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Toxicity Effects

CAS Registry Number: 149-57-5

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

  • 2-Ethylhexanoic acid
  • Ethyl Hexanoic Acid, 2-

Human Toxicity Excerpts

  • ALTERNATIVE and IN VITRO TESTS: ... Human polymorphonuclear leukocytes (PMNL) /were exposed/ to 2-Ethylhexanoic acid (2-EHA) in vitro and /the authors/ measured the production of reactive oxygen species (ROS) and explored the associated cellular mechanisms. 2-EHA (10-2000 uM) inhibited dose-dependently formyl-methionyl-leucyl-phenylalanine (FMLP)-induced respiratory burst in PMNL. Moreover, 2-EHA decreased oxidative burst evoked by the protein kinase C (PKC) activators, phorbol myristate acetate (PMA) and dioctanoyl-s,n-glycerol (DIC(8)). 2-EHA affected neither the levels of free intracellular calcium nor inhibited PKC. The results indicate that 2-EHA inhibits activation of PMNL to produce ROS, i.e. has an immunosuppressive effect in vitro. The site of action in the PKC is after activation of this enzyme.[Pennanen SM et al; Toxicol Lett 117 (1-2): 79-84 (2000)] **PEER REVIEWED** PubMed Abstract
  • BIOMONITORING: Sawmill workers in Finland were monitored for urinary excretion of 2-ethylhexanoic acid used in a wood preservative. Excretion ranged from 30 + or - 10 nmol 2-ethylhexanoic acid/mmol creatinine in urine samples taken from four workers with lower exposures to 1.8 + or - 1.6 umol 2-ethylhexanoic acid/mmol creatinine in five men from the group designated as having higher exposure.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:733] **PEER REVIEWED**
  • CASE REPORTS: ... Case of corneal injury, with prompt healing, has been reported.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:733] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: /Following ingestion/ abdominal pain; burning sensation; diarrhea. /from table/[International Program on Chemical Safety/Commission of the European Communities; International Chemical Safety Card on 2-Ethylhexanoic acid (April 2005). Available from, as of July 12, 2007: http://www.inchem.org/pages/icsc.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Harmful if swallowed, inhaled, or absorbed through skin. Material is extremely destructive to tissues of mucous membranes and upper respiratory tract, eyes, and skin. Inhalation may be fatal as a result of spasm, inflammation, and edema of the larynx, and bronchi, chemical pneumonitis, and pulmonary edema. Symptoms of exposure may include burning sensation, coughing, wheezing, laryngitis, shortness of breath, headache, nausea, and vomiting.[Prager, J.C. Environmental Contaminant Reference Databook Volume 2. New York, NY: Van Nostrand Reinhold, 1996., p. 462] **PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ALTERNATIVE and IN VITRO TESTS: ... /The authors/ investigated the ability of two phthalate esters di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) and selected metabolites to activate peroxisome proliferator-activated receptor (PPAR alpha, beta/delta, gamma) using a transient transfection assay. The monoester of DEHP, mono-(2-ethylhexyl) phthalate (MEHP) activated all three subtypes of PPAR, but preferentially activated PPARalpha. A second metabolite of DEHP, 2-ethylhexanoic acid (2-EHXA) was a weaker activator of all three subtypes.[Lapinskas PJ et al; Toxicology 207 (1): 149-63 (2005)] **PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... /The authors/ investigated the effects of the peroxisome proliferator chemical di-(2-ethylhexyl)-phthalate (DEHP), a widely used plasticizer and ubiquitous environmental contaminant, and its selective metabolites, mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (EHA) on the lipid metabolome in a rat HRP-1 trophoblast model. The concentrations of ten lipid classes (cholesterol esters, diacylglycerol, triacylglycerides, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, lysophosphatidylcholine, cardiolipin, and sphingomyelin) were determined, as well as the individual fatty acid compositions, especially the omega-3 and omega-6 family of essential fatty acids (EFAs). The level of each lipid class was significantly increased upon exposure to the agents, with MEHP and EHA generally showing higher increases than DEHP. The same trends were observed in comparing the fatty acid compositions. For example, the omega-3/omega-6 fatty acids ratio did not change, although the levels of omega-3 and omega-6 fatty acids were significantly elevated upon exposure. These results suggest that DEHP and its metabolites can alter lipid metabolome in a rat placental cell line.[Xu Y et al; Arch Toxicol 80 (5): 293-8 (2006)] **PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... In most species / di-(2-ethylhexyl)-phthalate (DEHP)/ is rapidly metabolized to mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (2-EHA). ... The aim of this study was to determine the nephrotoxic potential of both DEHP metabolites by use of cultured kidney epithelial cells (Opossum kidney cells; OK cells). For this purpose, OK cells were exposed for 3 days to MEHP and 2-EHA at concentrations ranging from 0.1 -500 micromol/L and the toxicity as well as the effects on migratory activity and intracellular cytoskeleton were studied by cell biological, morphological and morphometric methods. When compared with corresponding controls, treatment of OK cells with MEHP and 2-EHA, respectively, showed marked differences in cell viability between both DEHP metabolites. ... 2-EHA did not cause a reduced viability or an altered cell volume. The migratory activity of OK cells was not significantly influenced by both metabolites. Moreover, MEHP toxicity resulted in a largely reduced and altered organization of F-actin (stress fibers), but not of myosin, microtubules and vimentin. ... As demonstrated in this study, only MEHP, but not 2-EHA, has a marked nephrotoxic effect in vitro.[Rothenbacher KP et al; Hum Exp Toxicol 17 (6): 336-42 (1998)] **PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... Using HRP-1 rat trophoblastic cells, the effects of di-(2-ethylhexyl)-phthalate (DEHP) and two of its metabolites, mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (EHA), on the mRNA and protein expression of the three known peroxisome proliferator-activated receptor (PPAR) isoforms (alpha, beta, and gamma), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), and the heart cytoplasmic fatty acid binding protein (HFABP) were investigated. This study also investigated the functional effects of exposure on the uptake and transport of six long chain fatty acids (LCFAs): arachidonic acid (AA), docosahexaenoic acid (DHA), linoleic acid (LA), alpha-linolenic acid (ALA), oleic acid (OA), and stearic acid (SA). In the presence of DEHP, MEHP, and EHA, the expression of PPARalpha, PPARgamma, FATP1, and HFABP were up-regulated in a dose- and time- dependent manner, while PPARbeta and FABPpm demonstrated variable expression. The uptake rates of the essential fatty acids (EFAs: AA, DHA, LA, ALA) increased significantly upon exposure, and the transport of AA (omega-6) and DHA (omega-3) were directionally induced. These results suggest that DEHP, MEHP, and EHA can influence EFA transfer across HRP-1 cells, implying that these compounds may alter placental EFA homeostasis and potentially result in abnormal fetal development.