2-Ethyl hexanol is an eight-carbon branched chain oxo alcohol having a high boiling point and slow evaporation rate.2-Ethyl hexanol is a versatile solvent featuring excellent reactivity as a chemical intermediate. It serves as a chain terminator in synthesizing condensation polymers and as an intermediate for plasticizers.2-Ethylhexanol has low volatility and enhances the flow and gloss of baking enamels.2-Ethyl hexanol is also used as dispersing agent for pigment pastes.
CAS no.: 104-76-7
2-ETHYL HEXANOL;2-Aethylhexanol [German];Ethylhexanol, 2-;FEMA No. 3151;CCRIS 2292;HSDB 1118;NSC 9300;EINECS 203-234-3;MFCD00004746; BRN 1719280;AI3-00940;CHEBI:16011;DSSTox_CID_605;DSSTox_RID_75686;DSSTox_GSID_20605;2-Ethyl-1-hexanol, 99%;2-Aethylhexanol;2-Ethyl-hexan-1-ol; 2-ethylhexanol group;2-ethyl hexyl alcohol;ACMC-20msz8;EC 203-234-3;ACMC-1B65F;SCHEMBL16324;4-01-00-01783 (Beilstein Handbook Reference);KSC175S7B;NCGC00091294-03;NCGC00254215-01;NCGC00259620-01
2-Ethyl hexanol is an alcohol.Flammable and/or toxic gases are generated by the combination of alcohols with alkali metals, nitrides, and strong reducing agents. They react with oxoacids and carboxylic acids to form esters plus water. Oxidizing agents convert them to aldehydes or ketones. Alcohols exhibit both weak acid and weak base behavior. They may initiate the polymerization of isocyanates and epoxides. 2-Ethyl hexanol is incompatible with strong oxidizing agents and strong acids.2-ethyl hexanol , also called octanol, is an 8-carbon higher alcohol species.2-Ethyl hexanol is hardly soluble in water, but is soluble in almost all organic solvents.2-Ethyl hexanol has very low-level impurities and may be used as a raw material for a wide variety of chemicals.The largest market for 2-ethyl hexanol has been the plasticiser dioctyl phthalate (DOP) which is used in the manufacture polyvinyl chloride (PVC) products. An issue for 2-ethyl hexanol producers is that DOP has been dogged by health hazard and environmental concerns. In Europe, DOP and some other phthalate plasticisers have been banned in children’s articles or children’s articles that can be put in their mouths.
As a result, producers have been developing alternative plasticisers. For example, BASF has switched from 2-ethyl hexanol to 2-propylheptanol (2-PH) to make a plasticiser called di-isononyl-cyclohexane dicarboxylate (DINCH) for use in sensitive applications where exposure to toxicological and exposure issues are of concern. 2-ethyl hexanol has received approval from the European Food Safety Authority (EFSA) for use in food contact applications such as cling film, tubes and sealants. Citrates, or citric acid esters, are also being used as plasticisers for PVC products.Other plasticisers such as trioctyl trimellitate, dioctyl adipate and dioctyl terephthalate can be made from 2-ethyl hexanol and the corresponding acid.2-ethyl hexanol is also used to make heavy metal salts to serve as thermal stabilizers for PVC.However, a growing area for 2-ethyl hexanol has been 2-ethyl hexanol use in the manufacture of acrylate and methacrylate esters. Their principal markets are acrylic emulsion polymers for pressure-sensitive adhesives, textiles and surface coatings, which includes high-solids automotive paints.Demand for waterborne acrylic products that replace organic solvent-based products is being driven by increasingly stringent air emission regulations.
There are a number of other uses for 2-ethyl hexanol. 2-ethyl hexanol is used as a low volatility solvent for resins, waxes, animal fats, vegetable oils, disinfectants and insecticidal sprays, and petroleum derivatives. 2-ethyl hexonol derivatives are used as an additive for diesel fuel to reduce emissions and to improve the performance of lube oils and mining chemicals. 2-ethyl hexanol can be used in very low concentrations for aqueous anti-foam formulations used in the textiles and paper industries. 2-ethyl hexanol is used in the production of the diester of maleic acid, which is a starting material for surfactants, while it is a feedstock for 2-ethyl hexanol sulphate for use as a surfactant for electrolytes.
