing maternal toxicity. In pregnant rats administered 0, 130, 650, and 1300 mg/kg-bw per day of 2-ethylhexanol by gavage during days 6 to 15 of gestation, skeletal malformations, variations and retardations were noted at the highest dose. Increases in the number of resorption and post-implantation losses and a reduction in fetal weights were also observed at that dose, as well as a reduction in body weight gain in dams (BASF AG 1991l). In a study in which pregnant mice were exposed by gavage to 2-ethylhexanol at 0 (control) or 1525 mg/kg-bw per day during days 7-14 of gestation, significant reductions in the number of live pups and in their weight compared with controls were observed in the presence of maternal toxicity (Hazleton 1983; Hardin et al. 1987).

In these studies, the lowest oral LOAEL for developmental toxicity was 100 mg/kg-bw per day in fetuses of pregnant Han Wistar rats exposed to 2-EHA via drinking water, based on skeletal variations (wavy ribs and reduced cranial ossification) and malformations (club foot) (Pennanen et al. 1992). The lowest LOAEL for maternal toxicity, identified in rabbits, was 125 mg/kg-bw per day based on treatment related death and abortion in dams (Bushy Run 1988b; Hendrickx et al. 1993).

No data on the potential developmental toxicity via inhalation exposure to 2-EHA was identified. However, developmental effects were not reported in an inhalation study in which pregnant rats were exposed to 2-ethylhexanol at 850 mg/m3 for 7 hours/day, on days 1 to 19 of gestation. A lowest-observed-effect concentration (LOEC) for maternal toxicity was identified at the same dose level based on significant reduction in feed consumption in dams (Nelson et al. 1988, 1989, 1990).

No dermal developmental toxicity studies conducted with 2-EHA were identified. Dermal application of its parent compound, 2-ethylhexanol, at doses up to 2520 mg/kg-bw per day during gestation days 6-15 did not cause developmental toxicity in rats, but maternal toxicity was observed at 1680 mg/kg-bw per day based on decreased body weight gain in the dams (Bushy Run 1989; Fisher et al. 1989; Tyl et al. 1992). However, it has been reported that 2-ethylhexanol may be absorbed through the skin to a lesser extent than 2-EHA (Deisinger et al. 1994).

Effects on the male reproductive system were observed in rats exposed orally to 2-EHA. The lowest LOEL for reproductive toxicity was 100 mg/kg-bw per day based on reduction in sperm motility in male Han Wistar rats exposed via drinking water to 0, 100, 300, or 600 mg/kg-bw per day for 10 weeks before mating and 3 weeks during mating with treated females (Pennanen et al. 1992). A parental LOEL of 600 mg/kg-bw per day was identified based on reversible decreased body weight gain in females.

In short-term and subchronic studies, 2-EHA causes liver toxicity following oral administration in experimental animals. In a study in which rats were exposed to 2-EHA in the diet for 15 days, a dose-dependent increase in liver weight was observed in both sexes at doses of 706-2276 mg/kg-bw per day. Histological changes in the liver (cellular atrophy and necrosis) were also reported at 1351 mg/kg-bw per day (Eastman Kodak 1987c). In a 3-month study in rats, a slight (but statistically significant) reduction in body-weight gain in conjunction with reduced feed consumption was observed at the highest dose during the treatment period (917 mg/kg-bw per day). Increased relative liver weight in males and females was also observed at 303 mg/kg-bw per day and higher. Again, this increase was accompanied by histological changes in the liver (hepatocyte hypertrophy) in males from 303 mg/kg-bw per day and in females at the highest dose tested only, i.e., 1068 mg/kg-bw per day (Eastman Kodak 1988; Juberg et al. 1998). In rats exposed orally to 2-ethylhexanol for short-term or subchronic duration, reduced body weight and liver and stomach effects were among the principal effects observed. When rats were administered 2-ethylhexanol by gavage nine times over a period of 12 days, dose-dependent effects such as local damage to the stomach, effects on the immune system, and effects on the haematopoietic system were observed in both sexes at 275 mg/kg-bw per day and above (Bushy Run 1988c). In a 90-day study, in which rats were given 2-ethylhexanol in the diet, reduced body weight gain was observed at 500 mg/kg-bw per day, the highest dose tested (BASF AG 1991g, 1991h; Astill et al. 1996a). In this study, other effects in rats such as hepatic peroxisome proliferation and increases in relative liver and stomach weight were also observed. The lowest LOAEL for repeated-dose oral exposure was 275 mg/kg-bw per day as 2-ethylhexanol, based on effects on the stomach, immune system, and the haematopoeietic system in male and female rats.

No repeated-dose inhalation studies have been identified for 2-EHA. Inhalation of 2-ethylhexanol was investigated in one study. No treatment-related adverse effects were observed in rats exposed for 6 hours/day, 5 days/week, for 90 days at concentrations up to 120 ppm (638 mg/m3) (BASF AG 1992a).

Likewise, no short-term or subchronic dermal toxicity studies have been reported for 2-EHA. However, the LOAEL for dermal repeated-exposure to 2-ethylhexanol was 834 mg/kg-bw per day, the highest dose tested, based on lymphopenia, an increase in triglyceride levels, reduced spleen weight, and histopathological effects on the skin (exfoliation, acanthosis, hyperkeratosis, dermatitis, oedema, and eschar formation) in both sexes in rats (Bushy Run 1988c).

With regards to chronic toxicity studies (including carcinogenicity bioassays), no data are available for 2-EHA. In chronic lifetime studies in rats dosed by gavage with 2-ethylhexanol, no increased incidence of neoplastic lesions (liver adenomas, hepatocellular carcinomas) were noted at any tested concentrations (50, 150, or 500 mg/kg-bw per day). In a similar study in mice (dosed with 2-ethylhexanol by gavage at 50, 200, or 750 mg/kg-bw per day), a significant increase in hepatocellular carcinomas was observed in female mice at 750 mg/kg-bw per day when compared with the vehicle control group. However, the study investigators concluded that the tumours were spontaneous and not biologically relevant because the increase was not statistically significant when compared with the control group, historical controls, or relevant data from the literature, and no metastases were observed. No significant increase in incidence of hepatocellular carcinomas when compared with the control groups were observed in males (BASF AG 1991k, 1992b, 1992c, 1992d). In the published version of the same study (Astill et al. 1996b), the liver tumour findings in mice were reported slightly differently than those reported in the original study. Time-dependent and time-independent statistical analyses showed a weak adverse trend in the incidence of hepatocellular carcinomas in male and female mice at high dose levels. The time-adjusted incidence of hepatocellular carcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in female mice (13.1%) was outside the normal range (0.2%). It was concluded that 2-ethylhexanol was not carcinogenic in male mice and that a weak or equivocal carcinogenic response was observed in female mice. Non-cancer effects observed in rats included reduced body weight gain and isolated occurrences of mild clinical signs of toxicity in males and females at 150 mg/kg-bw per day, and increased mortality in females and reduced body weight gain, occurrence of clinical signs of toxicology, and significant increases in relative brain, stomach, kidney and liver weights occurred in both sexes at 500 mg/kg-bw per day (BASF AG 1992b, 1992c; Astill et al. 1996b). Non-neoplastic effects observed in mice included increased mortality, reduction in body weight gain, and effects on the blood count (slight increase in polynuclear neutrophils and a slight drop in lymphocytes) in both sexes at 750 mg/kg-bw per day. A significant change in some organ weights and foci in the liver and stomach were also noted after 13 months of exposure at that dose level (BASF AG 1991k, 1992d; Astill et al. 1996b). The LOAEL for non-neoplastic effects was 150 mg/kg-bw per day, based on increased mortality, reduced body weight gain, occurrence of clinical signs of toxicology, and a significant increase in some organ weights in rats.

In in vitro assays, 2-EHA was not mutagenic in bacterial mutation assays that used Salmonella typhimuriumand Escherichia coli, with and without metabolic activation (Hoechst 1982; Warren et al. 1982; Zeiger et al. 1988; JETOC 2000). Similarly, an assay for chromosomal aberration in Chinese hamster ovary cells in the absence of metabolic activation showed a negative response. However, in this assay, a weak positive result was observed in the presence of metabolic activation (NTP 1986, 1991). Positive results were also reported in assays for DNA damage and unscheduled DNA synthesis in rat hepatocytes in absence of metabolic activation, and for sister chromatid exchange (SCE) in Chinese hamster ovary cells in the presence and absence of metabolic activation (NTP 1986, 1991; Plant et al. 1998). Also, a weak positive result for SCE was noted in human lymphocytes in the absence of metabolic activation (Sipi et al. 1992).

In vivo assays for 2-EHA have not been identified in the literature. However, 2-ethylhexanol was not found to be genotoxic in in vivo assays in experimental animals. 2-Ethylhexanol produced negative results in a dominant lethal assay in mice exposed orally and did not cause DNA binding in the liver of mice given 2-ethylhexanol by gavage (Rushbrook et al. 1982; von Däniken et al. 1984). Also, no increase in the number of polychromatic erythrocytes containing micronuclei was seen in mice exposed to 2-ethylhexanol via intraperitoneal injection and negative results were obtained in a chromosome aberration assay in bone marrow cells of rats dosed orally (Litton Bionetics, Inc. 1982; Putman et al. 1983).

Based on the collective evidence on genotoxicity, especially the negative in vivo results for 2-ethylhexanol, it is considered that 2-EHA is not mutagenic.

No epidemiological data and no standard carcinogenicity assays in experimental animals have been identified for 2-EHA, and oral carcinogenicity studies in rats and mice using 2-ethylhexanol have reported only a weak or equivocal carcinogenic response in female mice. However, although a thorough analysis of the mode of action of 2-EHA is beyond the scope of this screening assessment, it has been shown that the compound induces peroxisome proliferation in rats and mice treated orally (see Appendix 3), and that a range of other peroxisome proliferators have induced liver cancer in rodents following longer-term administration. It is well established that the peroxisome proliferator-activated receptor PPARα plays a role in peroxisome proliferation-induced liver cancer (Corton and Lapinskas 2005). The relevance of the induction of PPARα and peroxisome proliferation by 2-EHA in rodents to health effects in humans remains to be established, as does the role of PPARs in reproductive toxicity. However humans are, in general, much less susceptible than rodents to peroxisome proliferation, suggesting that the peroxisome proliferating effects of 2-EHA in rodents are unlikely to be relevant to a human risk assessment (Klaunig et al. 2003).

2-EHA was not irritating to eyes in a study in rabbits (Hoechst 1985). Other studies showed that 2-EHA is severely irritating to the eye and capable of causing injury to the cornea, based on the results of studies in which the clinical signs (clouding of the cornea, severe reddening and oedema formation, iritis, and ocular discharge) were not reversible or not reversible in all animals within the 8- or 6-day observation periods (BASF AG 1953, 1967, 1978a, 1978b; BG Chemie 2000). Application of 2-EHA to the skin of rabbits resulted in severe irritation with erythema, oedema, and necrotic changes which were not reversible within the observation period or healed up only very slowly. Evaluation of skin irritancy by the various authors is extremely divergent, spanning all assessments from not irritating, mildly irritating, moderately irritating and severely irritating to corrosive (BASF AG 1953, 1967, 1978a, 1978b; Eastman Kodak 1955, 1986, 1987e; Mellon Institute 1972a, 1972b; Hoechst 1985; BG Chemie 2000).