[Xu Y et al; Toxicol Sci 84 (2): 287-300 (2005)] **PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: Rats fed 2-ethylhexanoic acid for 2 or 3 weeks showed decreased serum triglycerides, hepatomegaly, and a large increase in hepatic peroxisomes. Similar hepatic changes occur in vitro in hepatocyte cultures incubated with 2-ethylhexanoic acid. 2-Ethylhexanoic acid has a marked effect on lipid metabolism, in vivo and in vitro, causing inhibition of triglyceride biosynthesis in intestinal mucosa. This leads to changes in absorption of fatty acids and cholesterol. In mice, hepatic microsomal and cytosolic epoxide hydrolases are induced by 2-ethylhexanoic acid, possibly in response to the increased oxygen stress resulting from peroxisome proliferation. Rabbits fed for 10 weeks on a diet with 2 percent cholesterol and 2.5 percent lard and containing 2.5 percent 2-ethylhexanoic acid had a marked inhibition of atherosclerosis compared to those fed a diet with only lard and cholesterol.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:731] **PEER REVIEWED**
  • GENOTOXICITY: Negative in Ames test using Escherichia coli WP2uvrA at 4-2500 ug/plate with and without metabolic activation.[European Chemicals Bureau; IUCLID Dataset, 2-Ethylhexanoic acid (149-57-5) p.62 (2000 CD-ROM edition). Available from, as of July 10, 2007: http://esis.jrc.ec.europa.eu/] **PEER REVIEWED**
  • GENOTOXICITY: Negative in Ames test using Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 at 4-2500 ug/plate with and without metabolic activation.[European Chemicals Bureau; IUCLID Dataset, 2-Ethylhexanoic acid (149-57-5) p.61 (2000 CD-ROM edition). Available from, as of July 10, 2007: http://esis.jrc.ec.europa.eu/] **PEER REVIEWED**
  • GENOTOXICITY: Negative in bacterial gene mutation assay using Escherichia coli WP2uvrA at 4-2500 ug/plate with and without metabolic activation.[European Chemicals Bureau; IUCLID Dataset, 2-Ethylhexanoic acid (149-57-5) p.63 (2000 CD-ROM edition). Available from, as of July 10, 2007: http://esis.jrc.ec.europa.eu/] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: ...Rated 2 on rabbit eyes. ...Tested externally on eyes of rabbits and... rated numerically on scale of 1-10 according to degree of injury... after 24 hr /observation/, paying particular attention to condition of cornea. Most severe injuries have been rated 10.[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 1008] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: 2-Ethylhexanoic acid (undiluted or as a 20% solution in 90% acetone/10% corn oil) was applied at levels of 5, 10, or 20 mL/kg to the skin of guinea pigs in an occluded patch test for 24 hr. Slight edema, erythema, and necrosis were observed with neat material. No edema or very slight edema, with slight to moderate redness, was observed after treatment with the 20% solution. Slight necrosis with subsequent eschar formation (slight to moderate) was observed in five of six New Zealand white rabbits 4 hr after application of undiluted 2-ethylhexanoic acid.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:728] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... In the present work the effects of developmentally toxic doses of 2-ethylhexanoic acid (EHXA), 2-ethylhexanol (EHXO), and valproic acid (VPA) on Zn metabolism were investigated in the pregnant rat. In experiment 1, dams were intubated with EHXA (3.13, 6.25, 9.38 or 12.5 mmol/kg), EHXO (6.25, 9.38 or 12.5 mmol/kg), VPA (1.56, 3.13, 6.25 or 9.38 mmol/kg), or corn oil (control; 1.0 ml/kg) at 14:00 hr on gestation day (GD) 11.5, intubated with 32 microCi 65Zn at 22:00 hr, and then killed at 08:00 hr on GD 12.5. At the higher dose levels of EHXA and EHXO, and at all dosages of VPA, the percentage of 65Zn retained in maternal liver was higher, while that in the embryos was lower, than in controls. Chemical-associated changes in 65Zn distribution were associated with increased maternal liver metallothionein (MT) concentrations. In experiment 2, dams were fed diets containing 1, 25 or 97 microg Zn/g from GD 0-16 and intubated with 3.5 mmol EHXA or 1.0 ml corn oil/kg/d from GD 8-15. Dams were killed on GD 16 or 19. High incidences of encephalocele and tail defects were noted in the GD 16 fetuses of EHXA-treated dams fed either the low or adequate Zn diet, the highest incidences being in the low Zn group. On GD 19 the incidence of tail defects tended to be higher in the EHXA groups than in oil-treated controls, the highest incidence occurring in the low Zn EHXA group. Encephalocele was only observed in the low Zn EHXA-treated group. Fetal weight and crown-rump lengths were decreased by EHXA treatment and low dietary Zn. The incidence of rib anomalies was higher in the EHXA-exposed groups than in their respective oil controls. In experiment 3, GD 10.5 embryos collected from control dams were cultured for 48 h in serum from control or EHXA-treated male rats fed 4.5 or 25.0 microg Zn/g diets. Embryos cultured in either EHXA or low Zn sera exhibited delayed development; the addition of Zn to these sera eliminated their developmental toxicity.[Bui LM et al; Toxicology 126 (1): 9-21 (1998)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Wistar rats (20-21 pregnant females/dose) ... were exposed to 2-ethylhexanoic acid in their drinking water at doses of 100, 300, or 600 mg/kg/day on Days 6-19 of gestation. Control animals received vehicle water. The fetuses were examined (on Gestational Day 20) for external, visceral, and skeletal malformations and variations. 2-Ethylhexanoic acid was marginally toxic to the dams at 600 mg/kg, but not at lower doses, since the mean near term body weight was reduced by 11%. This dose level was also slightly fetotoxic as indicated by a 5 to 8% decrease in the mean fetal body weight both in males and females. No treatment-related effects were observed in the number of implantations or live fetuses. At doses of 100 mg/kg and above, 2-ethylhexanoic acid caused skeletal malformations (clubfoot, absence of fibula, polydactylyl, while the development of visceral tissues was less affected. The number of affected fetuses increased in a dose-dependent way (4.9, 8.9, and 15.3% of treated offspring at 100, 300, and 600 mg/kg/day, respectively, vs 2.4% control). These results indicate that 2-ethylhexanoic acid is teratogenic in rats already at doses which are not yet maternally toxic. The skeleton appears to be the main target of 2-ethylhexanoic acid in developing rats.