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EC number: 247-426-5
CAS number: 26040-51-7
Physicochemico data, in-vitro and limited in vivo studies, as well as
toxicological studies indicate a low bioaccumulation potential of
bis(2-ethylhexyl) tetrabromophthalate. As metabolites only minor amounts
of mono(2-ethylhexyl) tetrabromophthalate (TBMEHP) and tetrabromo
phthalic acid (TBPA) were found.
Bis(2-ethylhexyl) tetrabromophthalate (TBPH) is an organic liquid
(melting point -27°C) with a MW of 706.2 g/mol and a high boiling point
(calculated boiling point = 539.75°C (at 1013 hPa)). The QSAR
determination of the vapour pressure of the substance using the model
MPBPWIN included in the Estimation Program Interface (EPI) Suite v4.11
revealed a value of 3.56E-7 Pa at 25°C. Due to the low vapour pressure
and high boiling point human exposure via the inhalation route is
assumed to be limited.
The calculated values for water solubility is 1.983E-9 mg/L at 25°C and
11.95 for Log Pow (according High Production Volume (HPV) challenge
Program, Test Plan for Phthalic acid tetrabromo bis 2-ethylhexyl-ester
(CAS #26040 -51 -7). In an experimental study, the water solubility of
the substance could not be detected without solubilizer and is reported
to be < 0.05 µg/l at 20°C. The partition coefficient of the substance
determined by HPLC was log Pow = 10.2 at 25°. Based on these values
there is no evidence of absorption due the insolubility of the substance
in water and the high octanol-water partition coefficient.
TBPH has very low acute toxicity (discriminating dose oral > 5000 mg/kg
bw and discriminating dose dermal > 2000 mg/kg bw (highest applied
doses). TBPH is not irritating to skin and eyes and not sensitizing.
In a subacute toxicity study with TBPH doses of 200, 2 000 or 20 000 ppm
(= ca. 21.97, 223.4 or 2331 mg/kg/day) there were no significant changes
in clinical signs, clinical chemistry, hematology, organ weights, or
histopathology. None of the animals died due to the application of the
test substance. Slightly low overall bodyweight gain was recorded for
females receiving the highest dietary concentration of the test item.
Males treated with the test substance were unaffected. Marginally low
alanine amino-transferase activities were seen in females receiving the
highest dietary concentration of the test substance, and marginally low
phosphorus concentrations were seen in all females and males receiving
the highest dietary concentration of the test substance.
In a subchronic 90 day repeated dose toxicity study according to OECD
408, oral administration of Bis(2-ethylhexyl) tetrabromophthalate (CAS
No. 26040-51-7) to male and female Wistar Han™:RccHan™:WIST strain rats
for ninety consecutive days at dose levels of 100, 300 and 1000 mg/kg
bw/day resulted in no treatment related changes. The No Observed Effect
Level (NOEL) is considered to be 1000 mg/kg bw/day, the highest dose
TBPH (called BEH-TEBP in this study) was administered to 4 female SD
rats per dose by oral gavage at 0.1 or 10 µmol/kg, and to 4 male
B6C3F1/Tac mice at 0.1 µmol/kg. The doses correspond to 0.07 (0.1
µmol/kg) and 7 mg/kg bw (10 µmol/kg). Disposition and elimination was
assessed (Knudsen et al., 2014 and 2017). The results of the current
studies indicate poor absorption and rapid elimination of BEH-TEBP as
parent compound. 92-98% of the radioactive compound was found unchanged
in feces after oral administration to mice and rats. A minor amount of
each dose (0.8-1%) was found in urine after 82 hours.
To determine disposition and elimination of systemically available TBPH,
TBPH was injected as a single intravenous bolus dose of 0.1 µmol/kg to
the SD rats (Knudsen et al., 2017). IV-administeredTBPH was slowly
eliminated in feces, with > 15% retained in tissues after 72 h. Bile and
feces contained the metabolite mono-ethylhexyl tetrabromophthalate.
Subsequent studies on four female SD rats with 10 daily oral doses of
0.1 µmol/kg radioactive TBPH were initated by Knudsen et al. (2017) to
determined the bioaccumulation potential of TBPH. Tissues and excreta
were collected 24 h after the last treatment and racioactivity
recoveries were recorded. Also after repeated oral exposure elimination
occurred mainly via feces (nearly 100%). Only a small amount of TBPH was
recovered in urine (about 0.6%). Thus, absoption was shown to be very
poor. Radioactivity was recorded in tissues, e.g. in liver and adrenals
with 113 and 207 pmol-eq/g, respectively. This accounts to 0.4% and
0.01% of the cumulated administered dose, respectively.
A parallelogram approach was used by Knudsen et al., (2016) to predict
human dermal absorption and flux for TBPH (called BEH-TEBP in this
study). [14C]-TBPH was applied to full thickness skin of 4 human
individuals and of 4 rats at 100 nmol/cm2 in toluene using a
flow-through system. Intact rats received analogous dermal doses.
