2-ethylhexanoic acid

Endpoint summary

Description of key information

Oral, intravenous, and dermal doses were absorbed and eliminated rapidly, predominantly in the urine during the first 24 hours following dosing. Washing of the skin promptly after dermal exposure prevented absorption through the skin. Occlusive dermal exposure to the test substance caused considerable damage to the epidermis in the first 24 hours after application, and the dermal absorption values that were observed were considered to be very different from those expected on intact skin. Elimination processes were saturated at the 1000 mg/kg oral dose level.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

In a toxicokinetic study with radiolabeled 2 -EHA (CMA, 1987), groups of eight F344 rats were administered single doses containing 100 or 1000 mg/kg bw of the test substance. In the repeat-dose oral studies, groups of 4 animals were given oral doses of 100 mg/kg bw day of the non-labelled test substance for 14 consecutive days; animals were placed in the metabolism chambers after administration of the radioactive (15th) dose. In the dermal studies, groups of eight animals were administered a single dose of either 100 or 1000 mg/kg bw of the test substance. Intravenous administration was accomplished by injecting 1 mg/kg bw of radioactive test substance mixed with physiological saline into the tail veins of eight animals.

Following a single oral dose of either 100 mg/kg bw or 1000 mg/kg bw, radioactivity was rapidly eliminated in the urine, with excretion of 72-75% of the dose within 24 hours. At the 100 mg/kg bw dose level, 50.4% was eliminated within 8 hr and 75.7% was eliminated in 24 hr. At the 1000 mg/kg bw dose level, means of 19.8% and 72.4% were eliminated in 8 and 24 hr, respectively. Small amounts of¹⁴C were detected in urine between 24 and 96 hr (3.6% at the lower dose, 9.8% at the higher dose). Fecal elimination of radioactivity was 12.4% and 6.7% of the 100 mg/kg bw and 1000 mg/kg bw doses, respectively, over the 96 hr collection period. Most was recovered within 24 hours of dosing. The total recovery of radioactivity after single oral administration was 91.7 +/- 2.8% (100 mg/kg bw) and 88.9 +/- 1.0% (1000 mg/kg bw).

Recovery of urine radioactivity from animals repeatedly administered unlabeled test substance, followed by a radioactive dose of 2-EHA, was 37.9% and 57.3% in 8 and 24 hours, with 3.3% recovery between 24 and 96 hr. Fecal elimination of radioactivity was 14.9% of the dose in these animals, mostly from the 24 hour sample. The total recovery of radioactivity after repeated oral administration of 100 mg/kg bw was 75.5 +/- 4.4%.

Following a dermal dose of 100 mg/kg bw, 10.3% of the¹⁴C was excreted in the urine in 8 hr, and 33.2% was eliminated in 24 hours. At a dermal dose of 1000 mg/kg bw, 4.0% was excreted in the urine in 8 hr, and 29.7% was eliminated in 24 hours. An additional 8.5% and 17.0% of the radioactivity was detected in the urine between 24 and 96 hr in the 100 mg/kg bw and 1000 mg/kg bw animals, respectively. Fecal elimination of radioactivity over the course of the study in the dermally exposed animals was 7.5% at the 100 mg/kg bw dose and 7.1% at the 1000 mg/kg bw dose, mostly from the 24-hour fecal samples. The total recovery of radioactivity after dermal application was 49.2 +/-17.3% (100 mg/kg bw) and 53.7 +/-14.2% (1000 mg/kg bw). The low recoveries of [¹⁴C] in the dermal studies may be largely due to losses through the exhalation of [¹⁴C]CO₂. In a similar study of 2-ethylhexanol, which is metabolized exclusively through the formation of 2-EHA, 23 % of the dose (1 mg/kg i.v.) was recovered as [¹⁴C]CO₂(Deisinger et al. 1994).

Radioactivity was rapidly excreted in the urine following intravenous administration of¹⁴C -2-ethylhexanoic acid. Within 8 hr, 47.9% was excreted in the urine, and 64.2% was excreted by 24 hr. Another 2.4% was excreted between 24 and 96 hours. Fecal elimination was 3.6% of the dose. The total recovery of radioactivity was 70.2 +/-4.2%.

Blood levels after intravenous injection appear to decay in a triphasic manner with half lives of 0.19 ± 0.11 hr, 6.6 ± 3.9 hr, and 117 ± 47 hr. After oral administration, peak blood levels occurred after 15 to 30 minutes and also declined in a triphasic manner. Half-lives after oral administration were similar to what had been estimated from intravenous administration (0.32 ± 0.04 hr, 6.8 ± 3.5 hr, and 98.3 ± 32.8 hr). Dermal application resulted in slower absorption with peak blood levels occurring 5.7 ± 0.4 hr after application and an absorption half life of 3.2 ± 0.1 hr. Elimination of¹⁴C was biphasic with half-lives of 4.2 ± 0.2 hr and 251 ± 135 hr. The major urinary metabolites were the glucuronide of 2-EHA, 2-ethyl-1,6-hexanedioic acid, 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-6-hydroxyhexanoic acid, and ethylketohexanoic acid. From 2-7% was excreted as unmetabolized 2-ethylhexanoic acid following all oral and dermal dosing regimens. No sulphate derivatives were detected. Evidence for metabolism via β-oxidation was also found, consistent with the incorporation of 2-EHA into normal cellular intermediary metabolism.