[Pennanen S et al; Fundam Appl Toxicol 19 (4): 505-11 (1992)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A study was conducted on the reproductive toxicity of 2-ethylhexanoic acid in Wistar-rats. Male rats treated for 10 weeks with 100, 300 or 600 mg/kg 2-ethylhexanoic acid in drinking water were mated to females treated with 2-ethylhexanoic acid for 2 weeks. Females were treated throughout gestation and lactation. Reproductive organs of nongravid females and all males were examined at the end of the mating period and those of pregnant females were examined 21 days postpartum, A decrease in maternal body weight was seen after 7 days gestation in the group treated with 600 mg/kg 2-ethylhexanoic acid . A nonuniform dose dependent effect on sperm quality was seen following 2-ethylhexanoic acid treatment along with a dose dependent delay in fertilization. Decreases in average litter size were seen in treated rats along with increases in the frequency of lethargy, abnormally thin hair, kinky tails, and abnormal legs. A delay in physical development was seen as well. Few histological changes in the reproductive organs and tissues of adult males, nongravid females, and dams were seen. In a second study, pregnant rats were treated with 600 mg/kg 2-ethylhexanoic acid on day four, six, or seven of gestation and the uterine contents examined on day ten of gestation. Exposure to 2-ethylhexanoic acid on day six of gestation resulted in the lowest number of implantations and highest number of resorptions. The authors conclude that 2-ethylhexanoic acid impairs fertility and delays postnatal development in rats.[Pennanen S et al; Fundam and Appl Toxicol 21 (2): 204-12 (1993)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Ethylhexanoic acid did not elicit any teratogenic or embryotoxic response, but Sprague-Dawley rats were gavaged on days 6 to 15 of gestation with 2-ethylhexanoic acid (900 or 1200 mg/kg/day) in corn oil, the dams were allowed to deliver, and their litters were examined through postnatal day 6. Effects on development included delayed parturition (day 22 instead of day 21), decreased progeny viability, reduced pup weights, and induced malformations of the vertebrae and ribs. These effects, however, occurred at highly maternally toxic doses. Maternal effects included mortality (27 and 40 percent at 900, and 1200 mg/kg, respectively), decreased body weight or body weight gain, maternal respiratory toxicity (rales or dyspnea), and transient signs of depressed motor activity (eg, ataxia, lethargy)[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:732] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Fifteen pregnant New Zealand white rabbits were treated by gavage with 0, 25, 125, or 250 mg/kg 2-ethylhexanoic acid on days 6 through 18 of gestation. One mid-dose level and one high-dose level animal died on test, and one mid-dose level animal aborted prior to term. High-dose level does experienced hypoactivity, ataxia, and gasping, and showed a slight reduction in body weight (5 percent) and feed consumption (32 percent). No differences in liver weight were observed, but thickened epithelium and ulceration of the glandular portion of the stomach occurred in high-dose level animals. No fetal or embryo toxicity was noted, all groups had comparable numbers of implants and live fetuses, and fetal body weights were comparable among groups. No treatment related malformations or developmental variations occurred. The no observable effect level for maternal animals was 25 mg/kg, and the no observable effect level for offspring was 250 mg/kg[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:732] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant female Wistar rats were treated by oral gavage with a single dose of 0, 1.0, or 2.0 ml/kg 2-ethylhexanoic acid (approximately 900 or 1800 mg/kg) on day 12 of gestation and the dams euthanized on day 20. The high-dose level produced embryo- and fetotoxicity (30 percent decrease in fetal weight and 30 percent increase in dead and resorbed fetuses). The incidence of malformed fetuses (hydronephrosis, levocardia, septal defects, short and kinky tail, ectrodactyly, misplaced digits, and bowed radius) increased from 0 in control animals to 67.8 percent in the high-dose level dams; no apparent toxic or teratogenic effect was observed at the low-dose level. No mortality or effect on maternal body weights and feed consumption occurred, although high-dose-level dams experienced hypoactivity, ataxia, and audible respiration, and liver weights (absolute and relative to body weight) were increased (9 percent). No embryotoxic effects were noted, and total implants, preimplantation loss, and viable fetuses were comparable among groups. Although fetal body weights of high-dose litters were lower than in the control group, differences in weight were <10 percent and were probably attributable to a higher average litter size in high-dose dams. There were no treatment related increases in the incidence of malformations. Increases in some common variations occurred in treated rats, but the total number of visceral or skeletal variations was not significantly altered by treatment. The no observable effect level for maternal animals was 250 mg/kg/day and the no observable effect level for offspring was 100 mg/kg/day.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:731] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The developmental toxicity of 2-ethylhexanoic acid was studied in rats and rabbits. Pregnant Fischer 344 rats were gavaged with 0, 100, 250, 500, or 1000 mg/kg 2-ethylhexanoic acid on days 6-15 of gestation. Pregnant New Zealand white rabbits were gavaged with 0, 25, 125, 250, 500, or 1000 mg/kg 2-ethylhexanoic acid on gestational days 6-18. Determinations were made regarding clinical signs of toxicity, body weight gain, and feed consumption. The rats and rabbits were killed on gestational days 21 and 29, respectively, and necropsied. The uteri were examined for the number of corpora lutea, resorptions, and live and dead fetuses. Live fetuses were weighed and examined for malformations. In rats, seven of eight dams given 1000 mg/kg 2-ethylhexanoic acid died. The surviving rat had a completely resorbed litter. Rats receiving 500 mg/kg 2-ethylhexanoic acid exhibited ocular discharge and periocular encrustation as well as significant increases in absolute and relative liver weight and decreased fetal body weight. No effects were seen with respect to body weight, feed consumption, number of resorptions, or fetal viability in rats exposed to 500 mg/kg. The 250 and 500 mg/kg doses caused a reduction in fetal skeletal ossification. In rabbits, the 500 and 1000 mg/kg doses caused 87.5 and 100%; mortality, respectively. One dam each in the 125 and 250 mg/kg groups aborted. Hypoactivity, labored breathing, and ataxia were frequently seen in all treated rabbits. Maternal body weight gain and feed consumption were decreased by 250 mg/kg 2-ethylhexanoic acid. 2-ethylhexanoic acid doses of 25, 125, and 250 mg/kg did not increase the number of resorptions, affect fetal viability, or induce fetal malformations. The /results suggest/ that 2-ethylhexanoic acid induces developmental toxicity in rats only at doses that cause maternal toxicity. 