2-Ethylhexyl alcohol;2-Ethylhexylalkohol;2-Etil esanolo;2-Äthylhexanol;alcol 2-etilesilico;Ethylhexanol;Ethylhexyl alcohol;Hexanol, 2-ethyl;Isooctanol;isoottanolo;Octanol;Octyl alcohol; 2-Ethylhexanol; 2-Ethylhexylalcohol;Isooctanol; Octylalcohol; 2-EH;2-Ethylhexanol; Ethylhexanol
2-ethyl hexanol;2-Ethyl-1-Hexanol;2-Ethyl-1-hexanol;2-ethyl-1-hexanol;2-ethylhexal-1-ol;2-Ethylhexan-1-ol;2-ethylhexan-1-ol;2-Ethylhexan-1-ol;2-ethylhexan-1-ol; 2-Ethylhexyl alcohol;;Ethyl hexyl alcohol;Ethylhexanol;ETHYLHEXANOL-2;Isooctyl alcohol, ; Isooctanol;2-Ethyl-1-hexanol;Octanol
China is a major 2-ethyl hexanol importer of over 250,000 tonnes/year.Exporters include western europe of more than 150,000 tonnes/year, middle east of over 70,000 tonnes/year and rest of asia at around 50,000 tonnes/year.Demand for 2-ethyl hexonol in China is predicted to grow at 7%/year from 2010-2015, with worldwide growth at over 2%/year in the same period. No growth and possibly some decline is expected in the US, europe and northeast asia (japan, south korea and taiwan) as legislation in most major industrial countries move to ban DOP in certain applications and end-users switch to alternative plasticisers.As a result, DOP consumption will decline in the US and western Europe by around 5%/year and 6%/year respectively over the next 10 years, and will remain flat in northeast asia. However, there will be need for additional DOP supplies in china and southeast asia. Demand in China has slowed since 2006 but still forecast to grow at just over 4%/year while southeast asia will see growth of nearly 3% /year.
The general population may be exposed to 2-ethyl hexanol from inhalation of ambient air, ingestion of food and drinking water, or dermal absorption of this compound or other products containing 2-ethyl hexanol.Studies have reported 2-ethyl hexanol emission from various sources, such as carpets, furnitures, computers, books and food wrappings. Building materials, such as insulation and gypsum board, wallpaper, paint, PVC flooring, and adhesives, are also sources of 2-ethyl hexanol emissions. Several reports point out that flooring is a prominent source of 2-ethyl hexanol air pollution in buildings. The region of the highest 2-ethyl hexanol concentrations in apartment houses was concrete slabs surface, which was directly in contact with a vinyl carpet.In a school conference room with a 2-ethyl hexanol air concentration of 1902 µg/m3 , the rates of 2-ethyl hexanol emission from the carpet tile and concrete surface beneath the carpet were 2492 μg/h/m2 and 12,697 μg/h/ m2 , respectively, measured using the double‐cylinder chamber method.2-ethyl hexanol was also reported that 2-ethyl hexanol concentrations in the air increased with the amount of 2-ethyl hexanol emitted from the floor.
In a study investigating 2-ethyl hexanol emission using a field and laboratory emission cell (FLEC) method, 2-ethyl hexanol was found to be 47%‐76% of the total VOCs emitted from the floor coverings.2-ethyl hexanol was emitted from the surface of a concrete floor after its PVC floor covering was removed.One study revealed that 2-ethyl hexanol emission by a PVC flooring material decreased over time during the 60‐ day experiment, which contradicted findings from a different study which found that 2-ethyl hexanol indoor concentration fluctuated over a long period of time—increasing in summer when the temperature rose and decreasing in winter when the temperature fell.Therefore, in addition to primary 2-ethyl hexanol emission by the 2-ethyl hexanol‐containing products, other emission mechanisms should also be considered. Some of these mechanisms have been identified and are described in the next section.
2‐Ethyl hexanol is absorbed by the gastrointestinal tract and skin. Alcohol dehydrogenase (ADH) rapidly oxidizes the hydroxyl group in 2-ethyl hexanol, forming 2‐ethyl hexanol. 2-ethyl hexanol is further oxidized by aldehyde dehydrogenase (ALDH), forming 2‐ethyl hexanol acid , which is excreted mainly as a glucuronate conjugate in urine. ADH activity for 2-ethyl hexanol was reported to be 8.6 nmol/ mg/min and 4.2 nmol/mg/min in humans and mice, respectively. Furthermore, ALDH activity for 2-ethyl hexanol was 3.6 nmol/mg/min and 5.6 nmol/mg/min in humans and mice, respectively.28 Within 24 hours of orally administrating 2-ethyl hexanol at 8.3 mmol/ kg, 86.9% of the compound was excreted in urine as the glucuronide conjugate metabolite.29,30 Following oral administration at doses of up to 300 mg/ kg, 2-ethyl hexanol was efficiently absorbed in male CD rats. Within 28 hours, 2-ethyl hexanol metabolite was excreted in exhaled breath (as CO2; 6%‐7%), feces (8%‐9%), and urine (80%‐82%). The major urinary metabolite of 2-ethyl hexanol was 2-ethyl hexanol, generated by decarboxylation of partially β‐oxidized 2-ethyl hexanol. The other identified metabolites were 2‐ethyl‐5‐hydroxyhexanoic acid, 2‐ ethyl‐5‐ketohexanoic acid, and 2‐ethyl‐1,6‐hexanedioic acid.
