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EC number: 204-528-4
CAS number: 122-20-3
- No signs
of toxicity were noted during the in-life phase of the study. The doses
delivered were within 7-12% of the targeted dose levels. Between 94% and
96% of the administered radioactivity was recovered in the urine, feces,
14CO2, tissues / carcass, and final cage wash.
principle route of excretion was urine, which contained 81-85% of the
total dose. Feces contained 4-7%, 3-5% was eliminated as 14CO2, <2% was
recovered in the tissues/carcass and final cage wash. The amount of 14C
in the traps for volatile organics was negligible.
concentration of radioactivity was found in the initial blood sample
0.25 hours post-dose. The concentration decreased in a triexponential
manner. A 5-fold decrease in radioactivity was accomplished in the first
Half-lives for the rapid initial, middle, and terminal phases were 0.76,
3.6, and 38.5 hours, respectively. Most of the dose of radioactivity
(64-70%) was excreted in the urine 0-6 hours post-dosing. An additional
9-14% was excreted in the 6-12 hour interval. By 24 hours post-dosing,
82.8% of the dose was excreted. As with urine, 84.6% of the fecal
radioactivity was eliminated during the first 24 hours.
This study examined the metabolism and
excretion of triisopropanolamine-1-14C (14C-TIPA) in male rats when
administered concomitantly with 2,4 -dichlorophenoxyacetic acid (2,4
-D), and was conducted to support re-registration of products containing
the TIPA salt of 2,4 -D (2,4 -D TIPA).
Four male Fischer 344 rats were given a
single oral dose of a solution providing targeted doses of 10 mg 2,4
-D/kg and 10.7 mg 14C-TIPA/kg of body weight.
The concentration of radioactivity in the
plasma peaked 0.25 hr post-dosing at 4.48 +/- 1.19 ug eq/g plasma and
then decreased in a tri-exponential manner. Between 94 and 96% of the
administered radioactivity was recovered in the urine, feces, expired
14CO2, tissues/carcass and final cage wash. The major route of excretion
was the urine with approximately 80% of the dose excreted by this route
in the first 24 hr post-dosing and 81 to 85% excreted by 72 hr
post-dosing. The feces accounted for only 4 to 7 % of the dose. Expired
14CO2 accounted for 3 to 5% and the final cage wash ~1% of the dose.
Less than 1% of the administered radioactivity remained in the tissues
and carcass when these rats were sacrificed 72 hr post-dosing.
Essentially all radioactivity excreted in the urine represented
unchanged 14C-TIPA based on GC/MS and GC/MS/radiogas analysis of the
urine excreted 0 -12 hr post-dosing. Additionally, the urinary excretion
of 2,4 -D during the 0 -12 hr post-dosing interval (70.5% of the dose)
was nearly identical to that excreted during this interval following
oral administration of a 1 mg 2,4 -D/kg dose (69.3 +/- 13.1%).
These data demonstrate that orally
administered 14C-TIPA was rapidly absorbed and rapidly excreted
primarily in the urine as unchanged TIPA. Due to its rapid elimination,
14C-TIPA should not accumulate in the rat upon daily administration.
The registered substance is known to be rapidly absorbed and rapidly
excreted primarily in the urine as unmetabolized TIPA after oral
administration. Thus, oral absorption is determined to be 90%. The
absorption for the inhalative route is determined to be 100% by default
in the absence of reliable study data. The dermal absorption is supposed
to be 20% based on knowledge from an acute oral study, dermal
toxicokinetic knowledge of the structurally similar analogue and QSAR
modelling for dermal penetration of TIPA. Distribution, metabolism and
bioaccumulation are assumed to be limited as TIPA is rapidly excreted
primarily unmetabolized in the urine.
The expected toxicokinetic behaviour is derived from an
experimental study in male Fischer 344 rats, the physico-chemical
properties and results from the available acute and repeated dose
Experimental study: metabolism and excretion in vivo (1992, RL1
Triisopropanolamine-1-14C (14C-TIPA) was administered
concomitantly with 2,4 -dichlorophenoxyacetic acid (2,4 -D) orally as a
single dose to four male Fischer 344 rats, according to OECD 417. A
single oral dose, equivalent to 10.7 mg 14C-TIPA/kg bw, was
administered, followed by blood sampling at intervals up to 72 hours
post-dose. Radioactivity peaked in the plasma at 0.25 hrs post-dosing
and declined tri-exponentially. The urine was the major route of
excretion with about 80% of the dose excreted in 24 hours and 81 to 85%
of the dose excreted in 72 hours, primarily unmetabolized. The faces and
expired air accounted for only 4% to 7% and 3% to 5%,
respectively. After 72 hours, 94% to 96% was recovered with only less
than 1% remaining in the tissues or carcass.