2-Ethylhexanoic acid causes maternal toxicity in rabbits without affecting fetal development. The no observable effect levels for maternal and developmental toxicity in rats are 250 and 100 mg/kg, respectively. The no observable effect levels for maternal and developmental toxicity in rabbits are 25 mg/kg and 250 mg/kg or more .[Hendrickx AG et al; Fundam and Appl Toxicol 20 (2): 199-209 (1993)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The stereoselectivity of the teratogenic activity of 2-ethylhexanoic acid, a metabolite of the widely-used plasticizer di-(2-ethylhexyl)phthalate, was investigated. The enantiomers of 2-ethylhexanoic acid were prepared via asymmetric synthesis with the aid of the chiral auxiliaries (R)- and (S)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP, SAMP). The aqueous solutions of the sodium salts of (R)- and (S)-2-ethylhexanoic acid and the racemic 2-ethylhexanoic acid (+ or - )-2-ethylhexanoic acid were injected each morning and evening of day 7 and 8 of gestation in the NMRI mouse (500 mg/kg, ip), a period highly sensitive in regard to the production of neural tube defects (exencephaly) by branched-chain carboxylic acids. (S)-2-Ethylhexanoic acid did not yield any teratogenic or embryotoxic response in this model, while (R)-2-ethylhexanoic acid was highly teratogenic (59% of living fetuses exhibited exencephaly) and embryotoxic (as indicated by embryolethality and fetal weight retardation); the exencephaly rate induced by (+ or -) 2-ethylhexanoic acid was between those of the two enantiomeres (32%). It is therefore likely that stereoselective interactions of the enantiomers of 2-ethylhexanoic acid with chiral molecules in the embryo are decisive in regard to the teratogenic response. This first example of the stereoselectivity of the teratological activity of an environmental pollutant suggests that the safety of man-made chemicals can be improved by the use of pure enantiomers instead of racemates.[Hauck RS et al; Life Sci 46 (7): 513-8 (1990)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Body weights and feed consumption of male and female B6C3F1, mice were unaffected by treatment with 0, 200, 800, or 1600 mg/kg 2-ethylhexanoic acid by gavage 5 days per week for 2 weeks. Male mice in the high-dose group had increased liver weight (absolute and relative to body weight), which was associated with hypertrophy of the hepatocytes. Liver weights and microscopic morphology of all other groups were comparable to controls. The no observable effect level was 800 mg/kg for males and 1600 mg/kg for females. In a feeding study, male and female B6C3F, mice received 0, 0.75, 1.5, or 3 percent 2-ethylhexanoic acid in the diet for 2 weeks (equivalent to median doses of approximately 1800 3500, and 7500 mg/kg/day, respectively). Body weights in the high-dose group were less than in the control group. Feed consumption was initially reduced in treated groups, but was eventually comparable to the control group. Absolute and relative (to body weight) liver weights of animals in the high- and mid-dose groups were significantly increased, and hepatocyte hypertrophy, primarily in the portal region, was observed in a dose related manner in all treated mice except a few low-dose animals, ranging from moderate to minor.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:729] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Groups of 10 male and 10 female Fischer 344 rats and B6C3F1 mice were fed diets containing either 0.0, 0.1, 0.5 or 1.5% 2-ethylhexanoic acid (EHA) for 13 wk. Additional groups of 10 male and 10 female rats or mice were fed either 0.0 or 1.5% EHA for 13 wk followed by a 4-wk recovery (non-treatment) period. Based on food consumption and body weight, the EHA diets provided doses of 61, 303 or 917 mg/kg/day for male rats and 71, 360 or 1068 mg/kg/day for female rats. The EHA diets provided doses of 180, 885 or 2728 mg/kg/day for male mice and 205, 1038 or 3139 mg/kg/day for female mice. No mortality or significant clinical signs of toxicity were observed during the study. Body weights and food consumption of both rats and mice fed 1.5% EHA were lower beginning after the first week of treatment, consistent with a reduction in food consumption. Other groups were unaffected by treatment. After 13 wk, lower triglyceride levels occurred in male mice fed 1.5% EHA and female mice fed 0.5 or 1.5% EHA, but not in other groups. Cholesterol levels were higher in all male rat test groups and in female rats and male and female mice fed either 0.5 or 1.5% EHA, although this effect was reversible following a 28-day recovery period. The principal effects of EHA involved the liver or metabolic processes associated with the liver. The 0.5 and 1.5% diets in both rats and mice were associated with increased relative liver weight and histological changes in hepatocytes, specifically hepatocyte hypertrophy and reduced cytoplasmic vacuolization. Observed histopathological and clinical pathological changes were reversible following recovery. These results indicate that EHA does not produce persistent. overt toxicity in rats or mice following subchronic dietary exposure at concentrations up to 1.5% in feed. The no-observed-adverse-effect level (NOAEL) for male rats was 61mg/kg/day and the no-observed-effect level (NOEL) for female rats was 71mg/kg/day, while 180 and 205 mg/kg/day represent NOELs for male and female mice, respectively.