Almost all (96.1%) of the administered 2-ethyl hexanol was excreted as a metabolite and only approximately 3% was excreted unchanged. In another study, dermal administration of 2-ethyl hexanol at 1 g/kg resulted in only 5% of the compound being absorbed at a rate of 0.57 mg/cm2 /h.32 In a comparative study, the percutaneous absorption rates of 2-ethyl hexanol in male rats and humans were 0.22 mg/cm2 /h and 0.038 mg/cm2 /h, respectively, with a (rat/human) ratio of 5.78.33 2-ethyl hexanol was detected in the exhaled breath at 4 μg/m3 (0.0008 ppm).34 2-ethyl hexanol was also detected on the skin surface.35 The concentration of 2-ethyl hexanol gas released from the hand skin was 39.9‐136.2 μg/ m3 (7.7‐25.6 ppb). Moreover, 2-ethyl hexanol was considerably more abundant in the stool of neonates than adults, suggesting that neonates may be more susceptible to risks from exposure than adults to plastic materials containing plasticizers.
A study showed that 2-ethyl hexanol is generated from hydrolysis of 2-ethyl hexanol in an environment simulating a concrete slab with a relative humidity (RH) between 70% and 100% and pH between 11 and 13. In the study, DEHP hydrolysis and 2-ethyl hexanol emission increased with an increase in pH.Since 2-ethyl hexanol has a half‐life of 100 years at pH 8 and 30°C, it is hardly degraded under normal indoor environment. Additionally, 2-ethyl hexanol on the surface of cement with higher moisture content emits higher amount of 2-ethyl hexanol. Thus, there is very little doubt that the amount of 2-ethyl hexanol emission by DEHP is related to the moisture content of the cement with which it has direct contact. Therefore, dampness seems to play a major 22 | WAKAYAMA et al. role in determining the amount of 2-ethyl hexanol emitted. A study examined the relationship between RH and 2-ethyl hexanol indoor air concentration, and showed that in buildings with RH values of 58%‐75% and 21%‐22%, the 2-ethylo hexanol indoor air concentrations are 9 μg/m3 and 3 μg/m3 , respectively. Additionally, in a room with high amount of 2-ethyl hexanol emission, the moisture content of its concrete floor was as high as 8.2%.
Using the FLEC method, 2-ethyl hexanol was detected after PVC flooring was directly attached to a concrete floor60 or after PVC flooring material was tightly attached to a self‐leveling (SL) material.51 The amount of 2-ethyl hexanol emission increases as the moisture content of an SL material increases. Taken together, long‐term emission of 2-ethyl hexanol can be attributed to the hydrolysis of DEHP contained in the flooring material,supported by the fact that 2-ethyl hexanol concentration in the air decreases significantly after plastic coverings, adhesives, and leveling layers are removed from the floor, all while the rooms were warmed to 55°C and simultaneously ventilated by additional exhaust fans for a week. Several published studies have reported on various materials that emit 2-ethyl hexanol. We postulated, based on the amount of 2-ethyl hexanol emission from flooring that compounds containing a 2‐ethyl‐1‐hexyl moiety, such as DEHP contained in PVC, and 2‐ethy hexyl acrylate contained in adhesives, are hydrolyzed to emit 2-ethyl hexanol when the backing of carpeting material was in contact with concrete floors.
At pH values and flooring materials composed of DEHP‐containing PVC and 2‐ethyl hexanol acrylate‐containing adhesives emitted a large amount of 2-ethyl hexanol. Additionally, adhesives that did not contain 2‐ethyl hexanol acrylate also emitted 2-ethyl hexanol when combined with PVC flooring, but did not when combined with linoleum flooring.64 These results confirmed our postulate that a contact between a compound having a 2‐ethyl hexanol group and a concrete floor causes secondary emission of 2-ethyl hexanol from a hydrolysis reaction , which seems to be dependent on the pH and moisture content of the concrete surface. A similar emission of n‐butanol and 2‐butanol from hydrolysis reaction can be observed. 2-ethyl hexanol is theorized that moisture in concrete is retained when the concrete is covering with a flooring material. Consequently, the amount of 2-ethyl hexanol emitted increases in summer when the temperature rises and decreases in winter when the temperature drops. As this cycle repeats itself over a long period of time, 2-ethyl hexanol will continue to be emitted, making it theoretically impossible to altogether prevent gradual and prolonged 2-ethyl hexanol emission by ventilation and bakeout. In order to fundamentally eliminate the problem associated with 2-ethyl hexanol emission, it is necessary to thoroughly dry concrete before covering it with a flooring material
A summary of 2-ethyl hexanol effects on human health is presented . Increased occurrence of ocular and nasal symptoms was observed in subjects working in buildings where 2-ethyl hexanol was detected at levels between 5 and 20 μg/m3 . Asthma symptoms may occur due to the humidity in concrete floor constructions that affect 2-ethyl hexanol emission.In a humid building where people developed nasal mucosal inflammation, it was observed that fungi and bacteria were also abundant, wherein average 2-ethyl hexanol concentration was 9.8 μg/m3 . At a university in Japan, where 2-ethyl hexanol concentration was 1086 μg/m3 in maximum, a case of a female professor who complained of coughing, throat irritation, and sore eyes was reported. 2-ethyl hexanol was detected at a prominently high concentration of 408‐1866 μg/m3 . Other staff members also complained of area‐associated SBS symptoms in rooms where 2-ethyl hexanol concentrations were higher than 160 μg/m3 .In comparison with the SBS symptom prevalence, there was no significant difference between classrooms where 2-ethyl hexanol concentration reached 65.5 μg/ m3 and 4.8 μg/m3 .
