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EC number: 249-079-5
CAS number: 28553-12-0
Dermal absorption of 14C-DINP was studied in male Fischer 344 rats in
both conditioned (pretreatment with non-labeled DINP) and
non-conditioned skin (ExxonMobil, 1983a; McKee et al., 2002). Following
exposure, the dosed area was occluded. Under all conditions, the amount
of DINP absorbed after 7 days ranged from 2 to 4% with approximately
93−99% of the administered radioactivity recovered at the site of
application. Radioactivity in feces and gut of the exposed rats
suggested some excretion occurred via the biliary route. These results
are in agreement with the work published by Elsisi et al (1989) which
demonstrated that dermal absorption decreases as carbon chain length
Absorption of DINP via the gastrointestinal tract decreases as dose
increases (49% at the low dose of 50 mg/kg compared to 39% at the high
dose of 500 mg/kg; eliminated in urine) leading to an estimated
absorption of approximately 50%. In addition, absorption of DINP seems
to be of a saturable process. Increasing the dose results in an
increased amount of unabsorbed compound being eliminated (fecal
radioactivity associated with parent compound increased from 8% to 41%
from a single low dose to the high dose).
Once absorbed, DINP is de-esterified to the monoester and then further
metabolized by side-chain oxidation of the ester group or by hydrolysis
to phthalic acid. Most of the 14C collected in the urine of rats
following a single oral dose of 14C-DINP was in the form of phthalic
acid or side-chain oxidation products of the monoester (MINP). The
relative amount of phthalic acid in the urine decreased at the high
dose. The monoester itself, as well as the diester, was present in only
trace amounts. In feces, 8 and 41% of the radioactivity was associated
with the diester following administration of a low (50 mg/kg) or a high
(500 mg/kg) oral dose of 14C-DINP. This indicates saturation of
metabolism at the high dose. The remainder of the fecal radioactivity
was associated with the monoester or its side-chain oxidation products.
Major metabolites in the liver were the monoester and its side-chain
oxidation products. The same metabolites and phthalic acid were in
testes. The fat compartments contained the monoester and its oxidation
products. Repeated exposures revealed similar metabolites in the
tissues. Repeated dosing did not result in accumulation of DINP and/or
its metabolites in blood and tissue, but rather in increased formation
and elimination of the monoester-oxidation products. In summary, in the
rat, DINP was de-esterified to the monoester, which was further
metabolized by side-chain oxidation of the ester group or by hydrolysis
to phthalic acid. Formation of oxidation products appeared to increase
following the high dose or repeated dosing, while the hydrolysis to
phthalic acid decreased.
In humans, DINP is also rapidly metabolized to the simple monoester,
mono-iso-nonylphthalate (MINP), and oxidized isomers with hydroxy
(OH-MINP), oxo (oxo-MINP) and carboxy (carboxy-MINP) functional groups
(Koch and Angerer., 2007).
In male and female Fischer 344 rats receiving single or repeated oral
doses of 14C-DINP, radioactivity cleared from the tissues rapidly, but
analysis of tissues within 1 hour after the exposure indicated that the
highest levels were in liver (4.7% of administered dose), kidneys
(0.31%), and blood (1.62 %). Fat and testes contained small amounts of
metabolites. No bioaccumulation occurred over 72 hours post-dosing.
DINP is rapidly excreted; the majority of orally administered material
excreted in urine and feces within 24-48 hours, and less than 0.1% of
radioactivity was recovered in tissues after 72 hours. The major routes
of excretion for orally administered DINP in rats were urine and feces,
with about equal amounts excreted by either route at low doses, but more
excreted in feces at high doses. The biological half-life is
approximately 7 hours. Repeated dosing did not cause accumulation of
DINP or its metabolites in blood or tissue, but rather increased
formation and elimination of the monoester side-chain oxidation products.