Toxicokinetic studies on 2-EHA in rats showed that it is rapidly and extensively absorbed from the gastrointestinal tract. Following dermal exposure, absorption up to 50 % of the substance was observed 96 hours after application (English et al. 1998). 2-Ethylhexanol is equally rapidly and extensively absorbed after oral administration in rats, but only 5 to 6 % of the substance was absorbed 96 hours after dermal exposure (Deisinger et al. 1994). In the mouse and rat, 2-EHA exhibits preferential distribution in the kidneys, liver, and blood. In pregnant mice, 2-EHA is able to cross the placenta and can be detected in the embryos at concentrations similar to those in the dams (BG Chemie 2000). The toxicokinetics studies of 2-EHA also demonstrated that it is subjected to oxidative metabolism and glucuronidation. Metabolites are rapidly excreted, primarily in the urine. Also, evidence for incorporation of 2-EHA into normal cellular intermediary metabolism was obtained (English et al. 1998). Oxidative and conjugated metabolites of 2-EHA have also been identified in urine of humans exposed to 2-EHA from plasticizers (Walker and Mills 2001). Rapid elimination of 2-EHA after intraperitoneal administration to rats and mice and in workers exposed by the dermal and inhalation routes has been reported (Kröger et al. 1990; Pennanen and Manninen 1991). After intraperitoneal administration of 14C-labelled 2-EHA to rats and mice, radioactivity detected within 1-2 hours in the blood, liver and kidney was cleared rapidly (Pennanen and Manninen 1991). After repeated administration, there is a decrease in total elimination of 2-EHA and its metabolites, compared with single-dose administration. It has been suggested that repeated dosing induces oxidation of 2-EHA and results in the compound being incorporated into normal cellular metabolism to a greater extent (Eastman Kodak 1987e; English et al. 1989).

The confidence in the health effects database for 2-EHA is considered to be low to moderate, as the data for this substance are supported by data on 2-ethylhexanol. Dermal and inhalation exposure studies (short-term, subchronic and chronic toxicity, carcinogenicity and genotoxicity, reproductive toxicity, and developmental toxicity) are limited.

Characterization of Risk to Human Health

Based on consideration of the weight-of-evidence-based classification of 2-EHA by the European Commission as Category 3 for developmental toxicity (European Commission 1995, 1996; ESIS c1995-2010) and consideration of available relevant data for the substance as well as for 2-ethylhexanol, a critical effect for characterization of risk to human health for 2-EHA is developmental toxicity based on skeletal variations and malformations observed in rat fetuses. Accordingly, upper-bounding estimates of exposure (females) were compared with critical effect levels for developmental toxicity. In addition, effects including liver and stomach effects and reduced body weight gain were observed in experimental animals following repeated-dose exposures at higher dose levels of 2-EHA. Therefore, margins of exposure were also derived for the general population comparing upper-bounding estimates of exposures with the lowest effect levels for these non-developmental effects.

The main contributor to the estimate of total daily intake from environmental media and food for the general population of Canada (see Appendix 1) is the estimate of exposure from foods packaged in glass jars sealed with metal lids such as those used for baby food. Exposure from air, water, or soil is not considered significant because releases to air were very low, soil concentrations are expected to be low because 2-EHA is expected to volatilize from dry soil, and intake based on the one drinking water measurement was significantly lower than intake from food and beverages.

A comparison between the lowest oral LOAEL available for developmental toxicity in experimental animals (i.e., 100 mg/kg-bw per day) and the highest estimate of oral daily intake in females (20–59 years old; 8 µg/kg-bw per day) results in a margin of exposure of approximately 12 500. A comparison of the most conservative oral intake of 107 µg/kg-bw per day for non-formula-fed infants up to 0.5 years of age with the lowest LOAEL from a chronic oral study (i.e., 150 mg/kg-bw per day) results in a margin of exposure of approximately 1400. These margins are considered adequate to account for uncertainties in the health effects and exposure databases.

Estimates of exposure to 2-EHA for the general population of Canada from the use of consumer products such as alkyd paint may result in dermal and inhalation exposures. While inhalation or dermal developmental toxicity studies were not available for 2-EHA, there were developmental toxicity studies conducted via inhalation and dermal routes with the analogue 2-ethylhexanol which were considered appropriate for characterizing risk.

In a dermal developmental toxicity study conducted with 2-ethylhexanol, there was no evidence of toxicity to the developing young up to a maximum tested dose of 2520 mg/kg-bw per day (Bushy Run 1989; Fisher et al. 1989; Tyl et al. 1992). A comparison of the NOAEL (2520 mg/kg-bw per day) and the highest range of estimated dermal applied doses (0.005 to 0.5 mg/kg-bw per event for an acute exposure to 2-EHA while using alkyd paint) results in margins of exposure ranging from approximately 5000 to 500 000. There is uncertainty regarding the relative dermal absorption of 2-EHA and 2-ethylhexanol. However, these margins are considered adequate taking into consideration the exposure duration of the study relative to the exposure scenario for the general population and the absence of acute endpoints of concern in the animal database.

There is a possibility of acute inhalation exposure to 2-EHA when using paints. Given the lack of inhalation toxicity studies for 2-EHA, a developmental toxicity study with 2-ethylhexanol was used. In this study, no effects were observed in rat fetuses at the maximum tested dose of 850 mg/m3 after exposure for 7 hours/day on days 1 to 19 of gestation (Nelson et al. 1988, 1989, 1990). Comparing this NOAEL with the highest estimated range of mean event air concentrations during the use of alkyd paint products (0.08 to 8.2 mg/m3, an acute exposure event) results in margins of exposure ranging from 104 to 10 625. These margins are considered adequately protective of human health. As supporting information, a study of workers noted a maximum concentration of 0.7 mg/m3 2-EHA in the breathing zone of employees treating wood with the sodium salt of this substance (Kröger et al. 1990). Since these workers were using products with a higher concentration (26% by weight) and their activities involved working in an oven (temperature 60°C) and still recorded relatively low breathing zone concentrations of 2-EHA, the acute inhalation exposure and risk characterization noted above is considered highly conservative.

Uncertainties in Evaluation of Risk to Human Health

This screening assessment does not take into account all possible intraspecies and interspecies variation. However, the liver effects related to peroxisome proliferation which have been observed in mice and rats are unlikely to be relevant in human health risk assessment. There is uncertainty with the carcinogenicity of 2-EHA owing to the lack of long-term studies, although the available information from genotoxicity tests and carcinogenicity studies available for 2-ethylhexanol does not indicate a concern. In addition, dermal and inhalation exposure studies (short-term, subchronic, and chronic toxicity, carcinogenicity and genotoxicity, reproductive toxicity, and developmental toxicity) were limited.

There is uncertainty regarding the estimation of population exposure because of the lack of data, including the lack of Canadian data, and because models were used. No quantitative information on concentrations of 2-EHA in air or soil were identified, and only one drinking water value was identified. Intake estimates for food were based on two publications reporting 2-EHA concentrations in baby foods and fruit juices, which are not representative of a typical non-infant diet. Also, the intake estimates for infants may be over-estimates as Health Canada recommends that infants be exclusively breastfed and solids not introduced until 6 months of age (Health Canada 2005; Health Canada 2007). There is some uncertainty related to actual exposures from the use of certain consumer products containing 2-EHA (e.g., paint dryers, stains, and antifreeze) since model parameters were not available for all potential scenarios. However, confidence is high that these exposures would be lower than the ones presented for alkyd paint and spray paint. There is also uncertainty regarding exposure from use of temporary tattoos. In addition, there is uncertainty related to the total exposure of the general population to the 2-EHA moiety from sources including salts, esters, and plasticizers.

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Conclusion

Based on the information presented in this screening assessment, it is concluded that 2-EHA 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. Additionally, 2-EHA does not meet the criteria for persistence and bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

On the basis of the adequacy of the margins between upper-bounding estimates of exposure to 2-EHA and critical effects levels, it is concluded that 2-EHA be considered to be 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 2-EHA does not meet any of the criteria set out in section 64 of CEPA 1999.

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

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References

ACD/PhysChem Suite. 2009. Version 12.01. Advanced Chemistry Development, Inc. Toronto (ON): ACD/Labs. ACD/Labs.

Albro PW. 1975. The metabolism of 2-ethylhexanol in rats. Xenobiotica 5:625–636.

[AOPWIN] Atmospheric Oxidation Program for Windows [Estimation Model]. 2008. Version 1.92a. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Arnot JA, Gobas FAPC. 2003. A generic QSAR for assessing the bioaccumulation potential of organic chemicals in aquatic food webs. QSAR Comb Sci 22(3):337–345.

Arnot JA, Mackay D, Bonnell M. 2008a. Estimating metabolic biotransformation rates in fish from laboratory data. Environ Toxicol Chem 27(2):341–351.

Arnot JA, Mackay D, Parkerton TF, Bonnell M. 2008b. A database of fish biotransformation rates for organic chemicals. Environ Toxicol Chem 27(11):2263–2270.

Arnot JA, Meylan W, Tunkel J, Howard PH, Mackay D, Bonnell M, Boethling RS. 2009. A quantitative structure–activity relationship for predicting metabolic biotransformation rates for organic chemicals in fish. Environ Toxicol Chem 28(6):1168–1177.

Astill BD, Deckardt K, Gembardt CHR, Gingell R, Guest D, Hodgson JR, Mellert W, Murphy SR, Tyler TR. 1996a. Prechronic toxicity studies on 2-ethylhexanol in F344 rats and B6C3F1 mice. Fundam Appl Toxicol 29:31–39.

Astill BD, Gingell R, Guest D, Hellwig J, Hodgson JR, Kuettler K, Mellert W, Murphy SR, Sielken Jr RL, Tyler TR. 1996b. Oncogenicity testing of 2-ethylhexanol in Fisher 344 rats and B6C3F1 mice. Fundam Appl Toxicol 31:29–41.

Barnabé S, Beauchesne I, Cooper DG, Nicell JA. 2008. Plasticizers and their degradation products in the process streams of a large urban physicochemical sewage treatment plant. Water Res 42:153–162.

Barnabé S, Beauchesne I, Cooper DG, Nicell JA. (unpublished data). Fate of plasticizers and related metabolites in biological sewage treatment plants. Manuscript to be submitted for publication. Montreal (QC): McGill University. Available from: Jim A. Nicell, Associate Vice-Principal, University Services..

BASF AG. 1953. Gewerbehygienisch-Pharmakologisches Institut. Bericht über die toxikologische Prüfung der α-Aethylhexansäure. Unpublished report No. II/212 [cited in BG Chemie 2000].

BASF AG. 1967. Gewerbehygienisch-Pharmakologisches Institut. Ergebnis der gewerbetoxikologischen Vorprüfung – α-Aethylhexansäure. Unpublished report No. XVI/366 [cited in BG Chemie 2000].

BASF AG. 1978a. Safety data sheet alpha-ethylhexanoic acid. NTIS/OTS 0206619 [cited in BG Chemie 2000].

BASF AG. 1978b. Safety data sheet alpha-ethylhexansäure. NTIS/OTS 0206619 [cited in BG Chemie 2000].