Treated skin was washed and tape-stripped to remove “unabsorbed”
[14C]-radioactivity after continuous exposure (24 h). “Absorbed” was
quantified using dermally retained [14C]-radioactivity; “penetrated” was
calculated based on [14C]-radioactivity in media (in vitro) or excreta +
tissues (in vivo).
TBPH in vitro penetrance was minimal (< 0.01%) for rat or human skin.
TBPH absorption was 12± 11% for human skin and 41± 3% for rat skin. In
vivo, total absorption was 27±9%; 1.2% reached systemic circulation. In
vitro maximal TBPH flux was 0.3±0.2 and 1±0.3 pmol-eq/cm²/h for human
and rat skin; in vivo maximum flux for rat skin was 16±7 pmol-eq/cm2/h.
TBPH-derived [14C]-radioactivity in the perfusion media could not be
characterized. Only <1% of the dose of TBPH is estimated to reach the
systemic circulation following human dermal exposure under the
In a metabolism study rats received by gavage 500 mg/kg bw (125 mg/250
mg bw) of technical grade Uniplex FRP-45 (> 95% TBPH) in corn oil (Silva
et al., 2015). No TBPH or oxidative metabolites were reported in urine
or serum. TBPA (2,3,4,5-tetrabromo phthalic acid) was identified as an
in vivo urinary and serum metabolite (mean urinary levels ca. 0.5
mg/liter and mean serum levels ca. 0.05 mg/liter). The rats used in the
experiment weighing ca. 250 g. Assuming that the rats produced ca. 20 ml
urine per day, about 0.01 mg in 20 ml were found. This means, about
0.008 % TBPA (tetrabromo phthalic acid) was found in the urine within 24
hours after application. Assuming a blood volume of 10 % (equivalent to
ca. 5% serum) in the rat, this correlates with 50 ml serum per kg/bw
(12.5 ml/250 mg bw). This means, of the 125 mg test substance per rat
about 0.0005% was detected as TBPA after 48 h in the rat serum.
Additionally, TBBA (2,3,4,5-tetrabromo benzoic acid; mean urinary levels
ca. 45.6 mg/l and mean serum levels ca. 1.2 mg/l), a known metabolite of
2-ethylhexyl-2,3,4,5-tetrabromo-benzoate was detected at concentrations
much higher than TBPA (2,3,4,5-tetrabromo phthalic acid), even thought
TBPH was the main component of Uniplex FRP-45 (> 95%) and
2-ethylhexyl-2,3,4,5-tetrabromo-benzoate was only a minor constituent
(<< 5%). Because Uniplex-45 was technical grade and
2-ethylhexyl-2,3,4,5-tetrabromobenzoate was present in the formulation,
2,3,4,5-tetrabromobenzoic acid likely resulted from the metabolism of
2-ethylhexyl-2,3,4,5-tetrabromobenzoate. The authors “hypothesized that
because of its relatively low solubility and high molecular weight,
BEH-TEBP [=TBPH] may excrete preferentially unchanged in feces.
Regrettably, we did not collect feces for this experiment” (Silva et al
2015). Due to the above mentioned limitation and insufficient
characterization of the test compound (Uniplex 45-FRP) the reliability
of the study is limited.
In experiments with human liver microsomes (HLM) of Roberts et al.
(2012), a significant loss of TBPH was not observed, and no metabolites
were detected by GC/MS analysis of the sample extracts. An LC/MS-MS
method was developed to monitor mono(2-ethylhexyl) tetrabromophthalate
(TBMEHP), a potential hydrolysis metabolite of TBPH. After a 6-h
incubation with HLM, TBMEHP was not detected as a metabolite of TBPH,
and no significant loss of TBPH was observed. However, TBPH was slowly
metabolized to form TBMEHP in the presence of 0.1mg/mL of porcine
hepatic carboxylesterase (PCE). This reaction was monitored at multiple
time points up to 6 h and maintained linearity at an approximate rate of
1.08 pmol/min/mg esterase.
In a previous study with PCE, DEHP (50 μM) was metabolized to form MEHP
at a rate of 127 pmol/min/mg protein. This rate was approximately 100
times faster than the hydrolysis of TBPH observed in this study (1.08
The prominent difference between the metabolic hydrolysis of DEHP and
TBPH may be a result of steric hindrance by the fully brominated phenyl
ring of TBPH.
Altogether, no metabolites of TBPH were observed with HLM in vitro. From
this study there is no indication that TBPH is degraded to TBMEHP in
vivo. In an in-vitro experiment the hydrolysis rate of TBPH with PCE is
by factor 100 slower compared with DEHP.
Overall, for the human health risk assessment it can be assumed that
TBPH is unreactive, insoluble, not inhalable and there is no evidence of
significant absorption and no evidence of severe toxicity in a 28-day
study at doses above the limit dose. In a subchronic 90 day repeated
dose toxicity study no treatment related changes were found. The No
Observed Effect Level (NOEL) is considered to be 1000 mg/kg bw/day, the
highest dose tested.
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