TIPA is a tertiary amine with three identical isopropanol
substituents with the molecular formula C9H21NO3. Its reactivity is
mainly triggered by its basicity, i.e. a dissociation constant (pKa) of
7.86 at 25 °C. The solid TIPA has a molecular weight of 191.27 g/mol,
melts at 45°C and boils at 301°C, measured at 1,013 hPa. The calculated
vapour pressure is 8x10E-6 hPa at 20 °C, the octanol-water partition
coefficient (log Pow) is ‑0.015 at 23 °C, and the measured solubility is
830 g/L at 20 °C.
In the experimental toxicokinetic study it was concluded that
orally administered TIPA was rapidly absorbed and therefore, an oral
absorption percentage of 90% is assumed for TIPA based on the study
results (1992, RL1).
In the acute and repeated dose toxicity studies low toxicity was
observed: In rats the oral LD50 was 4,000 mg/kg bw (1966, RL2). At this
dose and above various clinical signs were noted (e.g. piloerection,
high stepping gait, mouth and eye discharge, diarrhoea, lateral and
abdominal position, slight tremor, partly dyspnoea, eye and nose crusts,
ruffled fur smeared at the anogenital region, nose and mouth), and
gastro-intestinal irritation and remaining substance in the stomach were
observed upon macroscopic examination in one animal of the highest dose
group (i.e. 6,400 mg/kg bw). In other investigations, the established
oral LD50 values in rats were 6,500 mg/kg bw (Smyth et al., 1941, RL2)
and 6,000 mg/kg bw (1980, RL2).
In an oral repeated dose study, beagle dogs were administered 0,
500, 2,000 or 7,500 ppm TIPA in their diet for 102 - 104 days (1987,
RL2). Ophthalmology, haematology, serum chemistry, urinalysis, blood
methaemoglobin, macroscopic and microscopic examinations, and organ
weight evaluations showed no treatment-related effects, resulting in a
NOAEL of 272 -288 mg/kg bw/day (the highest dose tested). In a different
repeated dose study TIPA was administered to groups of male and female
CDF Fischer 344 rats in their drinking water for 2 weeks at targeted
doses of 0, 100, 300, 600, 1,200 or 2,000 mg/kg/day (1981, RL2). The
animals showed only slight evidence of treatment related effects at the
higher doses, i.e. slight decreases in body weight gain of both sexes.
The observed increase in kidney weights at doses of 300 mg/kg/day and
higher were suggested to be a functional adaptation rather than toxicity.
There are no reliable study data available on inhalation toxicity
for TIPA due to its extremely low vapour pressure of 8x10E-6 hPa (20°C)
resulting in a low volatility. Therefore, inhalation appears to be
report of an acute study (1966, RL3) where rats were whole-body exposed
to a saturated vapour atmosphere of TIPA for 8 hours, caused no deaths.
In a report about respiratory irritation (Detwiler-Okabayashi and
Schaper, 1996, RL2) mice were exposed to aerosol concentrations of 329 –
1070 mg/m3 for three hours without the finding of a dead animal.
Due to the lack of reliable studies, the absorption by inhalation
is assumed to be 100% for TIPA in a conservative approach.
There are no specific studies available in which the dermal
toxicokinetic properties have been investigated. No evidence of systemic
toxicity was reported upon dermal application of TIPA in acute and
repeated dose toxicity studies: In an acute toxicity study in New
Zealand White rabbit, the dermal LD50 was >5,000 mg/kg bw (1980, RL2).
Moderate erythema was noted in both rabbits, slight oedema and necrosis
was observed in one rabbit after 24h of application but no evidence of
systemic toxicity was reported.
The test results for dermal absorption of a structurally similar
substance with comparable physico-chemical and toxicological properties
are used to give a prediction of the dermal absorption for TIPA of 20%.
The identity of the two analogue isopropanolamines
1,1’-Iminodipropan-2-ol (DIPA, CAS: 110-97-4, MW = 133.2 g/mol) and TIPA
was assessed in a SIDS Initial assessment report for SIAM 29 (October
In the toxicokinetic study of the analogue DIPA, Fischer 344 rats
received a dermal application of 19.5 mg/ kg 14C-DIPA in acetone to an
area of 1 cm2 on the back and covered with a bandage (Saghir et al.,
2007, RL2). Time-course blood and excreta were collected, and
radioactivity determined. Urine was analysed for DIPA and
monoisopropanolamine (MIPA). Following dermal application, 20% of the
dose was absorbed in 48 h with the steady-state penetration rate of
0.2%/h. Most (14.4%) of the applied radioactivity was excreted in urine
at a relatively constant rate due to the presence of large amount of the
14C-DIPA at the application site. Faecal elimination was < 0.2% of the
dose. The absorbed DIPA did not accumulate in tissues; only 0.1% of the
administered dose was found in liver and kidney. The absolute systemic
dermal bioavailability (dose corrected AUCdermal/AUCi.v.) of 14C-DIPA
The high molecular weight of TIPA restricts its uptake to a higher
extent in comparison with DIPA. This physico-chemical nature combined
with a water solubility above 10 g/L and a log P value below 0 supports
the hypothesis that the substance may be too big and hydrophilic to
cross the lipid rich environment of the stratum corneum. The DERMWIN
version 2.02 application (US EPA, 2018) was used to estimate the dermal
permeability coefficient Kp (DERMWIN, 2012). Following the
interpretation of the JRC QSAR group of the European Commission (Bassan
and Patlewicz, 2005) the calculated Kp = 0.000129 cm/hr is classified to
be “very low”. These data support the conservative approach of the
dermal absorption for TIPA of 20%.