BASF AG. 1991a. Report on the study of the oral toxicity of 2-ethylhexanol in rats after administration by gavage for 11 days (9 applications; solution in corn oil). Unpublished report No.11C0631/87104. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991b. Report on the study of the oral toxicity of 2-ethylhexanol in rats after administration by gavage for 11 days (9 applications). Unpublished report No.11C0631/87068. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991c. Report on the study of the oral toxicity of 2-ethylhexanol in rats after administration of microencapsulated material via the diet for 11 days. Unpublished report No.10C0321/88022. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991d. Report on the study of the oral toxicity of 2-ethylhexanol in mice after administration by gavage for 11 days (9 applications; solution in corn oil). Unpublished report No.16C0631/87105. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991e. Report on the study of the oral toxicity of 2-ethylhexanol in mice after administration by gavage for 11 days (9 applications). Unpublished report No.16C0631/87070. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991f. Report on the study of the oral toxicity of 2-ethylhexanol in mice after administration of microencapsulated material via the diet for 11 days. Unpublished report No.15C0321/88023. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991g. Report on the study of the oral toxicity of 2-ethylhexanol in rats after administration by gavage (aqueous emulsion) for 3 months. Unpublished report No.31C0631/87077. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991h. Report on a limited study of the oral toxicity of 2-ethylhexanol in rats after administration by gavage (aqueous emulsion) for 3 months. Unpublished report No.31C0631/87082. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991i. Report on the study of the oral toxicity of 2-ethylhexanol in mice after administration by gavage (aqueous emulsion) for 3 months. Unpublished report No.36C0631/87085. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991j. Report on a limited study of the oral toxicity of 2-ethylhexanol in mice after administration by gavage (aqueous emulsion) for 3 months. Unpublished report No.36C0631/87086. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991k. Report on the study of oncogenic potential of 2-ethylhexanol in mice after administration by gavage (aqueous emulsion) for 18 months. Unpublished report No. 68C0622/88038. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1991l.Study of the prenatal toxicity of isodecanol, 2-ethylhexanol and 711 alcohol (T.C.) in rats after oral administration (gavage). Report, Project No. 92R0753/88069. NTIS/OTS 0524016-2 [cited in BG Chemie 1999].

BASF AG. 1992a. Study on the inhalation toxicity of 2-ethylhexanol as a vapour in rats, 90-day test. Unpublished report No. 50l0044/89022. On behalf of BG Chemie. [cited in BG Chemie 2000].

BASF AG. 1992b. Report on the study of the oncogenic potential of 2-ethylhexanol in rats after administration by gavage (aqueous emulsion), 24 months study duration, satellite study. Unpublished report No. 99C0622/88045. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1992c. Report on the study of the oncogenic potential of 2-ethylhexanol in rats after administration by gavage (aqueous emulsion) for 24 months study. Unpublished report No.77C0622/88037. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF AG. 1992d. Report on the study of the oncogenic potential of 2-ethylhexanol in mice after administration by gavage (aqueous emulsion), 18 months study duration, satellite study. Unpublished report No. 99C0622/88049. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

BASF. 2007. Technical data sheet: 2-ethylhexanoic acid [Internet]. Mississauga (ON): BASF The Chemical Company. [created 2007 Oct; cited 2010 May].

BASF. 2009. Material safety data sheet: 2-ethylhexanoic acid [Internet]. Mississauga (ON): BASF The Chemical Company. [revised 2009 Apr 24; cited 2010 May].

[BCFBAF] Bioaccumulation Program for Windows [Estimation Model]. 2008. Version 3.00. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Beauchesne I, Barnabé S, Cooper DG, Nicell JA. 2008. Plasticizers and related toxic degradation products in wastewater sludges. Water Sci Technol 57(3):367–374.

Berking S. 1991. Effects of the anticonvulsant drug valproic acid and related substances on developmental processes in hydroids. Toxic in Vitro 5(2):109–117.

BfR. 2004. 2-Ethylhexanoic acid in baby food and fruit juices packed in glass containers. Risiken erkennen – Gesundheit schützen. Berlin (DE): BfR.

BG Chemie. 1999. 2-Ethylhexanol. In: Toxicological evaluations. Vol. 14. Berufsgenossenschaft der Chemischen Industrie. Berlin (DE): Springer Verlag. p. 103–157 [cited in BG Chemie 2000].

BG Chemie. 2000. Toxicological evaluation 2-ethylhexanoic acid. CAS RN 149-57-5. No. 275. [last updated 2000 Jun; cited 2008 May].

Billig E. 2003. Butyraldehydes [Internet]. Kirk-Othmer Encyclopedia of Chemical Technology, online version. [restricted access].

[BIOWIN] Biodegradation Probability Program for Windows [Estimation Model]. 2008. Version 4.10. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Bizzari SN, Blagoev M, Kishi A. 2009. CEH marketing research report: OXO Chemicals [Internet]. Menlo Park (CA): SRI Consulting (SRIC). [restricted access]

Boethling RS, Howard PH, Beauman JA, Larosche ME. 1995. Factors for intermedia extrapolations in biodegradability assessment. Chemosphere 30(4):741-752.

Bushy Run (Bushy Run Research Center). 1988a. Developmental toxicity evaluation of 2-ethylhexanoic acid administered by gavage to Fischer 344 rats. Report, Project No. 51-529. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 2000].

Bushy Run (Bushy Run Research Center). 1988b. Developmental toxicity evaluation of 2-ethylhexanoic acid administered by gavage to New Zealand white rabbits. Report, Project No. 51-530. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 2000].

Bushy Run (Bushy Run Research Center). 1988c. 2-Ethylhexanol (2-EH): nine-day dermal, oral gavage, and drinking water probe studies in rats. Report, Project No. 50-614. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999].

Bushy Run (Bushy Run Research Center). 1989. Developmental toxicity evaluation of 2-ethylhexanol administered cutaneously to Fisher 344 rats. Report, Project No. 51-578. On behalf of the Chemical Manufacturers Association. [cited in BG Chemie 1999]

Canada. 1978. Food and Drug Regulations, C.R.C., c. 870.

Canada. 1999. Canadian Environmental Protection Act, 1999. S.C., 1999, c. 33, Canada Gazette, Part III, Vol. 22, No. 3.

Canada. 2000. Canadian Environmental Protection Act, 1999: Persistence and Bioaccumulation Regulations, P.C. 2000-348, 23 March, 2000, SOR/2000-107, Canada Gazette, Part II, Vol. 134, No. 7.

Canada, Dept. of the Environment, Dept. of Health. 2006.Canadian Environmental Protection Act, 1999: Notice of intent to develop and implement measures to assess and manage the risks posed by certain substances to the health of Canadians and their environment. Canada Gazette, Part I, Vol. 140, No. 49.

Canada, Dept. of the Environment, Dept. of Health. 2009a.Canadian Environmental Protection Act, 1999: Notice of eleventh release of technical information relevant to substances identified in the Challenge. Canada Gazette, Part I, Vol. 143, No. 39.

Canada, Dept. of the Environment. 2009b. Canadian Environmental Protection Act, 1999: Notice with respect to Batch 11 Challenge substances. Canada Gazette, Part I, Vol. 143, No. 39.

[CATABOL] Probabilistic assessment of biodegradability and metabolic pathways [Computer Model]. c2004-2008. Version 5.10.2. Bourgas (BG): Bourgas Prof. Assen Zlatarov University, Laboratory of Mathematical Chemistry. CATALOGIC.

[CCOHS] Canadian Centre for Occupational Health and Safety. 1997. CHEMINFO: 2-ethylhexanoic acid. Hamilton (ON): Canadian Centre for Occupational Health and Safety. [revised 2009 Sep 10; cited 2010 May]. [restricted access]

Chua H, Chen YF. 1995. A novel adsorption–anaerobiosis column for the removal of persistent organics from contaminated water. Mar Pollut Bull 31(4–12):313–316.

Chua H, Yap MGS, Ng NJ. 1995. Modeling and simulation of mixed-culture interactions in anaerobiosis of inhibitory substrate. Appl Biochem Biotechnol 51/52:705–716.

Chua H, Yap MGS, Ng WJ. 1996. Bacterial populations and their roles in a pharmaceutical-waste anaerobic filter. Water Res 30(12):3007–3016.

Chua H, Lo W, Yu PHF. 1998. Fate of branched-chain fatty acids in anaerobic environment of river sediment. Appl Biochem Biotechnol 70/72:853–862.

Chua H, Yu PHF, Lo W, Ngai Sin S. 2001. The degradation of xenobiotic branched carboxylic acids in anaerobic sediment of the Pearl River in Southern China. Sci Tot Environ 266:221–228.

[CNS] Cosmetic Notification System [Proprietary Database]. 2010. Available from Health

Canada, Cosmetics Division.

[ConsExpo] Consumer Exposure Model [Internet]. 2006. Version 4.1. Bilthoven (NL): Rijksinstituut voor Volksgezondheid en Milieu (National Institute for Public Health and the Environment).

Corton JC, Lapinskas PJ. 2005. Peroxisome proliferator-activated receptors: mediators of phthalate ester-induced effects on male reproductive tract? Toxicol Sci 83:4–17.

[CPOPs] Canadian POPs Model. 2008. Gatineau (QC): Environment Canada, Ecological Assessment Division; Bourgas (BG): Bourgas Prof. Assen Zlatarov University, Laboratory of Mathematical Chemistry. [Model developed based on Mekenyan et al. 2005]. Available from: Environment Canada, Ecological Assessment Division.

Cragg ST. 2001. Aliphatic carboxylic acids, saturated [Internet]. Patty’s Toxicology, online version. [restricted access]

Dawson DA. 1991. Additive incidence of developmental malformation for Xenopus embryos exposed to a mixture of ten aliphatic carboxylic acids. Teratology 44:531–546.

Dawson DA, Schultz TW, Hunter RS. 1996. Developmental toxicity of carboxylic acids to Xenopus embryos: a quantitative structure–activity relationship and computer-automated structure evaluation. Teratogen Carcinogen Mutagen 16:109–124.

Deisinger PJ, Boatman RJ, Guest D. 1994. Metabolism of 2-ethyhexanol administered orally and dermally to the female Fisher 344 rat. Xenobiotica 24:429–440 [cited in BG Chemie 1999].

Dow. 2008. Product safety assessment: 2-ethylhexoic acid [Internet]. The Dow Chemical Company. [created 2008 Jun 23; cited 2010 May].

Eastman Kodak (Eastman Kodak Company). 1955. Unpublished data [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1966. Toxicity and health hazard summary, chemical: 2-ethyl hexanoic acid. NTIS/OTS 0206606 and NTIS/OTS 512928 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1982. Toxicity summary 2-ethylhexanoic acid. NTIS/OTS 0206606 and NTIS/OTS 512928 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1986. Dermal corrosivity test of 2-ethylhexanoic acid. Unpublished report No. TX-86-25 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1987a. Two-week oral (gavage) toxicity study of 2-ethylhexanoic acid in the rat. Report, EK Accession No. 904442, HAEL No. 87-0023. Eastman Kodak Company, Health and Environmental Laboratories, on behalf of Chemical Manufacturers Association. NTIS/OTS 0525547 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1987b. Two-week oral (gavage) toxicity study of 2-ethylhexanoic acid in the mouse. Report, EK Accession No. 904442, HAEL No. 87-0023. Eastman Kodak Company, Health and Environmental Laboratories, on behalf of Chemical Manufacturers Association. NTIS/OTS 0525547 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1987c. Two-week oral (dietary administration) toxicity study of 2-ethylhexanoic acid in the rat. Report, EK Accession No. 904442, HAEL No. 87-0023. Eastman Kodak Company, Health and Environmental Laboratories, on behalf of Chemical Manufacturers Association. NTIS/OTS 0525547 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1987d. Two-week oral (dietary administration) toxicity study of 2-ethylhexanoic acid in the mouse. Report, EK Accession No. 904442, HAEL No, 87-0023. Eastman Kodak Company, Health and Environmental Laboratories, on behalf of Chemical Manufacturers Association. NTIS/OTS 0525547 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1987e.Assessment of the condition of the skin after dermal exposure to 2-ethylhexanoic acid. Report, EK Accession No. 904442, HAEL No. 87-0023. Eastman Kodak Company, Health and Environmental Laboratories, on behalf of Chemical Manufacturers Association. NTIS/OTS 0525547 [cited in BG Chemie 2000].