[Juberg DR et al; Food Chem Toxicol 36 (5): 429-36 (1998)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In a 13-week feeding study, male and female Fischer 344 rats received 0, 0.1, 0.5, or 1.5 percent 2-ethylhexanoic acid in the diet (equivalent to median dose levels of approximately 65, 330, and 1000 mg/kg/day, respectively) with satellite groups allowed 28 days of recovery. No mortality or treatment-related signs of toxicity occurred. Body weight, body weight gain, and feed consumption were slightly lower in the high-dose groups compared with the control group. Minor changes in hematology occurred (lower mean corpuscular hemoglobin and mean corpuscular volume) in mid-dose males and high-dose males and females. Liver weights (absolute and relative to body and brain weight) were higher in the high-dose group, and in the mid-dose group the absolute liver weights (both sexes) and relative liver weights (versus brain weight in females, versus body weight in males) were increased. Minor increases in relative organ weights occurred for other organs (kidney, adrenals, brain, testes) but were considered to reflect lower terminal body weight. Hepatocyte hypertrophy and eosinophilia were observed in the livers of mid- and high-dose animals, with a lower severity and incidence in the mid-dose group. All effects were reversible within 28 days. The NOEL and no observable adverse effect level were 0.1 percent and 0.5 percent 2-ethylhexanoic acid in the diet (approximately 65 and 330 mg/kg/day), respectively.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:729] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male Fischer 344 rats fed 2% 2-ethylhexanoic acid in the diet for 3 weeks gained 15% less body weight compared to controls and showed hepatomegaly. No increases in mortality were reported. The liver-to-body weight ratio increased by 55%, and there was a substantial increase in hepatic peroxisomes. Cholesterol levels in treated animals were 17% below the level in control animals, and triglycerides were 68% less than in controls.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:728] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male and female Fischer 344 rats were treated with 0, 200, 800, or 1600 mg/kg by gavage 5 days/week for 2 weeks. Weakness and lethargy, hypothermia, sialorrhea, tremors, poor body condition, and substantial losses to mortality were observed in both sexes of the high-dose group. Mid-dose animals showed generally less severe signs than in the high-dose animals, and no mortality. Body weights in surviving high-dose animals and mid-dose male rats were lower than in the control group. Feed consumption in surviving high-dose animals was decreased. Liver weights (absolute and relative to body weight) were significantly increased in a dose-related manner in the high- and mid-dose rats. Hepatocyte hypertrophy was observed in high-dose animals that survived to termination. The no observable effect level (NOEL) was 200 mg/kg for males and <200 mg/kg for females.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:729] **PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Guinea pig dermal 5690 mg/kg[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:696] **PEER REVIEWED**
  • LD50 Mouse ip 270 mg/kg[European Chemicals Bureau; IUCLID Dataset, 2-Ethylhexanoic acid (149-57-5) p.33 (2000 CD-ROM edition). Available from, as of July 10, 2007: http://esis.jrc.ec.europa.eu/] **PEER REVIEWED**
  • LD50 Mouse sc 910 mg/kg[European Chemicals Bureau; IUCLID Dataset, 2-Ethylhexanoic acid (149-57-5) p.33 (2000 CD-ROM edition). Available from, as of July 10, 2007: http://esis.jrc.ec.europa.eu/] **PEER REVIEWED**
  • LD50 Rabbit dermal 1260 mg/kg[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:696] **PEER REVIEWED**
  • LD50 Rabbit oral 1.3 g/kg[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:728] **PEER REVIEWED**
  • LD50 Rat oral 1.6 to 3 g/kg[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:728] **PEER REVIEWED**

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Absorption, Distribution And Excretion

  • ... 2-(14)C-ethylhexanoic acid in rat blood, brain, liver and kidney was quantitated by liquid scintillation analysis and by wholebody autoradiography in mice. A single intraperitoneal dose of 2-(14)C-ethylhexanoic acid was injected in both species. Animals were sacrificed 30 min, 2 and 6 hr after the administration of 2-(14)C-ethylhexanoic acid in autoradiography experiments. The highest uptake of 2-(14)C-ethylhexanoic acid was observed in the liver, kidney and blood in mice. In contrast, low uptake of 2-(14)C-ethylhexanoic acid was seen in the brain. 2-(14)C-ethylhexanoic acid was well detectable in the olfactory bulb and in the salivary gland. In rats, at 2 hr after administration the highest concentration of 2-(14)C-ethylhexanoic acid occurred in blood (0.3%; of the total dose/g tissue). The radioactivity in the liver (0.2%) and kidney (0.1%) was also relatively high. The concentrations of 2-(14)C-ethylhexanoic acid was low in the brain (0.02%). By 6 hr, the radioactivity had decreased rapidly and was hardly measurable at 24 hr after the administration. The results suggest that 2-ethylhexanoic acid is rapidly cleared from the tissues.[Pennanen S et al; Pharmacol Toxicol 68 (l): 57-9 (1991)] **PEER REVIEWED** PubMed Abstract
  • ... The hypothesis that infants undergoing exchange transfusion are exposed to toxic levels of di-(2-ethylhexyl)-phthalate and the presumed metabolite 2-ethylhexanoic acid was tested by measuring serum levels of di-(2-ethylhexyl)-phthalate in 16 newborn infants (gas-liquid-chromatography) and urine concentrations of 2-ethylhexanoic acid in 6 of these infants (gas chromatography-mass spectrometry). Di-(2-ethylhexyl)-phthalate levels were undetectable (< 1 ug/mL) before exchange but ranged from 6.1 to 21.6 ug/mL of serum (average, 12.5 to 6.2 ug/mL) after a single exchange transfusion. Di-(2-ethylhexyl)-phthalate uptake did not result in cholestasis. 2-Ethylhexanoic acid peak levels were 127 to 416 ng per mL of urine, with a median of 174 ng per mL. Concentrations of 2-ethylhexanoic acid were lower than anticipated, which indicates that 2-ethylhexanoic acid is not a major metabolite in the neonatal infant.[Plonait SL et al; Transfusion (Bethesda) 33 (7): 598-605 (1993)] **PEER REVIEWED**
  • Nine sawmill workers were divided into two groups according to their exposure to 2-ethylhexanoic acid, a pesticide which has replaced the older pentachlorophenol. The men with lower exposure excreted 30 + or - 10 nmol 2-ethylhexanoic acid/mmol creatinine (mean SD, n = 4) in urine samples taken after the workshift, whereas men with higher exposure excreted 1.8 + or - 1.6 umol 2-ethylhexanoic acid/mmol creatinine (mean + - SD, n = 5, p < 0.01). The urinary ornithine and arginine concentrations were at the lower exposure 1.4 0.4 and 1.5 + or - 0.8 umol/mmol creatinine, respectively (mean + or - SD, n = 4), and they increased significantly (p < 0.01) to 4.5 2.5 and 3.2 + or - 1.5 umol/mmol mean + or - SD, n = 5), respectively, at the higher exposure. This might have been caused by the inhibitory effect of 2-ethylhexanoic acid on urea synthesis which was partially compensated for by elevated arginine and ornithine concentrations to drive the urea cycle more efficiently.[Pennanen S et al; Arch Toxicol 64 (5): 426-7 (1990)] **PEER REVIEWED** PubMed Abstract