However, symptoms of the nose, throat, and lower respiratory tract were observed only in rooms with high 2-ethyl hexanol concentrations. Faculty members who used a conference room with 2-ethyl hexanol concentration of over 336 μg/m3 showed a high prevalence of such complaints. Therefore, 2-ethyl hexanol was estimated that the threshold at which symptoms appeared excessively in a population should be in the range of 65.5‐336 μg/m3 .In Finland, several respiratory and dermal symptoms and irritation in the eyes were reported in environments with 2-ethyl hexanol concentration of 1‐4 μg/m3 .In a rehabilitation center in Sweden, where airborne concentrations of 2-ethyl hexanol were very low (0.3‐0.6 μg/m3 ), the staff who had been previously exposed to VOCs as well as 2-ethyl hexanol developed SBS symptoms after 2 days of re‐exposure regardless of a 4‐month period without VOC exposure. In a newly built university building in Japan, as the indoor concentration of 2-ethyl hexanol decreased by ventilation, the number of occupants who complained about headache and eye irritations decreased.At a technical university in Switzerland, employees and students had complained about deteriorated indoor air quality after the building was renovated.
Some employees even suffered from sickness and headache. Indoor concentration of 2-ethyl hexanol was 4‐17 µg/m3 . As described above, there are reports which claim that 2-ethyl hexanol is present indoors, even in a general living environment. possibly causing irritation and inflammation in the mucous membranes of the respiratory tract and nasal cavity. However, the dose‐response relationship and the discrepancy in the lowest‐observed‐adverse‐effect‐level (LOAEL) among the countries remain to be further clarified.
Experimental inhalation or topical exposure settings To assess the acute effects of 2-ethyl hexanol, volunteers were exposed to 2-ethyl hexanol vapor (1 mg/m3 ) for 2 hours. During exposure, the volunteers reported a significant increase in nasal and eye discomfort. No differences in response were observed between the sexes, or between the atopic and nonatopic treatments. Twenty‐four young men were assessed before, during, and after the 4‐hour exposure. As 2-ethyl hexanol concentration increased in three levels, 8.14, 56.6, and 116 mg/m3 , nasal flow reduction and substance P concentration were increased.To evaluate the effect of 2-ethyl hexanol on sensory irritation, 2-ethyl hexanol at mean concentrations of 1.5, 10, and 20 ppm (7.98, 53.2, and 106 mg/m3 , respectively) were used for either constant or variable for the 4‐hour exposure.
The study revealed a strong dose‐response relationship between the concentration of the airborne solvent and blinking rate. The study suggested a critical dose for 1‐hour constant exposure lied between 10 and 20 ppm, and the LOAEL for eye irritation due to 4‐hour exposure was 10 ppm under variable concentration conditions at a peak concentration of 20 ppm. Experiments with human volunteers at three time‐ weighted average 2-ethyl hexanol concentrations (1.5, 10, and 20 ppm) were performed for 4 hours under conditions of either constant or variable concentrations. At 10 ppm, nasal irritation increased with time, and 20 ppm resulted in remarkable irritation. Additionally, attention reduction was considered to occur around 20 ppm. Therefore, the LOAEL for irritability and nasal irritation was 10 ppm. Olfactory‐ and trigeminal‐ mediated symptoms and intensities of odor, eye, and nasal irritations showed a dose‐dependent response. Over the course of the 4‐hour exposure, only olfactory symptoms decreased, while nasal irritations remained nearly unchanged and eye irritations slightly increased.96,97 With regard to skin sensitization to 2-ethyl hexanol, a maximization test was carried out on 29 volunteers. Tested at 4% in petrolatum, 2-ethyl hexanol produced no irritation or sensitization after 48 hours in a closed‐patch test on human subjects.