Eastman Kodak (Eastman Kodak Company). 1988. 90-Day oral (dietary administration) toxicity study of 2-ethylhexanoic acid in the rat. Report, EK Accession No. 904442, HAEL No. 87-0023. Eastman Kodak Company, Health and Environmental Laboratories, on behalf of Chemical Manufacturers Association. NTIS/OTS 0525548 [cited in BG Chemie 2000].

Eastman. 2008. Product data sheet: Eastman 2-ethylhexanoic acid [Internet]. Eastman. [revised 2008 Dec 4; cited 2010 May].

Eastman. 2010. Material safety data sheet: Eastman™ 2-ethylhexanoic acid [Internet]. Eastman Chemical Company. [revised 2010 Feb 8; cited 2010 May].

[ECOSAR] Ecological Structural Activity Relationships [Internet]. 2008. Version 1.00. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Elss S, Grunewald L, Richling E, Schreier P. 2004. Occurrence of 2-ethylhexanoic acid in foods packed in glass jars. Food Add Contam 21(8):811–814.

English JC, Deisinger PJ, Perry LG, Guest D. 1989. Pharmacokinetic studies with [2-14C-hexyl]2-ethylhexanoic acid (14C-EHA) in the female Fisher 344 rat. Toxicologist 9:87 [cited in BG Chemie 2000].

English, JC, Deisinger PJ, Guest D. 1998. Metabolism of 2-ethylhexanoic acid administered orally or dermally to the female Fischer 344 rat. Xenobiotica 28:699–714.

Environment Canada. 2007. Guidance for conducting ecological assessments under CEPA, 1999. Science Resource Technical Series, Technical Guidance Module: QSARs. Reviewed Draft Working Document. Gatineau (QC): Environment Canada, Ecological Assessment Division. Available upon request.

Environment Canada. 2008. National Pollutant Release Inventory [database on the Internet]. Gatineau (QC): Environment Canada. [cited 2010 May]. National Pollutant Release Inventory.

Environment Canada. 2009. Guidance for conducting ecological assessments under CEPA, 1999. Science Resource Technical Series, Technical Guidance Module: Mega Flush Consumer Release Scenario. Working Document. Gatineau (QC): Environment Canada, Ecological Assessment Division. Available upon request.

Environment Canada. 2010a. Data for Batch 11 substances collected under the Canadian Environmental Protection Act, 1999, Section 71: Notice with respect to certain Batch 11 Challenge substances. Data compiled by: Environment Canada, Program Development and Engagement Division.

Environment Canada. 2010b. Ionization data for CAS RN 149-57-5. Unpublished report. Available from Environment Canada, Ecological Assessment Division, Gatineau (QC).

Environment Canada. 2010c. Site specific analysis report: CAS RN 149-57-5, June 2010. Unpublished report. Gatineau (QC): Environment Canada, Ecological Assessment Division. Available upon request.

Environment Canada. 2010d. Mega Flush report: CAS RN 149-57-5, June 2010. Unpublished report. Gatineau (QC): Environment Canada, Ecological Assessment Division. Available upon request.

[EPIsuite] Estimation Programs Interface Suite for Microsoft Windows [Estimation Model]. 2008. Version 4.00. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models.

[ESIS] European Chemical Substances Information System [database on the Internet]. c1995-2010. European Chemical Bureau (ECB). [cited 2010 Apr].

European Commission. 1995. Summary record: Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances.Ispra (IT): ECB, 14–16 February 1995. European Commission, Directorate General JRC, Joint Research Centre, Institute for Health and Consumer Protection, European Chemicals Bureau. ECBI/23/95 – Rev. 2.

European Commission. 1996. 2-ethylhexanoic acid. Commission Directive 96/54/EC of 30 July 1996. Annex II. Official Journal of the European Union. 30.9.96. L248/142. European Commission. 22nd ATP.

European Commission. 2000. IUCLID dataset [2-ethylhexanoic acid], CAS No. 149-57-5 [Internet]. Year 2000 CD-ROM edition. Ispra (IT): European Commission, Joint Research Centre, Institute for Health and Consumer Protection, European Chemicals Bureau. [cited 2010 Apr].

Ežerskis Z, Pastorelli S, Contini C, Simoneau C. 2007. Survey of 2-ethylhexanoic acid in baby food. Food Add Contam Part A 24:792–797.

Fisher LC, Tyl RW, Kubena MF. 1989. Cutaneous developmental toxicity study of 2-ethylhexanol (2-EH) in Fisher 344 rats. Teratology 39:83 [cited in BG Chemie 1999].

Francis AJ. 1982. Microbial transformation of low-level radioactive waste. In: Environmental migration of long-lived radionuclides. IAEA-SM-257/72. Vienna (AT); International Atomic Energy Agency. As cited in the Syracuse Research Corporation biodegradation database for CAS 149-57-5, accessed through ChemIDplus Advanced [database on the Internet].

Fu W, Franco A, Trapp S. 2009. Methods for estimating the bioconcentration factor of ionizable organic chemicals. Environ Toxicol Chem 28(7):1372–1379.

Hamdoune M, Duclos S, Mounie J, Santona L, Lhuguenot JC, Magdalou J, Goudonnet H. 1995. In vitro glucuronidation of peroxisomal proliferators: 2-ethylhexanoic acid enantiomers and their structural analogs. Toxicol Appl Pharmacol 131:235–243 [cited in BG Chemie 2000].

Hammock BD, Ota K. 1983. Differential induction of cytosolic epoxide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities. Toxicol Appl Pharmacol 71:254–265 [cited in BG Chemie 1999].

Hansen OC, Pedersen E. 2005. Migration and health assessment of chemical substances in surface treated wooden toys. Danish Ministry of the Environment, Environmental Protection Agency (Danish EPA). Survey of Chemical Substances in Consumer Products No. 60.

Hansen PL, TØnning K, Malmgren-Hansen B, Jacobsen E. 2008. Survey and health assessment of chemical substances in hobby products for children. Danish Ministry of the Environment, Environmental Protection Agency (Danish EPA). Survey of Chemical Substances in Consumer Products No. 93.

Hardin BD, Schuler RL, Burg JR, Booth GM, Hazelden KP, MacKenzie KM, Piccirillo VJ, Smith KN. 1987. Evaluation of 60 chemicals in a preliminary developmental toxicity test. Teratogen Carcinogen Mutagen 7:29–48 [cited in BG Chemie 1999].

Hazleton Laboratories America, Inc. 1983. Screening of priority chemicals for potential reproductive hazard. Report, study No.6125-101 through 6125-110. On behalf of the Center for Disease Control, Atlanta, GA. NTIS/PB 85-220143 [cited in BG Chemie 1999].

Health Canada. 1994. Human health risk assessment for priority substances. Ottawa (ON): Health Canada, Environmental Health Directorate.

Health Canada. 1998. Exposure factors for assessing total daily intake of priority substances by the general population of Canada. Unpublished report. Ottawa (ON): Health Canada, Environmental Health Directorate.

Health Canada. 2005. Transition to solid foods [Internet]. Ottawa (ON): Health Canada, [updated 2005 Dec 8; cited 2011 Feb].

Health Canada. 2007. Breastfeeding [Internet]. Ottawa (ON): Health Canada, [updated 2007 May 2; cited 2011 Feb].

Health Canada. 2010. The cosmetic ingredient hotlist June 2010 [Internet]. Ottawa (ON): Health Canada, Consumer Product Safety. [cited 2010 June]. Cosmetics and Personal Care.

Hendrickx AG, Peterson PE, Tyl RW, Fisher LC, Fosnight JJ, Kubena MF, Vrbanic MA, Katz GV. 1993. Assessment of the developmental toxicity of 2-ethylhexanoic acid in rats and rabbits. Fundam Appl Toxicol 20:199–209 [cited in BG Chemie 2000].

[HENRYWIN] Henry’s Law Constant Program for Microsoft Windows [Estimation Model]. 2008. Version 3.20. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Herrmann K. 1993. Effects of the anticonvulsant drug valproic acid and related substances on early development of the zebrafish (Brachydanio rerio). Toxic in Vitro 7(1):41–54.

Hodgson JR. 1987. Results of peroxisome induction studies on tri(2-ethylhexyl)trimellitate and 2-ethylhexanol. Toxicol Ind Health 3:49–60 [cited in BG Chemie 1999].

Hoechst (Hoechst AG, Pharma Forschung Toxikologie und Pathologie). 1982. Study of the mutagenic potential of the compound 2-ethylhexansäure in strains of Salmonella typhimurium(Ames test) and Escherichia coli. Unpublished report No. 275/82 [cited in BG Chemie 2000].

Hoechst (Hoechst AG, Pharma Forschung Toxikologie und Pathologie). 1985. 2-Ethylhexansäure – Prüfung auf Hautreizung am Kaninchen. Unpublished report No. 85.0591 [cited in BG Chemie 2000].

Hoechst (Hoechst AG, Pharma Forschung Toxikologie und Pathologie). 1986. 2-Ethylhexansäure – Prüfung der akuten dermalen Toxizität an der männlichen und weiblichen Wistar-Ratte. Unpublished report No. 86.1428 [cited in BG Chemie 2000].

Hoff PM, Chan KW. 1987. Measurement of polycyclic aromatic hydrocarbons in the air along the Niagara River. Environ Sci Technol 21:556–561

Horn O, Nalli S, Cooper D, Nicell J. 2004. Plasticizer metabolites in the environment. Water Res 38(17):3693–3698. 

[HPD] Household Products Database [database on the Internet]. 2009a. 2-Ethylhexanoic acid. Bethesda (MD): National Library of Medicine (US). [revised 2009 Sep; cited 2010 Jun].

[HPD] Household Products Database [database on the Internet]. 2009b. Cobalt 2-ethylhexanoate. Bethesda (MD): National Library of Medicine (US). [revised 2009 Sep; cited 2010 Jun].

[HSDB] Hazardous Substances Data Bank [database on the Internet]. 1983 – . Bethesda (MD): US National Library of Medicine. [revised 2003 Feb 14; cited 2010 May]. TOXNET - Databases on toxicology, hazardous chemicals, environmental health, and toxic releases.

Hu TM, Layton WL. 2001. Allometric scaling of xenobiotic clearance: uncertainty versus universality. AAPS PharmSci [Internet]. [2010 Jun]. Vol. 3(4): Article 29.

[HYDROWIN] Hydrolysis Rates Program for Microsoft Windows [Estimation Model]. 2008. Version 2.00. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

JETOC. 2000. Mutagenicity test data of existing chemical substances based on the toxicity investigation system of the industrial safety and health law. Supplement 2. Tokyo (JP): Japan Chemical Industry Ecology–Toxicology & Information Center.

