Bis(2-ethylhexyl) adipate

Endpoint summary

Additional information

Summary

The data show that DEHA, administered orally to mice, rats, and monkeys, is readily absorbed, distributed to various tissues, metabolized and excreted in urine and to a lesser extent in feces and as exhaled CO₂ (CMA, 1984 study report). Dose-dependent changes in absorption, tissue uptake, metabolism, and elimination could be found. Sex differences were apparent in the hepatic uptake and metabolism. The data indicate little, if any, prolonged retention of DEHA or its metabolites in blood and tissue after oral administration in all three species. As could be expected based on the high logPoW of app. 9, dermal penetration is fairly limited.

Hydrolysis and Absorption in Mice

14C-DEHA and/or its metabolites was rapidly absorbed from the GI tract. The highest 14C levels were found in blood and liver 1 or 3 hr after dosing. In the GI tracts large amounts of the diester (DEHA) , monoester (MEHA) and alcohol (EH) were found. The quantities of DEHA decreased with time while other products increased. The major metabolites in the livers were more polar than EH. In general, only small amounts of DEHA, MEHA and EH were found. The livers of male mice also contained large amounts of an early eluting metabolite which was found in female livers in only small quantities. The extent of the two major metabolites recovered in livers of female mice differed significantly.

 

Dermal absoption

After occlusive application of 5 or 100 mg DEHA as a component of a roll-on deodorant onto human breast skin in vitro, 50 to 20% did not penetrate the skin, while 20 - 30% stayed within the skin. No differentiation was made in the study between stratum corneum and further layers of the skin. Only a small fraction (< 0.1%) were absorped through the skin at a constant rate of 2.2ng/cm²/h within 24h. Because DEHA is highly lipophilic, low penetration and high retention within and on top of the skin meet the expectations. But limited solubility of DEHA in the receiver solution (app. factor 4 above the actual concentration reached during the experiment) might lead to an underestimation of the maximum penetration, despite the use of a non-static system. Additionally, only 56 - 81% of the initial amount of DEHA was recovered. One explantion might be hydrolysis by esterases in the skin, which could lead to an additional uptake of DEHA metabolites.

Disposition in Mice

Preliminary studies with males: after treatment with 50 and 500 mg/kg 14C-DEHA, 95-102% of the 14C was eliminated in urine, feces and expired air within 24 hr. After 5,000 mg/kg, most of the 14C was excreted in 24 hr but ~12% were also recovered in the GI tracts. Definitive studies with male and female mice (50, 500 and 5,000 mg/kg 14C-DEHA): urinary elimination of 14C was rapid and extensive. About 91% of the low and mid doses were eliminated in urine in 24 hr; only 75% after 5,000 mg/kg. Elimination in feces was 7-8% at the low and mid doses and 4% at the high dose. The latter group showed high recovery in the GI tract. Only 0.8 to 1.2% in males and 1.5 to 3.8% in females were eliminated in the expired air. Respiratory elimination was highest in the female low dose group. Only small amounts were found in blood and tissue 24 and 48 hr after dosing. Adrenals and livers showed the highest levels at low and mid dose, especially in males. After 5,000 mg/kg, blood also contained high 14C levels; blood and liver content of the females were significantly higher than of males. At 48 hr, the skin (both sexes) and the fat (females) showed higher retention of 14C than other tissues.

 

Disposition in Rats and Monkeys

Compared to mice, rats showed lower elimination in urine(~74%) and higher in feces(~20%). 14C elimination in the expired air was 1.4 to 2.1%. About 4% of the dose was recovered in the GI tract. 14C levels in livers and adrenals were higher than in other tissues. Males showed significantly higher tissue contents than the females. Tissue contents in rats were higher than in mice treated with 500 mg/kg (same conditions). The monkeys also showed rapid elimination of 14C in urine and to a lesser extent in feces. Absorption was rapid, as indicated by the fast rates of elimination and by the fast appearance of 14C in blood after 2 hr. Radioactivity disappeared faster from blood of male monkeys compared to females. At 48 hr following dosing, the skin, fat, and livers of males showed the highest levels. In females the 14C concentrations in livers were significantly higher than in other tissues.

 

Metabolism

The data show that DEHA is rapidly hydrolyzed to the monoester, then the alcohol and acid, without accumulation of MEHA. Supporting data from an in vitro study indicate that this reaction already takes place in the small intestine after oral exposure (in vitro half life of DEHA = 6min) (Eastman, 1984). The alcohol is oxidized by ß-oxidation, W-, and W-l oxidation generating acids, ketones, keto-acids, hydroxy acids, and diacids. Metabolism appeared to be less extensive in monkeys, which mostly excreted MEHA and EH (as their glucuronides). In contrast, mice and rats mostly excreted products of faster oxidation, mainly glucoronidated EHA, 5-OH EHA and diEHA.

In humans and monkeys EHA (glucuronide) plays only a minor role (CMA, 1984).

In an in vitro study with human liver microsomes, 1-mono-(2 -ethyl-5-hydroxyhexyl) adipate (5OH-MEHA) and 1-mono-(2-ethyl-5 -oxohexyl) adipate (5oxo-MEHA) were additionally identified as metabolites, but only at 1/10 to 1/1000 of the concentration of adipic acid (Manori, 2013). In studies with human volunteers similar metabolites were found in urine. However, 1-mono-(2-ethyl-5 -carboxylpentyl) adipate (5cx-MEPA) was excreted at considerably higher concentrations compared to 5oxo-MEHA and 5OH-MEHA (Nehrig, 2019) and MEHA was only a minor metabolite of low quantitative relevance compared to the oxidized monoester metabolites (Nehrig, 2020).

In another study 5OH-MEHA was detected at a significantly lower frequency in finger nails than in urine in humans, suggesting that its accumulation is rather low (Alves, 2017).

MEHA was also found in fecal samples (Loftus, 1993, IUCLID chapter 7.10.5).