  • The disposition of di-2-(ethylhexyl)adipate in humans following administration of the stable isotope labeled test substance was investigated. Blood and urine samples were collected from six male volunteers following the administration of 46 mg of 2H10 labeled di-2-(ethylhexyl)adipate. Blood was collected at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after administration. Urine was collected for up to 96 hours after administration. No adverse effects were observed in any of the volunteers and no significant changes in biochemical or hematological parameters were seen. The plasma contained no parent molecule; however, the metabolite 2-ethylhexanoic-acid was detected, but levels were below the limit of quantitation. 2-ethylhexanoic-acid, as a conjugated product, was also the principal metabolite detected in urine. Urinary elimination of the di-2-(ethylhexyl)adipate metabolites peaked within 8 hours of dosing in all volunteers; beyond 36 hours, no metabolites were detected in urine. The conjugated 2-ethylhexanoic acid in urine accounted for an average of 8.6% of the administered dose. A further 3.5% of the dose was accounted for by 2-ethyl-5-hydroxyhexanoic acid, 2-ethylhexanedioic acid, 2-ethyl-5-keto-hexanoic acid, and 2-ethylhexanol. /It was/ concluded that 2-ethylhexanoic acid is an appropriate marker for biological monitoring in estimating the dietary di-2-(ethylhexyl)adipate intake as it is the major metabolite identified and as its rate of elimination is similar to that of other measured di-2-(ethylhexyl)adipate metabolites.[Loftus NJ et al; Food and Chemical Toxicol 31 (9): 609-14 (1993)] **PEER REVIEWED**
  • [2-14(C)-Hexyl]2-ethylhexanoic acid in corn oil was administered to female Fischer 344 rats either as a single oral gavage at 100 or 1000 mg/kg, or after 14 days of oral unlabeled 2-ethylhexanoic acid (100 mg/kg only). An aqueous solution of [2-14(C)-hexyl]2-ethylhexanoic acid was applied topically at either 100 or 1000 mg/kg and another group of rats received 2-ethylhexanoic acid by intravenous injection (1 mg/kg). Urine, feces, and blood were collected at various intervals for 96 hr. Approximately 72 to 75 percent of the oral dose was excreted in the urine within 24 hr, and <10 percent was excreted after 24 hr. About 50% of the 14(C) was excreted in the first 8 hr after the 100-mg/kg dose versus 20 percent after the 1000 mg/kg dose. Fecal excretion accounted for 7 to 12 percent of both doses. After intravenous injection, 64 percent of the l4(C) was excreted in the urine and 2 percent in the feces. Repeated dosing with unlabeled 2-ethylhexanoic acid (100 mg/kg) appeared to reduce the urinary elimination of 14(C) slightly to 55 percent in urine, whereas the fecal excretion increased to 15 percent in the first 24 hr. After dermal application, approximately 30 percent of the applied dose was excreted in the urine during the first 24 hr, followed by an additional 8 and 17 percent from 24 to 96 hr for the 100- and 1000-mg/kg doses, respectively. Fecal excretion was 7 percent for both dose levels. Dermal absorption was estimated to be 63 to 70 percent relative to intravenous administration. After dermal application, peak blood levels of 14C occurred about 5.7 hr after application and the absorption half-life was 3.2 hr. Major urinary metabolites included the glucuronide of 2-ethylhexanoic acid, the glucuronides of 2-ethyl-6-hydroxyhexanoic acid and 2-ethyl-1,6-hexanedioic acid, and unmetabolized 2-ethylhexanoic acid. The proportions of each metabolite changed with the dose and route of administration.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:730] **PEER REVIEWED**

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Metabolism/Metabolites

  • ... Liver microsomes were extracted from male Han/Wistar rats, male DBA/2N/Kuo mice, and humans undergoing liver surgery. 2-Ethylhexanoic acid metabolism was determined in-vitro by incubating the microsomes in the presence and absence of the cytochrome P450 inhibitors triacetyloleandomycin, metyrapone, quinidine, and SKF-525A. In-vivo, 2-ethylhexanoic acid metabolism was determined by administering 2-ethylhexanoic acid to rats with and without the cytochrome P450 inhibitors, and by assessing metabolite levels in human urine samples taken from 2-ethylhexanoic acid exposed sawmill workers. The main 2-ethylhexanoic acid metabolite produced in all microsomes was 2-ethyl-1,6-hexanedioic acid. Production of this metabolite was prevented by triacetyloleandomycin, metyrapone, quinidine, and SKF-525A. /It was/ concluded that some cytochrome P450s may contribute to 2-ethylhexanoic acid metabolism in the liver, that the same 2-ethylhexanoic acid metabolites are formed in rats and humans, and that 2-ethylhexanoic acid resembles the hepatotoxicant 2-envalproic acid.[Pennanen S et al; Human and Experim Toxicol 15 (5): 435-42 (1996)] **PEER REVIEWED**
  • ... The present study was designed to investigate urinary 2-ethylhexanoic acid concentrations following a controlled dose of di-2-(ethylhexyl) adipate presented with food, and to assess the average daily intake of di-2-(ethylhexyl) adipate in a limited population survey. The urinary elimination profile of 2-ethylhexanoic acid, following a dose of di-2-(ethylhexyl) adipate in food, showed that in order to extrapolate di-2-(ethylhexyl) adipate intake from 2-ethylhexanoic acid measurements, a 24-hr urine sample was required. In the survey the elimination of 2-ethylhexanoic acid was determined in 24-hr urine samples in 112 individuals from five different geographical locations in the UK. No restrictions were placed on age or gender. Estimates of daily intake of di-2-(ethylhexyl) adipate show a skewed distribution with a median value of 2.7 mg. This is similar to an estimated maximum daily intake of 8.2 mg/day, derived using an indirect method by the UK Ministry of Agriculture, Fisheries and Food.[Loftus NJ et al; Food Chem Toxicol 32 (1): l-5 (1994)] **PEER REVIEWED**