Juberg DR, David RM, Katz GV, Bernard LG, Gordon DR, Vlaovic MS, Topping DC. 1998. 2-Ethylhexanoic acid: subchronic oral toxicity studies in the rat and mouse. Food Chem Toxicol 36:429–436 [cited in BG Chemie 2000].

Karpe P, Kirchner S, Rouxel P. 1995. Thermal desorption-gas chromatography-mass spectrometry-flame ionization detection-sniffer multi-coupling: a device for the determination of odorous volatile organic compounds in air. J Chromatogr A 708:105–114.

Keith Y, Canning PM, Lhuguenot JC, Elcombe CR. 1985. Peroxisome proliferation due to di-(2-ethylhexyl)adipate and 2-ethylhexanol. Hum Toxicol 4:551–552 [cited in BG Chemie 1999].

Keith Y, Cornu MC, Elcombe CR, Lhuguenot JC. 1988. Di-(2-ethylhexyl) adipate and peroxisome proliferation: identification of proximate peroxisomal proliferator in vivo and in vitro. Arch Toxicol Suppl 12:274–277 [cited in BG Chemie 2000].

Keith Y, Cornu MC, Canning PM, Foster J, Lhuguenot JC, Elcombe CR. 1992. Peroxisome proliferation due to di-(2-ethylhexyl)adipate, 2-ethylhexanol and 2-ethylhexanoic acid. Arch Toxicol 66:321–326 [cited in BG Chemie 1999, 2000].

Kirchner S, Karpe P. 1996. Contribution of volatile organic compounds to the odour of building materials. Indoor Air ’96 2:663–667.

Klaunig JE, Babich MA, Baetcke KP, Cook JC, Corton J, David RM, DeLuca JG, Lai DY, McKee RH, Peters JM, Roberts RA, Fenner-Crisp PA. 2003. PPAR-alpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 33(6):655–780.

[KOCWIN] The Soil Adsorption Coefficient Program [Estimation Model]. 2008. Version 2.00. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

[KOWWIN] Octanol-Water Partition Coefficient Program for Microsoft Windows [Estimation Model]. 2008. Version 1.67. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Kröger S, Liesivuori J, Manninen A. 1990. Evaluation of workers’ exposure to 2-ethylhexanoic acid (2-EHA) in Finnish sawmills. Int Arch Occup Environ Health 62:213–216 [cited in BG Chemie 2000].

Kyowa Hakko. 2009. Material safety data sheet: 2-ethylhexanoic acid. Tokyo (JP): Kyowa Hakko Chemical Company, Ltd.

Lake BG, Gangolli SD, Wright MG, Grasso P, Lloyd AG. 1974. Studies on the effects of the oral administration of di-(2-ethylhexyl)-phtalate on some hepatic enzymes in the rat. Biochem Soc Trans 2:322–325 [cited in BG Chemie 1999].

Lake BG, Gangolli SD, Grasso P, Lloyd AG. 1975. Studies on the hepatic effects of orally administered di-(2-ethylhexyl)-phtalate in the rat. Toxicol Appl Pharmacol 32:355–367 [cited in BG Chemie, 1999].

Litton Bionetics, Inc. 1982. Mutagenicity evaluation of 2-ethylhexanol (2-EH) in the mouse micronucleus test. [cited in Metal Carboxylates Coalition 2002].

Lundgren B, Meijer J, DePierre JW. 1987a. Characterization of the induction of cytosolic and microsomal epoxide hydrolases by 2-ethylhexanoic acid in mouse liver. Drug Metab Dispos 15:114–121 [cited in BG Chemie 2000].

Lundgren B, Meijer J, DePierre JW. 1987b.Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2-ethylhexanoic acid. Eur J Biochem 163:423–431 [cited in BG Chemie 2000].

Lundgren B, Meijer J, Birberg W, Pilotti A, DePierre JW. 1988a. Induction of cytosolic and microsomal epoxide hydrolases in mouse liver by peroxisome proliferators, with special emphasis on structural analogues of 2-ethylhexanoic acid. Chem Biol Interact 68:219–240 [cited in BG Chemie 2000].

Lundgren B, Meijer J, DePierre JW. 1988b. Induction of cytosolic and microsomal epoxide hydrolases in murine liver by known peroxisome proliferators and structurally related substances. Arch Toxicol Suppl 12:288–293 [cited in BG Chemie 2000].

Malmgren-Hansen B, Olesen, S, Pommer K, Funch L, Pedersen E, Willum O, Olsen S. 2003. Emission and evaluation of chemical substances from selected electrical and electronic products. Danish Ministry of the Environment, Environmental Protection Agency (Danish EPA). Survey of Chemical Substances in Consumer Products No. 32.

Manninen A, Kröger S, Liesivuori J, Savolainen H. 1989. 2-Ethylhexanoic acid inhibits urea synthesis and stimulates carnitine acetyltransferase activity in rat liver mitochondria. Arch Toxicol 63:160–161 [cited in BG Chemie 2000].

Mekenyan G, Dimitrov SD, Pavlov TS, Veith GD. 2005. POPs: a QSAR system for creating PBT profiles of chemicals and their metabolites. SAR QSAR Environ Res 16(1–2):103–133.

Mellon Institute. 1961a. Gross results of three months of inclusion of 2-ethyl hexanol in the diet of rats – special report. Report 23-61. Prepared on behalf of Union Carbide Corporation. NTIS/OTS 0515388 [cited in BG Chemie 1999].

Mellon Institute. 1961b. Results of three months of inclusion of 2-ethyl hexanol in the diet of rats. Report 24-8. Prepared on behalf of Union Carbide Corporation. NTIS/OTS 0515388 [cited in BG Chemie 1999].

Mellon Institute. 1972a. Miscellaneous toxicity studies. Report 35-15. Prepared on behalf of Union Carbide Corporation. NTIS/OTS 0512952 and 0206613 [cited in BG Chemie 2000].

Mellon Institute. 1972b. Miscellaneous toxicity studies. Results of Department of Transportation corrosive test (4-hour covered skin exposure). Report 35-67. Prepared on behalf of Union Carbide Corporation. NTIS/OTS 0512952 and 0206613 [cited in BG Chemie 2000].

Metal Carboxylates Coalition. 2002. U.S. High Production Volume (HPV) Chemical Challenge Program. Robust summaries for the metal carboxylates category. Prepared by MorningStar Consulting, Inc. on behalf of the Metal Carboxylates Coalition, a SOCMA affiliated consortium. 2002 December 20.

Moody DE, Azarnoff DL, Reddy JK. 1976. Induction of hepatic peroxisomes, peroxisome associated enzymes and hypolipidemia in rats treated with 2-ethyl hexanoic acid and 2-ethyl hexanol. J Cell Biol Abstract 1088 [cited in BG Chemie 1999].

Moody DE, Reddy JK. 1978. Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds. Toxicol Appl Pharmacol 45:497–504 [cited in BG Chemie 1999].

Moody DE, Reddy JK. 1982. Serum triglyceride and cholesterol contents in male rats receiving diets containing plasticizers and analogues of the ester 2-ethylhexanol. Toxicol Lett 10:379–383 [cited in BG Chemie 1999].

Mosche M. 2004. Anaerobic degradability of alcohol ethoxylates and related non-ionic surfactants. Biodegradation 15:327–336.

[MPBPVP] Melting Point Boiling Point Vapor Pressure Program for Microsoft Windows [Estimation Model]. 2008. Version 1.43. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Nalli S, Cooper DG, Nicell JA. 2002. Biodegradation of plasticizers by Rhodococcus rhodochrous. Biodegradation 13:343–352.

Nalli S, Cooper DG, Nicell JA. 2006. Metabolites from the biodegradation of di-ester plasticizers by Rhodococcus rhodochrous. Sci Tot Environ 366:286–294.

Narotsky MG, Francis EZ, Kavlock RJ. 1994. Developmental toxicity and structure–activity relationships of aliphatic acids, including dose-response assessment of valproic acid in mice and rats. Fundam Appl Toxicol 22:251–265 [cited in BG Chemie 2000].

[NCI] National Chemical Inventories [database on CD-ROM]. 2007. Issue 1. Columbus (OH): American Chemical Society. [cited 2009 Apr]. National Chemical Inventories.

Nelson BK, Brightwell WS, Khan A, Hoberman AM, Krieg EF. 1988. Teratological evaluation of 1-pentanol, 1-hexanol, and 2-ethyl-1-hexanol administered by inhalation to rats. Teratology 37:479–480 [cited in BG Chemie 1999].

Nelson BK, Brightwell WS, Khan A, Krieg EF, Hoberman AM. 1989. Developmental toxicology evaluation of 1-pentanol, 1-hexanol, and 2-ethyl-1-hexanol administered by inhalation to rats. J Am Coll Toxicol 8:405–410 [cited in BG Chemie 1999].

Nelson BK, Brightwell WS, Krieg EF. 1990. Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats. Toxicol Ind Health 6:373–387 [cited in BG Chemie 1999].

Ng WJ, Yap MGS, Sivadas M. 1989. Biological treatment of a pharmaceutical wastewater. Bio Wastes 29:299–311.

[NHW] Dept. of National Health and Welfare (CA). 1990. Present patterns and trends in infant feeding in Canada. Ottawa (ON): Department of National Health and Welfare. NHW Cat. No. H39-199/1990E. [cited in Health Canada 1998].

Nichols JW, Fitzsimmons PN, Burkhard LP. 2007. In vitro–in vivo extrapolation of quantitative hepatic biotransformation data for fish. II. Modeled effects on chemical bioaccumulation. Environ Toxicol Chem 26:1304-1319.

Nilsson NH, Malmgren-Hansen, Bernth N, Pedersen E, Pommer K. 2006. Survey and health assessment of chemical substances in sex toys. Danish Ministry of the Environment, Environmental Protection Agency (Danish EPA). Survey of Chemical Substances in Consumer Products No. 77.

Nilsson NH, Malmgren-Hansen B, Thomsen US. 2008. Mapping, emissions and environmental health assessment of chemical substances in artificial turf. Danish Ministry of the Environment, Environmental Protection Agency (Danish EPA). Survey of Chemical Substances in Consumer Products No. 100.

[NTP] National Toxicology Program (US). 1986. Annual plan for fiscal year [cited in BG Chemie 2000].

[NTP] National Toxicology Program (US). 1991. Unpublished data [cited in BG Chemie 2000].

Pennanen S, Manninen A. 1991. Distribution of 2-ethylhexanoic acid in mice and rats after an intraperitoneal injection. Pharmacol Toxicol 68:57-59 [cited in BG Chemie 2000].

Pennanen S, Tuovinen K, Huuskonen H, Komulainen H. 1992. The developmental toxicity of 2-ethylhexanoic acid in Wistar rats. Fundam Appl Toxicol 19:505–511 [cited in BG Chemie 2000; Metal Carboxylates Coalition 2002].

Plant NJ, Horley NJ, Savory RL, Elcombe CR, Gray TJB, Bell DR. 1998. The peroxisome proliferators are hepatocyte mitogens in chemically-defined media: glucocorticoid-induced PPARalpha is linked to peroxisome proliferator mitogenesis; Carcinogenesis 19:925–931.

Pors J, Fuhlendorff R. 2002. Mapping of chemical substances discharge when heating clay. Danish Ministry of the Environment, Environmental Protection Agency (Danish EPA). Survey of Chemical Substances in Consumer Products No. 14.

Putman DL, Moore WA, Schechtman LM, Hodgson JR. 1983. Cytogenic evaluation of di(2-ethylhexyl)phthalate and its major metabolites in Fischer 344 rats. Environ Mutagen 5:227–231 [cited in BG Chemie 1999].