The effects of 2-ethyl hexanol inhalation on animals are summarized . Inhalable 2-ethyl hexanol at 1210 mg/m3 (227 ppm) was administered by a single 6‐hour inhalation exposure to groups of Swiss mice, Wistar rats, and English Short Hair guinea pigs. 2-ethyl hexanol‐induced local irritation was occurred in the mucous membranes of the eyes, nose, throat, and respiratory tract. However, these responses were temporary, and all animals had recovered within an hour of terminating exposure.11 In another study, mice exposed to 2-ethyl hexanol at 234 mg/ m3 (44 ppm) by inhalation exhibited a decrease in respiratory rate (RD50) by 50%.99 A 90‐day subchronic inhalation toxicity study of 2-ethyl hexanol was performed in Wistar rats. In total, 10 males and 10 females per group were exposed to 2-ethyl hexanol vapors at concentrations of 15, 40, and 120 ppm for 6 hours/day over a 90‐day period. No 2-ethyl hexanol‐related adverse effects were observed. The highest concentration tested under these conditions (120 ppm) was described as the no‐observed‐adverse‐effect‐level (NOAEL) of 2-ethyl hexanol in both male and female rats.23 Male ICR mice were exposed to 0, 20, 60, or 150 ppm 2-ethyl hexanol for 8 hours/day each week, 5 days every week over 3‐ month period. After a week of exposure to 2-ethyl hexanol, the mice showed inflammation and degeneration in the olfactory epithelium, and mice exposed to 2-ethyl hexanol at ≥20 ppm showed a significant concentration‐dependent reduction in the number of olfactory receptor neurons and globose basal cells.
The olfactory bulb showed a reduction in the diameter of glomeruli and in the number of olfactory nerves at 3 months. These histopathology data suggested that 2-ethyl hexanol has persistent effects on the olfactory system.The acute dermal LD50 value was 2.38 (1.51‐2.76) g/kg102 in rats, over 2.6 g/kg11 in rabbits. Signs of percutaneous toxicity were not observed, and skin irritation was moderate when 2-ethyl hexanol (at 0.10, 0.316, 1.00, and 3.16 ml/kg) was dermally administered to the closely clipped, intact abdominal skin of albino rabbits.11 Additionally, 2-ethyl hexanol was administered to rabbit eyes and the subsequent corneal injury was graded as 5 on a scale of 10,102,115 indicating severe acute eye irritation. 2‐Ethyl‐1‐hexanol diluted by polyethylene glycol (1%, 3%, 10%, 30%, and 100%) was administered to rabbit eyes. The potent ocular irritant 2-ethyl hexanol produced moderate eye irritation from concentrations between 3% and 30%, and severe eye irritation at 100%.Doses of 16.7, 58.3, and 175 mg/kg/day to male Fischer 344 rats were administered by gavage for 5 consecutive days. 2-ethyl hexanol did not induce detectable chromosomal aberrations.
Oral gavage doses of 2-ethyl hexanol were administered 5 times a week to B6C3F1 mice at up to 750 mg/kg for 18 months and Fischer 344 rats at up to 500 mg/kg for 24 months. 2-ethyl hexanol was not oncogenic in rats, but there were weak trends of adverse hepatocellular carcinoma incidence in mice at higher doses. There are several in vitro bacterial studies. Some group reported that 2-ethyl hexanol was found to be mutagenicand cause DNA damage. However, other groups reported that 2-ethyl hexanol was found to be non‐mutagenic in the Ames test and Rec assay.133-138 Using a modified Ames Salmonella/microsome assay to determine mutagenicity, urine was pooled from male Sprague‐Dawley rats dosed daily for 15 days with 1000 mg/ kg of 2-ethyl hexanol. No mutagenic substances were excreted in the urine.
2-ethyl hexanol also exhibited no chromosome damage or mutagenic activity.In a carcinogenesis bioassay of DEHP and related compounds, it was reported that 2-ethyl hexanol was not bound to hepatic DNA of Fischer rats 24 hours following oral gavage administration. In vitro promoting activity of DEHP and its hydrolysis product, 2-ethyl hexanol, were studied using promotable mouse epidermis‐derived JB6 cells, which revealed that 2-ethyl hexanol did not promote the anchorage of JB6 cells.Intraperitoneal treatment of rats with 0.32 g/kg 2-ethyl hexanol decreased plasma ketone bodies (from 0.8 to 1.6 mmol/L), increased hepatic triglycerides, and increased lipids predominantly in periportal regions of the liver lobule. After intraperitoneal injection, 2-ethyl hexanol did not induce a significant production of hydrogen peroxide generated by peroxisome proliferators in the rat hepatocytes
The acute dermal LD50 value was 2.38 (1.51‐2.76) g/kg102 in rats, over 2.6 g/kg11 in rabbits. Signs of percutaneous toxicity were not observed, and skin irritation was moderate when 2-ethyl hexanol (at 0.10, 0.316, 1.00, and 3.16 ml/kg) was dermally administered to the closely clipped, intact abdominal skin of albino rabbits.11 Additionally, 2-ethyl hexanol was administered to rabbit eyes and the subsequent corneal injury was graded as 5 on a scale of 10,102,115 indicating severe acute eye irritation.11 2‐Ethyl‐1‐hexanol diluted by polyethylene glycol (1%, 3%, 10%, 30%, and 100%) was administered to rabbit eyes. The potent ocular irritant 2-ethyl hexanol produced moderate eye irritation from concentrations between 3% and 30%, and severe eye irritation at 100%.Doses of 16.7, 58.3, and 175 mg/kg/day to male Fischer 344 rats were administered by gavage for 5 consecutive days. 2-ethyl hexanol did not induce detectable chromosomal aberrations.130 Oral gavage doses of 2-ethyl hexanol were administered 5 times a week to B6C3F1 mice at up to 750 mg/kg for 18 months and Fischer 344 rats at up to 500 mg/kg for 24 months. 2-ethyl hexanol was not oncogenic in rats, but there were weak trends of adverse hepatocellular carcinoma incidence in mice at higher doses.