There are no specific studies available in which the toxicokinetic
distribution have been investigated. In the experimental oral
toxicokinetic study it was concluded that the absorbed TIPA was rapidly
excreted primarily in the urine as unchanged TIPA (1992, RL1). Less than
1% of the administered dose remained in the carcass and tissues 72 hr
post-dosing. Concentrations of radioactivity were low in all tissues
with the liver containing the greatest concentration, approximately
0.02% of the dose/g wet weight. A higher volume of distribution is
therefore highly unlikely and is not suggested for TIPA.
The distribution of radioactive TIPA in the experimental oral
toxicokinetic study (1992, RL1) was discussed before. The fast
absorption and excretion lead to the finding that very small amounts of
TIPA remained in the liver (~ 0.02%) of the dose/g wet weight. The
remaining tissues and carcass contained less than 0.01% of the dose/g
wet weight. Based on these findings, TIPA is not assumed to accumulate
in the rat upon daily administration.
In the described experimental toxicokinetic study the pooled urine
samples were stored frozen (-80°C) until analysed for 2,4-D and for
14C-TIPA and metabolites (1992, RL1). The GC/MS analysis of the
specimens indicated that virtually all radioactivity in the urine
represented unchanged 14C-TIPA. Mass spectra and extracted ion
chromatograms for the derivatised urine extract and TIPA standard were
identical. Only a single peak, with the same retention time as
derivatised TIPA standard, was observed in the GC/MS/Radiogas
chromatogram of the derivatised urine extract. Additionally, 95% and 80%
of the radioactivity in the 0-6 and 6-12 hr pooled urine sample,
respectively, could be accounted for by the amount of TIPA found in
these samples by GC/MS.
The experimental toxicokinetic study found that most of the dose
(64-70%) was excreted in the urine during the 0-6 hr collection interval
(1992, RL1). An additional 9-14% of the radioactivity was excreted in
the 6-12 hr interval. By 24 hr post-dosing, 82.8% of the dose was
recovered in the urine and only 1% of the dose was excreted in the urine
between 24 and 72 hr post-dosing. As with the urine, most (84.6%) of the
faecal radioactivity was eliminated during the first 24-hr postdosing.
The amount of radioactivity in the 0-12 hr collection interval (3-4% of
the dose) represented over 86% of the 14CO2 excreted during the entire
72 hr post-dosing interval.
The principle route of excretion was urine, which contained 81-85%
of the total dose. Faeces contained 4-7%, 3-5% was eliminated as 14CO2,
<2% was recovered in the tissues/carcass and final cage wash. The amount
of 14C in the traps for volatile organics was negligible.
There is experimental evidence that TIPA can be absorbed after
oral exposure. An oral absorption of 90% was experimentally determined.
The absorption by the inhalative and the dermal route were assessed in
conservative approaches. TIPA has a low volatility and therefore
inhalation is assumed to be limited, however, in the absence of reliable
studies an absorption of 100% is determined. The dermal absorption was
supposed to be 20% for TIPA based on findings in an acute dermal
toxicity study,dermal toxicokinetic knowledge of the structurally
similar analogue DIPA and QSAR modelling for dermal penetration of TIPA.
As TIPA was rapidlyexcreted primarily unmetabolized in the urine in the
oral toxicokinetic study, metabolism was suggested to be limited and
bioaccumulation was not assumed.
Arianna Bassan and Grace Patlewicz, 2005, “User Manual for the
Internet Version of the Danish (Q)SAR Database - Database Version 1 May
2005”, QSAR Group, Institute for Health and Consumer Protection (IHCP),
Joint Research Centre, European Commission, Via E Fermi, 21020 Ispra
US EPA, 2018: Estimation Programs Interface Suite™ for Microsoft®
Windows, v 4.11. United States Environmental Protection Agency,
Washington, DC, USA.
DERMWIN, 2012: Kp (est): 0.000129 cm/hr
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