Reemtsma T, Jekel M. 1997. Dissolved organics in tannery wastewaters and their alteration by a combined anaerobic and aerobic treatment. Water Res 31(5):1035–1046.

Ritter EJ, Scott WJ Jr, Collins MD, Nau H. 1987. Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine. Teratology 35:41–46 [cited in BG Chemie 2000].

[RIVM] Rijksinstituut voor Volksgezondheid en Milieu. 2007. Paint products fact sheet: to assess the risks for the consumer. Updated version for ConsExpo 4 [Internet]. Bilthoven (NL): RIVM (National Institute for Public Health and the Environment).RIVM Report No: 320104008/2007. [cited 2010 Jun].

Rushbrook CJ, Jorgenson TA, Hodgson JR. 1982. Dominant lethal study of di(2-ethylhexyl)phthalate and its major metabolites in ICR/SIM mice. Environ Mutagen 4:387 [cited in BG Chemie 1999].

Salthammer T. 1997. Emission of volatile organic compounds from furniture coatings. Indoor Air 7:189–198.

Schmidt P, Gohlke R, Rothe R. 1973. Zur Toxizität einiger C8-Aldehyde und –Alkohole. Z Gesamte Hyg 19:485–490 [cited in BG Chemie 1999].

SimpleTreat [Sewage Treatment Plant Removal Model]. 1997. Version 3.0. The National Institute for Public Health and the Environment (RIVM). Available from: Jaap Struijs, The National Institute for Public Health and the Environment (RIVM), Laboratory for Ecological Risk Assessment, PO Box 1, 3720 BA Bilthoven, The Netherlands, j.struijs@rivm.nl

Sipi P, Järventaus H, Norppa H. 1992. Sister-chromatid exchanges induced by vinyl esters and respective carboxylic acids in cultured human lymphocytes. Mutat Res 279:75–82 [cited in BG Chemie 2000].

Staples CA. 2001. A review of the environmental fate and aquatic effects of a series of C4 and C8 oxo-process chemicals. Chemosphere 45:339–346.

Sundberg C, Wachtmeiser CA, Lundgren B, DePierre JW. 1994. Comparison of the potencies of (+)- and (-)-2-ethylhexanoic acid causing peroxisome proliferation and related biological effects in mouse liver. Chirality 6:17–24 [cited in BG Chemie 2000].

[TOPKAT] TOxicity Prediction by Komputer Assisted Technology [Internet]. 2004. Version 6.2. San Diego (CA): Accelrys Software Inc.

Tyl RW, Fisher LC, Kubena MF, Vrbanic MA, Gingell R, Guest D, Hodgson JR, Murphy SR, Tyler TR, Astill BD. 1992. The developmental toxicity of 2-ethylhexanol applied dermally to pregnant Fisher 344 rats. Fundam Appl Toxicol 19:176–185 [cited in BG Chemie 1999].

Union Carbide. 1971. Data sheet 11/4/71 [cited in BG Chemie 2000].

[US EPA] U.S. Environmental Protection Agency. 2001. Robust study summaries and SIDS dossier for: 2-ethylhexanoic acid. CAS No. 149-57-5. Draft being prepared for the OECD (Organisation for Economic Co-operation and Development). Sponsor Country: USA. [date revised 2001 Jul].

[US EPA] U.S. Environmental Protection Agency. 2002. Category development and justification, and proposed test plan for the metal carboxylates category. Prepared by MorningStar Consulting, Inc., on behalf of the Metal Carboxylates Coalition. 2002 December 20. Submitted to the U.S. High Production Volume (HPV) Chemical Challenge Program. Washington (DC): US EPA, Office of Pollution Prevention and Toxics. Report No. 201-14172A.

[US EPA] U.S. Environmental Protection Agency. 2010. High production volume information system (HPVIS) [Internet]. Washington (DC): US EPA, Office of Pollution Prevention and Toxics. [cited 2010 Apr].

von Däniken A, Lutz WK, Jäckh R, Schlatter C. 1984. Investigation of the potential for binding of di(2-ethylhexyl) phthalate (DEHP) and di(2-ethylhexyl) adipate (DEHA) to liver DNA in vivo. Toxicol Appl Pharmacol 73:373–387 [cited in BG Chemie 2000].

Waggy GT. 1994. Union Carbide Chemicals and Plastics Company, Inc., South Charleston, WV. [cited in US EPA 2001].

Walker V, Mills GA. 2001. Urine 4-heptanone: a beta-oxidation product of 2-ethylhexanoic acid from plasticisers. Clin Chim Acta 306:51–61.

Warren JR, Lalwani ND, Reddy JK. 1982. Phthalate esters as peroxisome proliferators carcinogens. Environ Health Perspect 45:35–40 [cited in BG Chemie 2000].

[WSKOW] Water Solubility for Organic Compounds Program for Microsoft Windows [Estimation Model]. 2008. Version 1.41. Washington (DC): US Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models

Yap MGS, Ng WJ, Chua H. 1992. Performance of an anaerobic biofilter for 2-ethylhexanoic acid degradation. Bioresour Technol 41:45–51.

Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K. 1988. Salmonella mutagenicity tests: IV. Results from the testing of 300 chemicals. Environ Mol Mutagen 11 (Suppl 12):1–158 [cited in BG Chemie 2000].

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Appendix 1: Upper-bounding estimates of daily intake of 2-EHA by the general population in Canada (µg/kg-bw per day)

Route of exposure0–6 months[1], [2], [3]0.5–4 years[4]5–11 years[5]12–19 years[6]20–59 years[7]60+ years[8]
breast fedformula fednot formula fed
Air[9]N/A[10]N/AN/AN/AN/AN/A
Drinking water[11]N/A0.00530.00130.00060.00060.00030.00030.0003
Food and beverages[12]N/AN/A18.9–107.33.60–20.41.47–8.30.75–4.261.49–8.430.80–4.52
Soil[13]N/AN/AN/AN/AN/AN/A
Total intakeN/A<0.0118.9–107.33.60–20.41.47–8.30.75–4.261.49–8.430.80–4.52
[1] No data describing concentrations of 2-EHA in breast milk were identified.
[2] Assumed to weigh 7.5 kg, breathe 2.1 m3 of air per day, drink 0.8 L of water per day (formula fed) or 0.2 L/day (not formula fed) and ingest 30 mg of soil per day (Health Canada 1998).
[3] For exclusively formula-fed infants, intake from water is synonymous with intake from food. The concentration of 2-EHA in water used to reconstitute formula was based on a tap water measurement in Montreal, Québec (Horn et al. 2004). No data describing concentrations of 2-EHA in formula were identified. Approximately 50% of infants not formula fed are introduced to solid foods by 4 months of age and 90% by 6 months of age (NHW 1990, in Health Canada 1998).
[4] Assumed to weigh 15.5 kg, breathe 9.3 m3 of air per day, drink 0.2 L of water per day, and ingest 100 mg of soil per day (Health Canada 1998).
[5] Assumed to weigh 31.0 kg, breathe 14.5 m3 of air per day, drink 0.4 L of water per day, and to ingest 65 mg of soil per day (Health Canada 1998).
[6] Assumed to weigh 59.4 kg, breathe 15.8 m3 of air per day, drink 0.4 L of water per day, and ingest 30 mg of soil per day (Health Canada 1998).
[7] Assumed to weigh 70.9 kg, breathe 16.2 m3 of air per day, drink 0.4 L of water per day, and ingest 30 mg of soil per day (Health Canada 1998).
[8] Assumed to weigh 72.0 kg, breathe 14.3 m3 of air per day, drink 0.4 L of water per day, and ingest 30 mg of soil per day (Health Canada 1998).
[9] 2-EHA was identified but not quantified in one study that sampled along the Niagara River (Hoff and Chan 1987). Canadians are assumed to spend 3 hours outdoors each day (Health Canada 1998).
[10] N/A = not available
[11] One report of 2-EHA in drinking water was identified; the publication reported 0.050µg/L from a single sample of Montreal, Québec tap water (Horn et al. 2004).
[12] Estimates of intake from food are based upon concentrations in foods that are selected to represent the 12 food groups addressed in calculating intake (Health Canada 1998). Two reports describing concentrations of 2-EHA in baby food and fruit juices, products packaged in glass jars with metal lids, were identified (Elss et al. 2004; Ežerkis et al. 2007). The source of 2-EHA was determined to be the plastic gasket. Estimates of intake from food were based on food products considered to be packaged in glass jars sealed with metal lids: baby food, condiments, juice, beer, and sauces. The concentrations of 2-EHA in these products was estimated to range from 0.6–3.4 mg 2-EHA/kg food product, representing the >89% and the maximum concentration (Elss et al. 2004; Ežerkis et al. 2007). Amounts of foods consumed on a daily basis by each age group are described by Health Canada (Health Canada 1998).
[13] No information reporting the concentration of 2-EHA in soil or house dust was identified.

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Appendix 2: Estimates of exposures to 2-EHA from use of alkyd paint and spray paint

Consumer
product scenario
AssumptionsEstimated exposure
Alkyd paint (use brush/roller painting, high solid paint scenario from RIVM 2007)Concentration in paint product ranging from 0.01% to less than 1% (Environment Canada 2010a). One percent is used as an upper-bounding concentration.

Inhalation: evaporation from increasing area

Exposure duration of 132 minutes, application duration of 120 minutes, product amount of 1300 g, room volume of 20 m3, ventilation rate of 0.6/hour, release area of 10 m2, temperature of 20°C, Langmuir method for mass transfer rate, molecular weight matrix of 550 g/mol (RIVM 2007), vapour pressure of 4 Pa (refer to Table 2, footnote *) (US EPA 2010).

Dermal: constant rate

Contact rate of 30 mg/minute, release duration of 120 min (RIVM 2007)

Adult body weight of 70.9 kg (Health Canada 1998), inhalation rate of 36.7 m3/day (rate while doing light exercise a body weight of 70.9 kg) (RIVM 2007).
Inhalation – Mean

event concentration

0.08 to 8.2 mg/m3

Dermal – Acute

applied dose

0.005 to 0.5 mg/kg-bw per event
Spray paint (use spraying paint with a spray can from RIVM 2007)Concentration in paint product ranging from 0.01% to less than 1% (Environment Canada 2010a). One percent is used as an upper-bounding concentration.

Inhalation: spray model

Spray duration of 15 minutes, exposure duration of 20 minutes, room volume of 34 m3, room height or 2.25 m, ventilation rate of 1.5/hour, mass generation rate of 0.33 g/second, airborne fraction of 1 g/g, total fraction of non-volatile compounds in products of 0.3, mass density of total non-volatile compounds of 1.5 g/cm3, initial droplet distribution of 30 µm (coefficient of variance of 0.8), inhalation cut-off diameter of 15 µm (RIVM 2007), vapour pressure of 4 Pa (refer to Table 2, footnote *) (US EPA 2010).

Dermal: constant rate

Contact rate of 100 mg/minute, release duration of 15 minutes (RIVM 2007).