  • Excretion balance studies were conducted with 2-ethylhexanol (2-EH) in female Fischer 344 rats following single high (500 mg/kg) and low (50 mg/kg) oral doses of l4(C) 2-ethylhexanol, following repeated oral dosing with unlabelled 2-ethylhexanol at the low level, following dermal exposure for 6 hr with a 1 g/kg applied dose of (14)C 2-ethylhexanol, and following a 1 mg/kg iv dose of (14)C2-ethylhexanol. The high, low and repeated low oral dose studies with 2-ethylhexanol showed similar excretion balance profiles of (14)C, with some evidence of metabolic saturation at the high dose. 3. No evidence of metabolic induction was seen following the repeated low oral dosing. 4. All of the oral doses were eliminated rapidly, predominantly in the urine during the first 24 hr following dosing. 5. The dermal dosing resulted in only about 5% absorption of the 1 g/kg dose, with the major portion of the dose recovered unabsorbed from the dermal exposure cell at 6 hr. 6. Urinary metabolites eliminated following the oral and dermal doses were predominantly glucuronides of oxidized metabolites of 2-ethylhexanol, including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.[Deisinger PJ et al; Xenobiotica 24 (5): 429-40 (1994)] **PEER REVIEWED** PubMed Abstract
  • Major urinary metabolites included the glucuronide of 2-ethylhexanoic acid, the glucuronides of 2-ethyl-6-hydroxyhexanoic acid and 2-ethyl-1,6-hexanedioic acid, and unmetabolized 2-ethylhexanoic acid. The proportions of each metabolite changed with the dose and route of administration.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:730] **PEER REVIEWED**
  • Male Wistar rats receiving 2-ethylhexanoic acid in drinking water (600 mg/kg daily) for 9 weeks eliminated 10 different metabolites, including 2-ethyl-1,6-hexanedioic acid, 2-ethyl-6-hydroxyhexanoic acid, five other hydroxylated metabolites and two lactones, the unsaturated 5,6-dehydro-2-ethylhexanoic acid, and parent compound (partly as the glucuronic acid conjugate).[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:730] **PEER REVIEWED**
  • The metabolites of 2-ethylhexanoic acid ... were investigated in rat urine. Male Wister rats were give 2-ethylhexanoic acid in drinking water 1600 mg/kg daily for nine weeks, and then urine specimens were collected and analysed. ... In addition to 2-(ethylhexyl)adipate, ten different 2-(ethylhexyl)adipate related metabolites were found in the urine of 2-(ethylhexyl)adipate treated rats. The main metabolite was 2-ethyl-1,6-hexanedioic acid. Urine also contained 2-ethyl-6-hydroxyhexanoic acid and five other hydroxylated metabolites and two lactones, the detailed structures of which have not yet been elucidated. The unsaturated 5,6-dehydro-di-2-(ethylhexyl)adipate was also identified; this is the metabolite corresponding to 2-n-propyl-4-pentenoic acid, the hepatotoxic metabolite of valproic acid. At least part of the 2-(ethylhexyl)adipate is present in urine as a glucuronide conjugate.[Pennanen S et al; J Chromatogr Biomed Appl 568 (1): 125-34 (1991)] **PEER REVIEWED**

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Tsca Test Submissions

  • 2-Ethylhexanoic acid (2-EHA) was evaluated for subchronic toxicity in B6C3F1 mice (10/sex/dose group) administered 2-EHA in the diet at concentrations of 0, 0.1, 0.5, or 1.5% for 91 days. Additional groups of mice were examined after a 28-day recovery period. The diet provided doses of 0, 180, 885, or 2728 mg/kg bw/day for males, and 0, 205, 1038, or 3139 mg/kg bw/day for females. 2-EHA did not cause mortality. Final body weight in the 0.5% and 1.5% females and in the 1.5% males was significantly (p < 0.05) lower than in controls. Body weight remained low during the recovery period. Food consumption was reduced (p < 0.05) in high-dose males. 2-EHA did not induce ophthalmologic abnormalities or alter hematology values. Serum bilirubin and triglycerides were significantly reduced (p < 0.05) in high-dose females and in mid-dose males and females. Serum cholesterol was elevated (p < 0.05) in both males and females in the 0.5% and 1.5% groups. Relative and absolute liver weight was significantly (p < 0.05) increased in both sexes at 1.5% 2-EHA. Other differences in organs weight reflected effects of 2-EHA on body weight rather than organ-specific effects. Hepatocyte hypertrophy was observed at 0.5 and 1.5% 2-EHA. Increased renal cytoplasmic basophilia and gastric acanthosis and hyperkeratosis were seen only at 1.5% 2-EHA. Most histological changes were reversed after the recovery period.[CHEMICAL MANUFACTURERS ASSOCIATION; 90-Day Oral (DietaryAdministration) Toxicity Study of 2-Ethylhexanoic Acid in the Mouse, (1988), EPA Document No. 40-8897194, Fiche No. OTS0525548] **UNREVIEWED**
  • 2-Ethylhexanoic acid (2-EHA) was evaluated for toxicity in female Fischer 344 rats (4/dose group) administered single measured doses of 0 (vehicle control), 90, 722, 1445, or 2890 mg 2-EHA/kg bw/day by gavage in corn oil. Animals were observed for 14 days after dosing, then sacrificed. All rats treated with 2890 mg/kg died on day 1. The cause of death was not determined. The remaining rats survived the observation period. Rats given 722 mg/kg or higher exhibited weakness on the day of dosing. Weight loss was observed (14/16) during the first 24 hours after dosing, but by day 7, all had regained and exceeded their original weight. Absolute and relative liver (only organ examined) weight of the surviving rats did not differ from controls. An histopathological examination was not conducted. An LD50 of 2043 mg/kg bw/day was calculated.[CHEMICAL MANUFACTURERS ASSOCIATION; Acute Toxicity Study of 2-Ethylhexanoic Acid in the Rat, (1987), EPA Document No. 40- 8797175, Fiche No. OTS0525538] **UNREVIEWED**
  • 2-Ethylhexanoic acid (CAS # 149-57-5) was evaluated for corrosive dermal irritation under exposure conditions prescribed in adjunctive dermal pharmacokinetic study. Four groups of 2 female Fischer 344 rats were exposed with undiluted injections of approximately 1 g/kg through an occluded containment device (2 x 2 cm exposure area) attached to shaved dorsal skin. A pair of treated rats and one of four control rats, similarly attired without treatment, were sacrificed at 24, 48, 72, and 96 hours post-injection for gross and microscopic assessments of dermal corrosion. Gross changes associated with treatment were minimal at 96-hour final necropsy. A white powdery deposit on treated skin and one incidence of focal (2 mm diameter) erythema were observed in the 2 treated rats. Histopathological review, however, revealed a profound dermal response at 24 hours, characterized by necrosis with inflammation of underlying dermal and hypodermis indicative of a breakdown of epidermal integrity. Serial examinations revealed healing by regeneration of necrotic areas from adjacent, less damaged areas' increasing thickness at 48 hours, and a progressive reversal of epidermal thickening at 72 and 96 hours. At 48 hours, acanthosis and keratosis were apparent in most samples, as were prominent keratohyalin granules and parakeratosis. Mitotic figures gave testimony to regeneration from basal layer cells. The study authors offered the lack of residual test substance in the containment device at 24 hours with subsequent amelioration of dermal corrosion as evidence of rapid (24 hour) dermal absorption of 2-ethylhexanoic acid.[CHEM MFGS ASSN; Final Report - Assessment of the Condition of the Skin after Dermal Exposure to 2-Ethylhexanoic Acid; 12/7/87; EPA Doc No. 40-8797175; Fiche No. OTS0525538] **UNREVIEWED**