There are several in vitro bacterial studies. Some group reported that 2-ethyl hexanol was found to be mutagenicand cause DNA damage. However, other groups reported that 2-ethyl hexanol was found to be non‐mutagenic in the Ames test and Rec assay. Using a modified Ames Salmonella/microsome assay to determine mutagenicity, urine was pooled from male Sprague‐Dawley rats dosed daily for 15 days with 1000 mg/ kg of 2-ethyl hexanol. No mutagenic substances were excreted in the urine. 2-ethyl hexanol also exhibited no chromosome damage or mutagenic activity.In a carcinogenesis bioassay of DEHP and related compounds, it was reported that 2-ethyl hexanol was not bound to hepatic DNA of Fischer rats 24 hours following oral gavage administration.In vitro promoting activity of DEHP and its hydrolysis product, 2-ethyl hexanol, were studied using promotable mouse epidermis‐derived JB6 cells, which revealed that 2-ethyl hexanol did not promote the anchorage of JB6 cells.Intraperitoneal treatment of rats with 0.32 g/kg 2-ethyl hexanol decreased plasma ketone bodies (from 0.8 to 1.6 mmol/L), increased hepatic triglycerides, and increased lipids predominantly in periportal regions of the liver lobule. After intraperitoneal injection, 2-ethyl hexanol did not induce a significant production of hydrogen peroxide generated by peroxisome proliferators in the rat hepatocytes
Since there is no report in humans regarding reproductive toxicity effects, Japan Society for Occupational Health classified 2-ethyl hexanol as group 3 .Substances suspected to cause reproductive toxicity, based on the animal experimental data showing the effects on fetal growth and skeleton formation. Sprague‐Dawley rats were exposed to 2-ethyl hexanol vapor for 7 hours/day on gestational days (GD) 1‐19 at 850 mg/m3 (160 ppm). 2-ethyl hexanol reduced maternal food intake, but there were no significant decreases in weight gain, water intake, number of fetuses, and fetal weight.Teratological studies were conducted using Wistar rats orally treated with 2-ethyl hexanol at up to 1660 mg/kg on GD 12. Teratogenic fetal malformation was increased, but there was no clear description in the article whether an appropriate comparison with the control group was made or not. Developmental effects of 2-ethyl hexanol in Wistar rats at 0, 130, 650 and 1300 mg/kg (10 animals per group) by gavage, from GD 6 to 15, were investigated. 2-ethyl hexanol showed significant maternal toxicity with autopsy effects at 1300 mg/kg and six animals were found dead on GD 9, 10 and 13.
In this group, there was also an increased number of early resorptions and high post‐implantation loss. The mean fetal body weight markedly decreased and an increased frequency of fetuses with malformations was observed. Furthermore, the number of fetuses bearing skeletal variations, retardations and dilated renal pelvis increased. A 650 mg/kg dose of 2-ethyl hexanol showed slight clinical signs/symptoms in the mother without maternal body weight changes. Fetal body weights were slightly reduced, and the number of fetuses with skeletal variations and retardations increased. Six fetuses among the three litters in this group showed asymmetric dumbbell‐ shaped thoracic vertebrae. The NOAEL for the maternal and fetuses was 130 mg/kg.2‐Ethyl hexanol was orally administered to female mice at 1525 mg/kg/day from GD 6 to 15. Of 49 maternal mice, 17 died, and maternal body weight decreased. In addition, the number of births, the survival rate, and the weight of the infant significantly decreased.122 2‐Ethyl‐1‐hexanol was administered via occluded dermal application for 6 hours/day on GD 6 through 15 to pregnant Fischer 344 rats at 0‐2520 mg/kg/day. The NOAEL for the maternal toxicity of 2-ethyl hexanol was 252 mg/kg/day based on skin irritation, and 840 mg/kg/day based on systemic toxicity.