Adult body weight of 70.9 kg (Health Canada 1998), inhalation rate of 36.7 m3/day (rate while doing light exercise using a body weight of 70.9 kg) (RIVM 2007).
Inhalation – Mean

event concentration

0.03 to 3.4 mg/m3

Dermal – Acute

applied dose

0.002 to 0.2 mg/kg-bw per event

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Appendix 3: Summary of health effects information for 2-EHA

EndpointsLowest effect levels[a] / results
Acute toxicity

(2-EHA)
Lowest oral LD50(guinea pig) : >800-1600 mg/kg-bw (Eastman Kodak 1966, 1982)

Other oral LD50s : >1600-3640 mg/kg-bw from five studies (rat, guinea pig) (BG Chemie 2000)

Lowest inhalation LC50 (rat, guinea pig; 6 hours): >2356 mg/m3 (Eastman Kodak 1966, 1982).

Other inhalation LC50 : No other studies identified

Lowest dermal LD50 (rabbit): 1260 mg/kg-bw (Union Carbide 1971).

Other dermal LD50 : Two studies (rat, guinea pig), > 2000-6300 mg/kg-bw (BG Chemie 2000)
Short-term repeated-dose toxicity

(2-EHA)
Lowest oral LOAEL: 706 mg/kg-bw per day based on dose-dependent increase in liver weight in both sexes in F344 rat (five males and five females per dose) exposed in the diet to 0, 0.75, 1.5, or 3% (0, 706, 1351 or 2276 mg/kg-bw per day in males; 0, 756, 1411 or 2658 mg/kg-bw per day in females), for 15 days. This increase was accompanied with histological changes in liver (cellular atrophy and necrosis) at the highest and intermediate dose in both sexes (Eastman Kodak 1987c).

Oral LOEL: 9 mg/kg-bw per day based on dose-related increase in carnitine acetyltransferase activity and inhibition of citrulline biosynthesis in liver mitochondria in Wistar rats (five males per dose) exposed via drinking water to 0, 0.1, 1, 5, or 10 g/L (equivalent to 0, 33, 130, or 200 mg per day or 0, 9, 95, 370, or 570 mg/kg-bw per day using a dose conversion from Health Canada 1994) for 20 days (Manninen et al. 1989).

Other oral LOAEL: 800-1608 mg/kg-bw per day in mice or rat exposed for 15 days (Eastman Kodak 1987a, 1987d).

Other oral LOEL: 200-1600 mg/kg-bw per day in rat or mice exposed for 15 days (Eastman Kodak 1987a, 1987b). Also, numerous studies in the rat and mouse have demonstrated that oral administration of 2-EHA in the diet or by gavage for 3 to 21 days at dose levels ranging from 150 to 5332 mg/kg bw/day results in hepatic peroxisome proliferation, characterized by an increase in relative liver weight and elevated levels of various peroxisomal enzyme activities (Moody and Reddy 1978, 1982; Lundgren et al. 1987 a, 1987b, 1988 a, 1988b; Keith et al. 1988, 1992; Sunberg et al. 1994; Hamdoune et al. 1995).

No inhalation and dermal studies were identified.
Short-term repeated-dose toxicity

(2-ethylhexanol)
Lowest oral LOAEL: 275 mg/kg-bw per day based on dose-dependent effects such as local damage to the stomach, effects on the immune system and effects on the haematopoietic system in both sexes in F344 rats (10 males and 10 females per dose) dosed by gavage with 0, 0.1, 0.33, 1.0, and 1.5 mL/kg-bw (equivalent to 0, 83, 275, 834, and 1250 mg/kg-bw per day), 9 times over 12 days (Bushy Run 1988c).

Other oral LOAEL: 330 mg/kg-bw per day in rats exposed for 11, 17 and 22 days or mice exposed for 11 days (Schmidt et al. 1973; BASF 1991 a, 1991b, 1991c, 1991d, 1991e, 1991f)

Oral LOEL: 320-2857 mg/kg-bw per day in rats or mice exposed in the diet or by gavage for 7 to 21 days; hepatic peroxisome proliferation (increase in absolute and relative liver weight, increased activity of different liver enzymes) was observed (Lake et al. 1974, 1975; Moody et al. 1976; Moody and Reddy 1978, 1982; Hammock and Ota 1983; Keith et al. 1985, 1992; Hodgson 1987).

Lowest dermal LOAEL: 834 mg/kg-bw per day based on lymphopenia, reduced spleen weights and histopathological effects on the skin (exfoliation, acanthosis, hyperkeratosis, dermatitis, edema, and eschar formation) in both sexes in rats (10 males and 10 females per dose) exposed to 0, 0.5, or 1.0 mL (equivalent to 0, 417 or 834 mg) 2-ethylhexanol/kg-bw per day through dermal route for 9 times within 12 days. Other effects include increased triglyceride levels in both doses groups (Bushy Run 1988c).

Other dermal LOAEL: 1670 mg/kg-bw per day based on significant reductions in body weight, decreases in the relative and absolute thymus weight and histological effects on the liver, lungs, kidneys, heart, testes, thymus, and adrenal glands in rats (10 per group) exposed to 0 or 1670 mg/kg-bw per day through dermal route once daily, 5 days/week for 12 treatment days (Schmidt et al. 1973).

No inhalation studies were identified.
Subchronic toxicity

(2-EHA)
Lowest oral LOAEL: 917 mg/kg-bw per day based on reduced body weight gain (slight but statistically significant) in conjunction with reduced feed consumption in male and female F344 rats (10 males and 10 females per dose) exposed in the diet to 0, 0.1, 0.5, or 1.5% (0, 61, 303, or 917 mg/kg-bw per day in males; 0, 71, 360, or 1068 mg/kg-bw per day in females), for 91-93 days. A LOEL of 303 mg/kg-bw per day based on increased relative liver weight in both sexes accompanied with histological changes in liver (hepatocyte hypertrophy) at the highest and intermediate dose in males and in the highest dose only in females was also determined in this study (Eastman Kodak 1988; Juberg et al. 1998).

Other oral LOAEL: 1040 mg/kg-bw per day based on reduced body weight gain at the highest and intermediate dose in female and at the highest dose only in male B6C3F1 mice (10 males and 10 females per dose) exposed in the diet to 0, 0.1, 0.5, or 1.5% (0, 180, 885, or 2728 mg/kg-bw per day in males; 0, 205, 1038, or 3139 mg/kg-bw per day in females), for 91-93 days. A LOEL of 885 mg/kg-bw per day based on increased relative liver weight and histological changes in liver (hepatocyte hypertrophy and increased eosinophilia) in males and females was also determined. Changes in the epithelial cells of the proximal convoluted renal tubules in males and females kidneys and forestomach lesions in males at the highest dose were also observed (Eastman Kodak 1988; Juberg et al. 1998).

No inhalation and dermal studies were identified.
Subchronic toxicity

(2-ethylhexanol)
Lowest oral LOAEL: 500 mg/kg-bw per day based on reduced body weight gain in males and females F344 rats (10 males and 10 females per dose) given 0, 25, 125, 250 or 500 mg 2-ethylhexanol/kg-bw per day by gavage 5 days/week for 3 months. At this dose level, hepatic peroxisome proliferation was determined by measuring the increase in activity of hepatic cyanide-insensitive palmitoyl Coenzyme A in livers. Also, macroscopic examination revealed a slight increase in the number of individual and multiple foci in the mucosa of the forestomach. In addition, a small number of rats showed fatty infiltration at the margins of the liver lobes. At 250 mg/kg-bw per day, an increase in relative liver weight in males and females and increased relative stomach weight in females only was observed. Diminution in alkaline phosphatase activity and blood sugar in males and decrease in alanine aminotransferase activity in females was noted also at that dose level (BASF AG 1991g, 1991h; Astill et al. 1996a).

Other oral LOAEL: 833 mg/kg-bw per day based on increased absolute and relative liver weight and signs of liver and kidney damage (hyperaemic and/or swollen livers in females and degenerative effects in males’ kidneys) in DW rats (10 males and females per dose) exposed to 2-ethylhexanol in the diet to 0, 100, 500, 2500 or 12 500 ppm (equivalent to 0, 7, 33, 167, or 833 mg/kg-bw per day) for 90 days (Mellon Institute 1961a, 1961b).

Oral LOEL: 250 mg/kg-bw per day based on non-dose-dependent increased in relative stomach weight in males only in B6C3F1 mice (10 males and 10 females per dose) given 0, 25, 125, 250, or 500 mg 2-ethylhexanol/kg-bw per day by gavage 5 days/week for 3 months. At the highest dose, histological examination revealed mild focal or multi-focal acanthosis of the forestomach mucosa in two males and one female. No hepatic peroxisome proliferation was observed at all dose tested (BASF AG 1991i, 1991j; Astill et al. 1996a).

Inhalation NOAEL: 638 mg/m3 based on no treatment related toxic effects in both sexes in rats (10 males and 10 females per groups) exposed to 0, 15, 40, or 120 ppm (equivalent to 0, 80, 212, or 638 mg/m3), 6 hours/day, 5 days/week, for 90 days (BASF AG 1992a).

No other inhalation studies.

No dermal studies were identified.
Chronic toxicity/ carcinogenicity

(2-EHA)
No chronic study identified.
Chronic toxicity/ carcinogenicity

(2-EHA)
Oral study in rats: Groups of 50 F344 rats per sex were administered 0, 50, 150 or 500 mg 2-ethylhexanol/kg-bw per day in Cremophor EL by gavage 5 days/week for 24 months. At the top dose level, the sum of all primary benign and malignant tumours (liver adenomas, hepatocellular carcinomas) was clearly lower than that in either control group. Thus, no neoplastic lesions were attributed to exposure to 2-ethylhexanol in both male and female rats.

Non-neoplastic LOAEL: 150 mg/kg-bw per day based on reduced body weight gain in males and females and isolated occurrences of mild clinical signs of toxicity. Other non-neoplastic effects included increased mortality in females and reduced body weight gain and occurrence of clinical signs of toxicology in both sexes at 500 mg/kg-bw per day. Significant increase in relative brain, stomach, kidneys, and liver weights were also observed at the highest dose after 18 months (BASF AG 1992b, 1992c; Astill et al. 1996b).

Other oral studies: Groups of 50 B6C3F1 mice per sex were administered 0, 50, 200 or 750 mg 2-ethylhexanol/kg-bw per day in Cremophor EL by gavage 5 days/week for 18 months. No treatment-related differences from controls were observed in the incidence of liver adenomas in males and females but a significant increase in hepatocellular carcinomas (10% incidence) was observed in female mice at 750 mg/kg-bw per day compared with the vehicle control group. However, this increase was not statistically significant when compared with the water controls, the historical controls or the relevant data from the literature. As no metastases were observed either, the hepatocellular carcinomas were judged by the authors of the study to be spontaneous and biologically irrelevant. No significant increase in incidence of hepatocellular carcinomas (18% incidence) when compared with the control groups were observed in males. In the published version of the study by Astill et al. (1996b), the findings on the liver tumours in mice were reported slightly differently than those reported in the original study. Time-dependent and time-independent statistical analyses showed a weak adverse trend in the incidence of hepatocellular carcinomas in male and female mice at high dose levels. The time-adjusted incidence of hepatocellular carcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in female (13.1%) lay outside the normal range (0.2%). It was concluded that 2 ethylhexanol was nononcogenic in male mice and that a weak or equivocal oncogenic response was observed in female mice.

Non-neoplastic LOAEL: 750 mg/kg-bw per day based on increased mortality, reduction in body weight gain and effects on the blood count (slight increase in polynuclear neutrophils and a slight drop in lymphocytes) in both sexes. A significant change in some organ weight and foci in the liver and stomach were also noted after 13 months of exposure (BASF AG 1991k, 1992d; Astill et al. 1996b).