  • 2-Ethylhexanoic acid was evaluated for corrosive dermal irritation under exposure conditions prescribed in adjunctive dermal pharmacokinetics study. Four groups of 2 female Fischer 344 rats were exposed with undiluted injections of approximately 1 g/kg through an occluded containment device (2 x 2 cm exposure area) attached to shaved dorsal skin. A pair of treated rats and one of four control rats, similarly attired without treatment, were sacrificed at 24, 48, 72, and 96 hours post-injection for gross and microscopic assessments of dermal corrosion. Gross changes associated with treatment were minimal at 96-hour final necropsy. Histopathological review, however, revealed a profound dermal response at 24 hours, characterized by necrosis with inflammation of underlying dermal and hypodermis indicative of a breakdown of epidermal integrity. Serial examinations revealed healing by regeneration of necrotic areas from adjacent, less damaged areas' increasing thickness at 48 hours, and a progressive reversal of epidermal thickening at 72 and 96 hours. At 48 hours, acanthosis and keratosis were apparent in most samples, as were prominent keratohyalin granules and parakeratosis. Mitotic figures gave testimony to regeneration from basal layer cells. The study authors offered the lack of residual test substance in the containment device at 24 hours with subsequent amelioration of dermal corrosion as evidence of rapid (24 hour) dermal absorption of 2- ethylhexanoic acid.[CHEM MFGS ASSN; Final Report - Assessment of the Condition of the Skin after Dermal Exposure to 2-Ethylhexanoic Acid; 12/7/87; EPA Doc No. 40-8797175; Fiche No. OTS0525538] **UNREVIEWED**
  • 2-Ethylhexanoic acid was tested for developmental toxicity in groups of 15 bred female New Zealand white rabbits treated by gavage with dose levels of 0, 25, 125, or 250 mg/kg bw/day on gestation days 6-18, then sacrificed on gestation day 29 for examination of reproductive tracts and fetuses. High-dose does had clinical signs (hypoactivity, ataxia, audible respiration, gasping, and coughing), and decreased body weight gain and food consumption. Treatment killed 1 mid- and 1 high-dose doe, and 1 mid-dose doe aborted. The treatment had no adverse effects with respect to gravid uterine or relative liver weights of does, number of corpora lutea, total, viable, or nonviable implantations, sex ratio, fetal body weights, or incidences of external, visceral, or skeletal malformations or variations. The NOEL's for maternal and developmental toxicity in rabbits were 25 and at least 250 mg/kg bw/day, respectively.[BUSHY RUN RESEARCH CENTER; 90-day Oral (Dietary Administration) Toxicity Studies of 2-EHA in the Mouse & Rat & Developmental Toxicity Evaluations of 2-EHA Administered in Rats & White Rabbits, (1988), EPA Document No. 40-8697194, Fiche No. OTS0525548] **UNREVIEWED**
  • 2-Ethylhexanoic acid was tested for developmental toxicity in groups of 25 bred female Fischer 344 rats treated by gavage with dose levels of 0, 100, 250, or 500 mg/kg bw/day on gestation days 6-15, then sacrificed on gestation day 21 for examination of reproductive tracts and fetuses. The treatment had no adverse effects with respect to maternal survival, body weight gain, food consumption, or gravid uterine weight. Relative liver weights were significantly increased in high-dose dams. Clinical signs of toxicity observed in high-dose dams included hypoactivity, ataxia, audible respiration, ocular discharge, and periocular encrustation. The treatment did not affect the number of corpora lutea, total, viable, and nonviable implantations, sex ratio, or the incidences of external, visceral, or skeletal malformations. Mid- and high-dose fetuses had an increased incidence of skeletal variations (usually poorly ossified skeletal districts) and high-dose fetuses had an increased incidence of a visceral variation (dilated lateral ventricles on the brain with no tissue compression). The NOEL's for maternal and developmental toxicity in rats were 250 and 100 mg/kg bw/day, respectively.[BUSHY RUN RESEARCH CENTER; 90-day Oral (Dietary Administration) Toxicity Studies of 2-EHA in the Mouse & Rat & Developmental Toxicity Evaluations of 2-EHA Administered in Rats & White Rabbits, (1988), EPA Document No. 40-8697194, Fiche No. OTS0525548] **UNREVIEWED**
  • Acute dermal toxicity was evaluated in 4 rabbits (sex and strain not reported) receiving single occluded applications of 2-ethylhexanoic acid as a 40% solution in DMSO at a dose level of 6.4 g/kg of body weight. Mortality was observed in 1 animal; the LD50 value was reported to be 6.4 g/kg. Clinical observations were not reported. Gross necropsy revealed extensive autolysis.[Union Carbide Corporation; Summary of Environmental Data, (1984), EPA Document No. 40-8497047, Fiche No. OTS0512952] **UNREVIEWED**
  • Pharmacokinetics of 2-ethylhexanoic acid (EHA) was evaluated in 4-8 female Fischer 344 rats treated once by gavage with dose levels of 100 or 1000 mg 14C-EHA/kg bw. Blood sample, urine, feces, and cage rinsings were collected at intervals throughout a 96-hour sampling period and assayed for radiolabeled EHA by liquid scintillation spectrometry; urine was also assayed for metabolites of EHA by HPLC or GS-MS. After administering 100 mg/kg, peak blood levels of 85.1 ug equivalents/g blood were detected within 15-30 minutes followed by triexponential decline with a terminal half-life of 98 hours. The majority of the 2 administered doses (87%) were eliminated within the first 24 hours. Rats excreted 79.3% and 82.3% of the administered low and high dose, respectively, in the urine, and 12.4 and 6.7%, respectively, were excreted in the feces during the 96-hour sampling period. The primary urinary metabolites at both dose levels were the glucuronic acid conjugate of EHA, 2-ethyl hexanedioic acid, isomers of hydroxy-2-ethylhexanoic acid, and 2 lactones.[CHEMICAL MANUFACTURERS ASSOCIATION; Pharmacokinetics Studies with 2-Ethylhexanoic Acid in the Female Fischer 344 Rat, (1987), EPA Document No. 40-8797191, Fiche No. OTS0525547] **UNREVIEWED**

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Footnotes

1 Source: the NTP's CEBS database.

2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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