In humans, within 48 h of administration, 43.6% of the applied dose in
urine was recovered as DINP metabolites: 20.2% as OH-MINP, 10.7% as
carboxy-MINP, 10.6% as oxo-MINP and 2.2% as MINP (Koch and Angerer.,
2007). Elimination followed a multi-phase pattern; elimination
half-lives in the second phase (beginning 24 h post-dose) can only
roughly be estimated to be 12 h for the OH- and oxo-MINP-metabolites and
18 h for carboxy-MINP metabolites. After 24 h, the carboxy-MINP
metabolites replaced the OH-MINP metabolites as the major urinary
Discussion on bioaccumulation potential result:
The acute exposure toxicokinetic studies conducted in F344 rats by oral
administration showed that, at a low dose (50 mg/kg), approximately half
of the DINP was excreted in the urine within about 24 hours. The
remainder of the dose was excreted in the feces within 96 hours. At the
high dose (500 mg/kg) the fraction excreted in the urine was about 40%
of the administered dose. In the repeated dose studies (5 daily doses of
50, 150, and 500 mg/kg) approximately 60% of the administered dose was
excreted at all doses, suggesting an elevation of esterase activity and
more rapid conversion to monoester following repeated treatment. Based
on these urinary excretion data, the half-time for elimination of
absorbed phthalate was about 7 hours. The dermal absorption study
(approximately 0.2 ml/rat), by contrast, indicated that absorption was
very slow, with 2-4% of the applied dose being absorbed within 7 days.
However, the data indicated that DINP was rapidly metabolized and
excreted once it was absorbed; the approximately biological half life is
7 hours (McKee et al., 2002).
As shown in McKee et al (2002), most of the orally administered DINP was
recovered in urine (52-59%) and feces within 48 hours of
administration. Urinary metabolites were primarily oxidation products of
MINP (monoisononyl phthalate) and phthalic anhydride. There was little,
if any, un-metabolized DINP or MINP in the urine. The majority of the
material recovered from the feces was unmetabolized DINP. Measurements
of phthalate (as total radioactivity) in tissue indicated that the
majority of the absorbed material went into the blood, liver and kidney
compartments with little radioactivity elsewhere. In the liver, the
major metabolites were MINP and oxidized MINP. In
general, the highest levels of radioactivity in these compartments were
found 2 to 4 hours after oral dosing, and declined thereafter. Estimated
elimination half-times from the blood and tissue compartments were 3.5
to 4.5 hours. Repeated dosing caused no accumulation
of DINP and/or its metabolites in blood and tissue, but resulted in
increased formation and elimination of the monoester-oxidation products.
Similar results have been observed in other studies (Silva et al.,
Urinary metabolites of DINP have also been quantified in several human
studies with the hopes of using them as biomarkers of exposure. In a
single subject human metabolism study of DINP (Koch and Angerer., 2007),
it was observed that metabolites included the urinary excretion of the
simple monoester, mono-iso-nonylphthalate (MINP), and oxidized isomers
with hydroxy (OH-MINP), oxo (oxo-MINP) and carboxy (carboxy-MINP)
functional groups. Within 48 h, 43.6% of the applied dose in urine was
recovered as the above DINP metabolites: 20.2% as OH-MINP, 10.7% as
carboxy-MINP, 10.6% as oxo-MINP and 2.2% as MINP. Elimination followed a
multi-phase pattern; elimination half-lives in the second phase
(beginning 24 h post-dose) can only roughly be estimated to be 12 h for
the OH- and oxo-MINP-metabolites and 18 h for carboxy-MINP metabolites.
After 24 h, the carboxy-MINP metabolites replaced the OH-MINP
metabolites as the major urinary metabolites. With regard to ambient
exposure to DINP, studies that examined urinary metabolites identified
MINP and oxidative metabolites (Silva et al., 2004, 2006b), in agreement
with the work of Koch and Angerer (2007). Thus, in
humans, as in animals, approximately half the ingested DINP is absorbed
and then rapidly metabolized and excreted in urine and feces.
In summary, studies in both laboratory animals and humans demonstrate
that DINP is rapidly absorbed from an oral route of exposure and quickly
metabolized into the mono-ester (MINP) which can then be further
transformed into oxidative metabolites.
Discussion on absorption rate:
The dermal absorption 14C-DINP was determined to be slow in rats, but it
occurred at a steady rate as evidenced by the increased amounts of
radioactivity recovered in urine, feces, and tissues. The total amounts
absorbed during a 7-day period ranged from 2 to 4% of the applied doses.
Therefore, there is a low potential for dermal absorption of DINP since
most of the dose remains unabsorbed at the application site.
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