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EC number: 203-090-1
CAS number: 103-23-1
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
Absorption in Mice
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
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
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.
Rats and Monkeys
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.
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.
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
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).
also found in fecal samples (Loftus, 1993, IUCLID chapter 7.10.5).
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