The NOAEL for developmental toxicity was at least 2520 mg/kg/ day, with no teratogenicity.The rate of Sertoli cell proliferation was assessed in male CD Sprague‐Dawley pups. At 24 hours after treatment with 2-ethyl hexanol at 166.4 mg/kg, the number of Sertoli cells in the testicular sections was not diminished. 2-ethyl hexanol does not alter the morphology of Sertoli cells and gonocytes. It was investigated whether 2-ethyl hexanol is responsible for testicular damage. No testicular damage was observed in young rats orally administered with 2-ethyl hexanol at 351 mg/kg/day for 5 days. Additionally, administration of 2-ethyl hexanol at 130 mg/kg/day for 14 days resulted in no testicular atrophy.113 In another study, 2-ethyl hexanol were orally administered at 0, 50, 200, and 750 mg/kg to B6C3F1 mice 5 times a week for 18 months. The relative testicular weight was slightly increased in the groups treated with over 50 mg/kg/day 2-ethyl hexanol.
Similarly, 2-ethyl hexanol was orally administered at 0, 50, 150, and 500 mg/kg five times a week to Fisher 344 rats for 24 months. 2-ethyl hexanol induces a dose‐dependent increase in testis weight.Mixed cultures of Sertoli and germ cells were prepared from the testes of 27‐ to 30‐day‐old Sprague‐Dawley rats and the testicular toxicity was examined. The addition of 2-ethyl hexanol at 2 × 10−4 M to the culture medium did not cause an increase in the rate of germ‐cell detachment, compared with non‐ treated condition.126 Sertoli cells, which produce lactate and pyruvate are thought to be the initial target of testicular atrophy.127 The effect of 2-ethyl hexanol on lactate and pyruvate production was studied, but their production was unaffected by 2-ethyl hexanol at 200 μmol/L. The antiandrogenic potential of 2-ethyl hexanol in vitro with a mouse Leydig tumor cell line, MA‐10 cells, was evaluated. 2-ethyl hexanol did not have significant effects on cell viability and steroidogenesis.
The in vitro effects of 2-ethyl hexanol are summarized . The administration of 2-ethyl hexanol at a concentration of 1% to mitochondrial fractions from the liver of male Wistar rats exhibited insignificant inhibitory effect on State 3 respiration. Adult rat hepatocytes cultured for 48 hours in the presence of 0.2 mmol/L 2-ethyl hexanol contained more number of peroxisomes than controls. The activity of carnitine acetyltransferase (a mixed peroxisomal/mitochondrial marker) and 7‐ethoxycoumarin O‐deethylase (microsomal marker) increased ninefold and twofold, respectively, by the presence of 1 mmol/L 2-ethyl hexanol. The effect on peroxisomal enzyme activity in primary rat hepatocyte was determined after incubation with 2-ethyl hexanol at 0‐0.50 mmol/L for 72 hours. 2-ethyl hexanol at these concentrations had no effect on the oxidation of the peroxisomal marker, cyanide‐insensitive palmitoyl‐CoA. Therefore, it was inferred that 2-ethyl hexanol had no effect on peroxisomal β‐oxidation. One study examined the possibility of species differences in response to 2-ethyl hexanol. Hepatocytes were isolated from male mice, rats, guinea pigs, and marmosets, and incubated with 2-ethyl hexanol. Although 2-ethyl hexanol increased the activity of cyanide‐insensitive fatty acyl CoA oxidase in mice and rats, did not increase in guinea pig and marmoset.
Kupffer cells were isolated and incubated with 2-ethyl hexanol, but no effect of 2-ethyl hexanol on intracellular calcium and superoxide production.148,149 The inhibitory effect of 2-ethyl hexanol on mouse and rat liver cytosolic GST activities was monitored in vitro. The study revealed that inhibition of GST by 2-ethyl hexanol in mice was three times more potent than in rats.150 The activities of ADH and ALDH in mouse liver after 0.25, 0.50, and 1.00 mmol/L 2-ethyl hexanol treatments were examined. The in vitro study revealed a significant inhibition of ADH activity by 2-ethyl hexanol at concentrations of 0.50 and 1.00 mmol/L, but no appreciable effect on the activity of ALDH.151 2‐Ethyl‐1‐hexanol at concentrations between 2.5 and 15.0 mmol/L significantly inhibited the activity of aminopyrine N‐demethylase and aniline hydroxylase of rat liver.152 To investigate the effects of 2-ethyl hexanol on immune responses, spleen cells from female BALB/c mice were incubated with 2-ethyl hexanol. The activities of interleukin (IL)‐6 and immunoglobulin were not induced by 2-ethyl hexanol. IL‐2 was induced by 2-ethyl hexanol in CD4 cells, but not in CD8 cells. 2-ethyl hexanol induced activation of CD4 cells, which was accompanied by the activation of transcription factors, suggesting that 2-ethyl hexanol functions as a modulator of immune response.