No inhalation or dermal studies were identified.
Reproductive toxicity

(2-EHA)
Lowest LOEL for reproductive toxicity: 100 mg/kg-bw per day based on reduction in sperm motility in male Han Wistar rats exposed via drinking water to 0, 100, 300 or 600 mg/kg-bw per day for 10 weeks before mating and 3 weeks during mating with females treated 2 weeks before mating, 3 weeks during mating, and for a further 3 weeks postpartum during the entire gestation and lactation period. An increase in sperm abnormality was observed at the highest and intermediate doses, although it was non-significant. A slight but dose-dependent decrease in fertility was also observed in females, but no information is given on the extent to which the effect on fertility was statistically significant. LOEL for systemic toxicity = 600 mg/kg-bw per day based on reversible decreased body weight gain in females (Pennanen et al. 1992).

Other study: No other oral studies

No inhalation or dermal studies were identified.
Developmental toxicity

(2-EHA)
Lowest oral LOAEL: 100 mg/kg-bw per day based on skeletal variations (wavy ribs and reduced cranial ossification) and increase in skeletal malformations (club foot) in fetuses of pregnant Han Wistar rats (20-21 females per group) exposed via drinking water to 0, 100, 300, or 600 mg/kg-bw per day during days 6-19 of gestation. The increase in club foot was dose-dependent and statistically significant at the highest and intermediate dose. Slight but significantly reduced foetal body weight was noted at 300 mg/kg-bw per day and higher. A maternal toxicity LOAEL of 600 mg/kg-bw per day based on decreased maternal body weight gain was identified (Pennanen et al. 1992).

Other oral study: A study in pregnant F344 rats (25 females per groups) dosed by gavage during gestation days 6 to 15 to 0, 100, 250, or 500 mg/kg-bw per day resulted in a LOEL of 250 mg/kg-bw per day based on skeletal variations (reduced ossification) in fetuses. LOAEL for maternal toxicity: 500 mg/kg-bw per day based on maternal lethargy, ataxia, respiratory distress, and increased liver weight (absolute and relative to corrected body weight). The range-finding study in rats conducted by the same authors find a LOAEL of 500 mg/kg-bw per day based on reduction in fetal body weight and significant decrease in the percentage of living fetuses. A maternal toxicity LOAEL of 1000 mg/kg-bw per day based on mortality of seven out of eight (7/8) animals between days 7 and 9 of gestation was identified (Bushy Run 1988a; Hendrickx et al. 1993).

In a study in pregnant New Zealand white rabbits (15 females per groups) exposed by gavage during gestation days 6 to 18 to 0, 25, 125, or 250 mg/kg-bw per day, no treatment-relatedeffects on developmental parameters were observed, although the LOAEL for maternal toxicity = 125 mg/kg-bw per day, based on the treatment-related death of 1/15 dams and the abortion by 1/15 dams. Death of 1/15 dams and clinical signs of toxicity in surviving dams (lethargy, ataxia, respiratory distress and significant reduced body weight gain) were observed at 250 mg/kg-bw per day. In the range-finding study in rabbits done by the same authors, there was no clear indication of developmental toxicity in the offspring. A maternal toxicity LOAEL of 500 mg/kg-bw per day based on high mortality (7 or 8/8 animals died) was identified (Bushy Run 1988b; Hendrickx et al. 1993).

In a study in Wistar rat (7-10 per groups) exposed by gavage on day 12 of gestation to 0, 900, and 1800 mg/kg-bw per day, fetal malformations and early fetal deaths at 900 mg/kg-bw per day and above was observed. No data on maternal toxicity was reported (Ritter et al. 1987).

In a study in Sprague-Dawley rat (15-20 per groups) exposed by gavage on days 6-15 of gestation to 0, 900, and 1200 mg/kg-bw per day, fetal malformations and early fetal deaths at 900 mg/kg-bw per day and above was observed. Maternal deaths were also observed at the highest dose (Narotsky et al. 1994).

No inhalation or dermal studies were identified.
Developmental toxicity

(2-ethylhexanol)
Lowest oral LOAEL: 1300 mg/kg-bw per day based on skeletal malformations, variations, and retardations in fetuses of pregnant Wistar rats (10 females per group) dosed by gavage during gestation days 6 to 15 to 0, 130, 650, and 1300 mg 2-ethylhexanol/kg-bw per day. Increases in the number of resorption and post-implantation losses and reduction in fetal weights were also observed at 1300 mg/kg-bw per day.LOAEL for maternal toxicity = 1300 mg/kg-bw per day based on decreased body weight gain in the dams during the second half of the treatment period (BASF AG 1991l).

Other oral studies: A study in pregnant CD-1 mice (50 females per group) dosed by gavage during days 7-14 of gestation to 0 (control) or 1525 mg 2-ethylhexanol/kg-bw per day resulted in a LOAEL of 1525 mg/kg-bw per day based on significant reductions in the number of live pups and in their weight compared with the controls. LOAEL for maternal toxicity = 1525 mg/kg-bw per day based on deaths (of the 50 mice treated, 18 died during the study and the investigators attributed the deaths of 17 of these animals to 2-ethylhexanol), reduced body weight, reduced movement, ataxia, hypothermia, unkempts coats and blood in the urine (Hazleton 1983; Hardin et al. 1987).

Inhalation NOAEL: 850 mg/m3. 2-Ethylhexanol was neither teratogenic nor embryotoxic in fetuses of pregnant Sprague-Dawley rats (15 females per group) exposed by inhalation to 0 or 200 ppm (equivalent to 850 mg/m3, according to the investigators), 7 hours/day, on days 1 to 19 of gestation. LOEL for maternal toxicity = 850 mg/m3 based on significant reduction in feed consumption (Nelson et al. 1988, 1989, 1990).

No other inhalation studies were identified.

Dermal NOAEL: 2520 mg/kg-bw per day based on no treatment-related increases in external, visceral, or skeletal malformations or variations in pregnant F344rats (25 females per group) exposed to 0, 252, 420, 840, 1680, or 2520 mg 2-ethylhexanol/kg-bw per day through dermal route during gestation days 6-15. LOAEL for maternal toxicity = 1680 mg/kg-bw per day based on decreased body weight gain in the dams (Bushy Run 1989; Fisher et al. 1989; Tyl et al. 1992).
No other dermal studies were identified.
Genotoxicity and related endpoints: in vivo

(2-ethylhexanol)
Micronuclei

Negative:
polychromatic erythrocytes; B6C3F1 male and female mice; intraperitoneal (0 or 436 mg/kg-bw, once or twice within 24 hours) (Litton Bionetics Inc. 1982).

Dominant lethal assay

Negative: Male ICR/SIM mice; oral (0, 250, 500 or 1000 mg 2-ethylhexanol/kg-bw per day, on five consecutive days) (Rushbrook et al. 1982).

DNA binding

Negative: No activity attributable to covalent binding to DNA was detected in the liver in mice given 110 or 120 mg 14C-labelled ethylhexanol/kg-bw per day by gavage or in the liver in rats given 51 or 52 mg 14C-labelled ethylhexanol/kg-bw per day by gavage after a pre-treatment for 4 weeks with 1 % di(2-ethylhexyl) phthalate in the diet (von Däniken et al. 1984).

Chromosome aberration assay

Negative: Bone marrow cells; male and female F344 rats; oral (0.02, 0.07, or 0.2 mL 2-ethylhexanol (equivalent to 16.7, 58.9 and 167 mg/kg-bw per day) for 5 days) (Putman et al. 1983).
Genotoxicity and related endpoints: in vitro

(2-EHA)
Mutagenicity in bacteria

Negative:
Salmonella typhimurium, strains TA97, TA98, TA100, and TA1535, with and without activation (Zeiger et al. 1988).

Negative: S. typhimurium, strains TA98, TA100, TA1535, and TA1537, with and without metabolic activation (JETOC 2000).

Negative: S. typhimurium, strains TA98 and TA100, with and without metabolic activation (Warren et al. 1982).

Negative: S. typhimurium, strains TA98, TA100, TA1535, TA1537, and TA1538, with and without metabolic activation (Hoechst 1982).

Negative: Escherichia coli, strain WP2uvrA/pKM101, with and without metabolic activation (JETOC 2000).

Negative: E. coli, strain WP2uvrA, with and without activation (Hoechst 1982).

DNA damage

Positive: Rat hepatocytes, in absence of metabolic activation (Plant et al. 1998).

Positive: Unscheduled DNA synthesis in rat hepatocytes, in absence of metabolic activation (Plant et al. 1998).

Chromosome aberration assay

Negative: Chinese hamster ovary cells in absence of metabolic activation (NTP 1986, 1991).

Weak positive: Chinese hamster ovary cells in presence of metabolic activation (NTP 1986, 1991).

Sister chromatid exchanges (SCE) assay

Positive: Chinese hamster ovary cells in presence and absence of metabolic activation (NTP 1986, 1991).

Weak positive: Human lymphocytes in absence of metabolic activation (Sipi et al. 1992).
SensitizationNo evidence that 2-EHA has sensitizing potential (Hoechst 1986; BASF AG 1997).
IrritationSkin irritation

Application of 2-EHA to the skin of rabbits resulted in severe irritation with erythema, edema, and necrotic changes which were not reversible within the observation period or healed up only very slowly. Evaluation of skin irritancy by the various authors is extremely divergent, spanning all assessments from not irritating, mildly irritating, moderately irritating, and severely irritating to corrosive (BASF AG 1953, 1967, 1978a, 1987b; Eastman Kodak 1955, 1986, 1987e; Mellon Institute 1972a, 1972b; Hoechst 1985; BG Chemie 2000).
Eye irritation

2-EHA was not irritating to eye in a study in rabbit (Hoechst 1985). Other studies showed that 2-EHA is severely irritating to the eye and capable of causing injury to the cornea, based on the results of studies in which the clinical signs (clouding of the cornea, severe reddening and oedema formation, iritis and ocular discharge) were not reversible or not reversible in all animals within the 8- or 6-day observation periods (BASF AG 1953, 1967, 1978a, 1987b; BG Chemie 2000).
Human studiesNo relevant human studies were identified.
[a]Definitions; LD50: median lethal dose; LOEL/LOEC: lowest-observed-effect level/concentration; LOAEL/LOAEC: lowest-observed-adverse-effect level/concentration; NOAEL/NOAEC: no-observed-adverse-effect level/concentration.

Footnotes

[1] The Chemical Abstracts Service Registry Number (CAS RN) is the property of the American Chemical Society and any use or redistribution, except as required in supporting regulatory requirements and/or for reports to the government when the information and the reports are required by law or administrative policy, is not permitted without the prior, written permission of the American Chemical Society.
[2] A determination of whether one or more of the criteria of section 64 are met is based upon an assessment of potential risks to the environment and/or to human health associated with exposures in the general environment. For humans, this includes, but is not limited to, exposures from ambient and indoor air, drinking water, foodstuffs, and the use of consumer products. A conclusion under CEPA 1999 on the substances in the Chemicals Management Plan (CMP) Challenge Batches 1-12 is not relevant to, nor does it preclude, an assessment against the hazard criteria specified in the Controlled Products Regulations, which is part of the regulatory framework for the Workplace Hazardous Materials Information System (WHMIS) for products intended for workplace use. Similarly, a conclusion based on the criteria contained in section 64 of CEPA 1999 does not preclude actions being taken under other sections of CEPA or other Acts.

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