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EC number: 203-227-5
CAS number: 104-68-7
Toxicokinetic data are available from an OECD 422 study where ADME parameters were included into the range finding study. In addition, data on the structurally related substance phenoxy ethanol are provide for comparison and in support of the use of read across between these two substances
Toxicokinetic information on Di-EPh:
An assessment of toxicokinetics was included as part of the range finder
for the OECD 422 study using Di-EPh. Plasma and urine samples were
screened for biomarkers of exposure following dietary consumption of
rodent feed prepared to deliver Di-EPh doses of 0, 250, 500 and 1000
mg/kg/day. The primary purpose of the study was to characterise the
metabolism and excretion pathway and determine key parameters such as
the Cmax, AUC and half life for excretion. A complete mass balance was
not possible in the study since a radiolabel was not used. Therefore
although it was possible to identify metabolites and rates of excretion
it was not completely possible to assess oral bioavailability and
excretion via air and feces (although these two parameters are not
considered to be significant routes of excretion for this substance).
Based on the possible routes of metabolism several biomarkers were
identified. Plasma and urine were then screened to identify the presence
of these biomarkers.
• Diethylene glycol phenyl ether (Di-EPh),
• 2-(2-Phenoxyethoxy) acetic acid (PEAA)
glycol Phenyl Ether (EPh)
• Phenoxyacetic acid (PAA).
• ethylene glycol (EG),
• diethylene glycol (DEG),
• phenoxy ethanol (PE),
• hydroxylethoxy acetic acid (HEAA),
• diglycolic acid (DGA),
• glycolic acid (GA),
• oxalic acid (OA),
Of this set of biomarkers, the screening experiments identified only
Di-EPh, PEAA, and PAA. The levels of the other potential biomarkers were
low relative to both background PEAA or PAA levels. Therefore, no
definitive quantitative data was generated for EG, DEG, PE, HEAA, DGA,
GA, or OA.
Quantitative Toxicokinetic Assessment
Di-EPh was not present at levels above the lower limit of quantitation
(LLQ) in most of the blood samples. The two metabolites, PEAA and PAA,
were present at higher levels in the blood. PEAA was present well above
the limit of quantitation and in nearly all of the blood samples from
exposed animals, while PAA was present in 50 percent of the blood
samples. For this reason, systemic exposure (AUC24h) and elimination
half-life (t½) values could only be calculated for PEAA. PEAA systemic
exposure (AUC24h) values were dose-proportional in both males and
females. Half-life values based on PEAA blood levels were approximately
7.4 hours, on average, and ranged 3.9-15.6 hours.
Di-EPh, PEAA, and PAA all were present at concentrations above the LLQ
in all urine samples from treated animals. On average, only 1.3 percent
of the dose was excreted as Di-EPh in the 24 hour urine, whereas 39.3
percent of the dose was excreted as PEAA and 4.3 percent of the dose was
excreted as PAA. Urine levels of all three analytes were
dose-proportional. These data suggest Di-EPh was rapidly metabolized at
all dose levels. A major portion of the dose was metabolized to PEAA (≥
39.3% of the administered dose, 87.5% of the recovered dose). A smaller
portion was metabolized to PAA (≥ 4.3% of the administered dose, 9.6% of
the recovered dose). The administered dose was estimated using test
material concentration in the food and food intake data on the day
preceding the analysis. However, as indicated previously, the
estimations of intake do not represent an accurate assessment of
bioavailability since a full mass balance was not possible in the study
design. There was no apparent saturation of absorption, distribution or
elimination at any dose level. Thus, Di-EPh exhibits linear kinetics up
to, and including, 1000 mg/kg/day via dietary exposure.
From this data it is concluded that Di-EPh is rapidly absorbed via the
oral route and extensively metabolised in the liver to an acid
metabolite (PEAA) which is excreted via the urine. A relatively small
proportion of the dose is metabolised first to PE and then to PAA, which
is then excreted in the urine. This toxicokinetic data on Di-EPh
demonstrate that it has a parallel metabolic pathway, tissue
distribution and excretion pathway to phenoxyethanol.
Oral bioavailability of Di-EPh
As indicated, the study design did not permit an accurate assessment of
the oral bioavailability of Di-EPh. In order to complement the in vivo
data, a QSAR model was used to predict the potential oral
bioavailability and compare this to EPh. The model predicted that
following an oral exposure, >95% of the dose would be systemically
Dermal bioavailability of Di-EPh
No data are available. Read across to EPh is used.
Dermal absorption studies in rats (in vivo and in vitro) and humans (in
vitro) demonstrate that EPh is well absorbed via the dermal route,
particularly under occlusive conditions. Under non-occlusive conditions
the percent absorption in rats (24hr, flow through, approx 43%) was
comparable to humans (6 hr, flow through, 59%). Under occlusive
conditions the absorption through rat skin was higher (>90%); no human
data are available for comparison under occlusive conditions.