The effects of 2-ethyl hexanol on heterologously expressed transient receptor potential (TRP) ion channels that cause sensory irritations in primary cell cultures of mice trigeminal ganglia neurons were investigated. 2-ethyl hexanol activates heterologously expressed TRPA1 in a concentration‐dependent manner (1‐10 mmol/L). In Ca2+ imaging, 2-ethyl hexanol acted as an agonist of multiple channels (TRPA1, TRPV1, GPCRs) which activate the trigeminal neurons.Although 2-ethyl hexanol causes toxicity exclusively to periportal regions of the perfused liver, the toxicity is dependent on oxygen tension in isolated sublobular regions of the liver lobule. 2-ethyl hexanol is therefore unlikely for the selective injury to periportal regions in studies with perfused liver to be caused by drug delivery. 2-ethyl hexanol was reported that 2-ethyl hexanol inhibits β‐oxidation of fatty acids in mitochondria, but not in peroxisomes. A second group also assessed 2-ethyl hexanol toxicity in the liver. Livers from starved female Sprague‐Dawley rats were perfused with 2-ethyl hexanol (at 3 mmol/L) dissolved in Krebs‐ Henseleit buffer (pH 7.4, 37°C) saturated with 95% O2, 5% CO2.
Following infusion of 2-ethyl hexanol, O2 uptake and ketone body formation were diminished by 50% and 80%, respectively. Furthermore, cell damage, as assessed by the appearance of LDH in the effluent perfusate, was apparent. Only O2‐rich upstream regions of the liver lobule were damaged. This toxicity is dependent on oxygen tension in isolated sublobular regions of the liver lobule. Peroxisome proliferators accumulate in the liver due to their lipophilicity. They inhibit actively respiratory mitochondria in the periportal region of the hepatic lobule and cause partially toxicity.In this review, we focused on the toxicity of 2-ethyl hexanol from the viewpoint of an indoor air pollutant. 2-ethyl hexanol is metabolized to 2‐ethyl hexanol, and then to 2-ethyl hexanol, after which it is rapidly excreted from the body. However, drug‐metabolizing enzyme activity reportedly varies greatly among individuals.28 Thus, long‐term exposure to 2-ethyl hexanol, especially in populations with low metabolic activities, may cause health effects even below the minimum concentration that causes toxic effects. In both Japan and Northern Europe, 2-ethyl hexanol was detected in buildings where patients complained of SBS symptoms. 2-ethyl hexanol has been reported to induce mucosal irritation and effects on the central nervous system.
Thus, 2-ethyl hexanol is considered among the causative agents of SBS symptoms. Reports on the effects in animals of inhalation exposure to 2-ethyl hexanol are limited. In particular, there is no report on the liver effects of its inhalation exposure. Orally ingested 2-ethyl hexanol increases the number of peroxisomes. Peroxisome proliferators activate peroxisome proliferator‐activated receptor α (PPARα) and affect lipid metabolism, inflammation, glucose homeostasis, cell proliferation, and apoptosis.Because 2-ethyl hexanol, a metabolite of 2-ethyl hexanol, acts as a PPARα agonist, 2-ethyl hexanol may be responsible for the effects observed upon 2-ethyl hexanol oral administration on the liver. In most buildings where the 2-ethyl hexanol indoor air concentrations are high, plasticizer‐containing flooring materials have a direct contact with concrete. There are multiple sources of 2-ethyl hexanol in rooms, that is, primary emission from PVC products and/or building materials, and secondary emission resulting from chemically induced hydrolysis and/or microbial decomposition of plasticizers and/or adhesives.
2-ethyl hexanolwas reported that 2‐butanol is generated through the hydrolysis of several acrylic adhesives.2-ethyl hexanol is emitted from the floor, produced from di‐n‐butyl phthalate and 2‐butanol from isobutyl phthalate. As a measure against VOCs emissions like that of 2-ethyl hexanol, it is very important to use a flooring or other building material that does not emit VOCs even from the hydrolysis reaction, or to confirm that the moisture content in the concrete is sufficiently lowered before flooring the room.First check the victim for contact lenses and remove if present.Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician.Immediately transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.Immediately flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, Immediately call a physician and be prepared to transport the victim to a hospital for treatment.
Immediately leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital.Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, self-contained Breathing Apparatus (SCBA) should be used if not available, use a level of protection greater than or equal to that advised under protective clothing.Do not induce vomiting. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and immediately call a hospital or poison control center.Be prepared to transport the victim to a hospital if advised by a physician.If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. D not induce vomiting.Immediately transport the victim to a hospital.If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock down vapors. Avoid breathing vapors. Keep upwind.
Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. Avoid contact with skin and eyes. Avoid inhalation of vapor or mist. Keep away from sources of ignition - No smoking. Take measures to prevent the build up of electrostatic charge. Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. The scientific literature for the use of contact lenses by industrial workers is inconsistent. The benefits or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses.
However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. Fully encapsulating, vapor-protective clothing should be worn for spills and leaks with no fire. Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor-suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean, non-sparking tools to collect absorbed material. Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor, but may not prevent ignition in closed spaces.