Based on the available data it appears that the skin does not represent
a significant barrier to absorption of EPh. It is therefore expected
that in humans that the dermal bioavailability of both EPh and Di-EPH
would be approximately 60% unnoccluded and 100% occluded.
Inhalation Bioavailability of Di-EPh
No data are available. However, given the high level of absorption via
the oral route, the low molecular weight (<250) and high water
solubility, it is assumed that Di-EPh would be almost completely
absorbed following an inhalation exposure.
For certain endpoints (repeated dose and developmental toxicity) the use
of read across of data from EPh to Di-EPh is proposed. Supporting this
read across proposal is a comparison of the toxicokinetic data on these
two substances. As such, the available toxicokinetic data on EPh are
Data on EPh:
From the several studies available on EPh, it is clear that it is
rapidly absorbed via the oral route (>90%), rapidly and extensively
metabolised to PAA which is then excreted via the urine. Other
metabolites include hydroxylated ring metabolites and glucuronide and
sulphate conjugates. The glucuronide conjugates are excreted into the
bile and represent approximate 2-5% of the absorbed dose. The remaining
metabolites are excreted into the urine. There is some evidence that the
metabolism may become saturated at doses greater than 400 mg/kg bw
(bolus dose) and there also appears to be evidence of reuptake from the
urine in the kidney (also a saturable mechanism).
As with Di-EPh, the metabolism of EPh to PAA is via the alcohol
dehydrogenase enzyme system. In vitro data comparing the rate of
metabolism in different species demonstrates that humans metabolise EPh
significantly faster than rats and rabbits. A key toxicological effect
in animals is hemolysis of red blood cells at high doses. The metabolism
of EPh to PAA is a detoxification pathway and as such, the difference in
metabolic rate forms the basis for the differences in hemolysis observed
between humans, rats and rabbits.
Dermal absorption studies in rats (in vivo and in vitro) and humans (in
vitro) demonstrate that phenoxy ethanol is well absorbed via the dermal
route, particularly under occlusive conditions. When unoccluded the
percent absorption in rats (24hr, flow through, approx 43%) was
comparable to humans (6 hr, flow through, 59%). Given that the degree of
absorption was higher under occlusive conditions in the rat studies
(>90%), it appears that the skin does not represent a significant
barrier to absorption of phenoxyethanol. It is therefore expected that
in humans, under occlusive conditions, absorption would be close to 100%.
No data are available on the inhalation absorption of phenoxy ethanol,
however based on the complete oral and dermal absorption, the molecular
weight <200 and high water solubility, it is assumed that approximately
100% would be absorbed via inhalation.
Comparison of PE and Di-EPh
Attached to this endpoint summary is the QSAR model output of the oral
uptake and distribution of EPh and Di-EPh referred to previously. It is
clear from this comparison that based on the physical chemical
properties both substances are expected to be highly absorbed following
the oral route. This is consistent with the measured data on EPh, and so
there is confidence in accepting this prediction. The volumes of
distribution of both substances are also very similar (EPh: 1.4 L/Kg;
Di-EPh: 1.3 L/Kg) indicating that both would have similar distribution
following absorption and would tend to remain in the body fluids rather
than accumulating in any particular tissue.
EPh is well absorbed via the dermal route and based on this and the
structural similarities, Di-EPh is expected to be similarly well
absorbed. The same conclusion is true for the inhalation route.
Both substances are rapidly and extensively metabolised via the same
enzyme systems to produce structurally similar and common metabolites.
As such, both sets of parent compound and metabolites share common
functional groups and would be expected to have similar biological
Both substances are excreted from the body rapidly via the urine with a
minor portion of the internal dose excreted in the feces. The
toxicokinetic data on EPh indicate some active re-absorption of PAA from
the urine in the kidney; it is assumed that a similar process will occur
Di-EPh and PE have very similar toxicokinetics. The similarities in
bioavailability, metabolic pathway, volume of distribution and excretion
routes provide support for the use of read across between these
It should however be noted that a critical toxicological effect of EPh
is red blood cell hemolysis. This effect is due to the parent compound
rather than the acid metabolite. There is no evidence in the available
toxicity studies on Di-EPh that this substance produces a hemolytic
effect. However, if it is capable of producing this effect at higher
doses than those studied, the fact that it shows similar toxicokinetics
to EPh indicates that it would be similarly detoxified by the rapid and
extensive metabolism to PEAA, and that the same differences in species
sensitivity (most sensitive - rabbits, least sensitive - humans) would
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