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EC number: 457-310-8
CAS number: 127733-97-5
PLATINUM(2+), TETRAAMMINE-, (SP-4-1)-, DIACETATE (9CI)
diacetate is likely to be poorly absorbed after administration by the
oral route; what small proportion of the substance is taken up is
likely to be rapidly excreted. Based on experimental rat data on a
related soluble platinum salt, an oral absorption figure of 0.5% is
availability by the inhalation route is anticipated to be low,
inhalation absorption is likely extensive based on its water soluble
nature and relatively-low molecular weight, as well as limited
experimental data. Based on ECHA guidance, a conservative assumption
of 100% inhalation absorption is proposed.
dermal bioavailability is unlikely, notably based on its low log Pow
and high water solubility as well as experimental dermal penetration
data (human in vitro studies) for a closely-related surrogate. A value
of 10% absorption is proposed.
absorbed, distribution and excretion are expected to be rapid, with
little or no bioaccumulation occurring, due to its highly water
soluble nature. The potential for bioaccumulation of certain other
metals and ions is recognised.
data indicate that absorption of soluble Pt compounds is very low
following oral exposure. Seventy-one fasted male rats were administered
a dose of radiolabelled 191Pt (as PtCl4) by oral gavage, to provide 25
μCi of radiation. Routes of excretion, levels of whole-body retention
and organ distribution were determined. Less than 0.5% of the
orally-administered dose was absorbed (Moore et al., 1975b,c).
Similarly, mice given a single gavage administration of radiolabelled
Pt(SO4)2 were found to have absorbed only a very small fraction of the
dose (Lown et al., 1980). [The authors of this study stated that, while
they did not quantify the distribution of the radiolabel, their findings
were consistent with those of Moore et al.].
from the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
used an oral absorption figure of 10% when converting an oral permitted
daily exposure figure for platinum compounds to a parenteral equivalent
A study in
21 humans, in which absorption of dietary platinum was estimated,
reported 42-60% of a hypothetical dietary intake was absorbed. US EPA
reports the authors of this study as having presented the hypothesis
that the approximately 50-fold difference between this value and the
measured oral absorption in rodents is a reflection of the greater
bioavailability of dietary sources of platinum (US EPA, 2009). There is,
however, an inherent imprecision in estimations of dietary absorption,
especially from a “hypothetical” dietary intake. Also, differences
between the rat and human absorption figures are likely an artefact of
the relative doses – absolute dietary Pt content is very low compared to
the gavage doses administered to the rats, and so it follows that a
higher percentage of the lower dose is absorbed and was detected.
Moreover, using the lowest oral absorption figure (in this case, 0.5%)
results in the most health precautionary DNELs (when extrapolating for
both inhalation and dermal long-term systemic values). Further, ECHA
guidance is clear that the preferred approach is to undertake
route-to-route extrapolation within one species as the first step. Thus,
when deriving DNEL values from experimental studies in the rat, it is
most appropriate to use the figures obtained in the toxicokinetic study
in rats. Consequently, a figure of 0.5% oral absorption has been taken
forward for use in subsequent risk assessments.
studies provide only very limited insights into the extent of absorption
of platinum compounds following inhalation. When two volunteers inhaled
a mixture of soluble platinum salts (mainly diammonium
hexachloroplatinate) at calculated mean air concentrations of 1.7 and
0.15 µg Pt/m3, respectively, urinary Pt concentrations peaked
(15-100-fold increases were seen) about 10 hr later. The results
indicated rapid absorption and urinary excretion, but gave no
quantitative insights into the extent of absorption (Schierl et al.,
1998). Urinary Pt measurements in rats
following an acute inhalation of radiolabelled Pt, PtO2, PtCl4 or
Pt(SO4)2 (particle diameter around 1 µm) indicated only small fractions
of the administered dose were absorbed, even for the two soluble salts.
Most of the radiolabel appeared in the faeces, presumably reflecting
mucociliary clearance and a lack of significant absorption from the
gastrointestinal tract (Moore et al., 1975a).
diacetate has a very low vapour pressure (<0.002 Pa at 20°C;
Mekelburger, 2004c), indicating that only a small proportion of the
substance may be available for inhalation as a vapour. A particle size
distribution (PSD) study, using laser diffraction, reported d10, d50 and
d90 values of 254, 673 and 1242 μm, respectively for dried
tetraammineplatinum(II) diacetate (Mekelburger, 2017). In this dried
form the physical size of the powder is rather coarse; hence, given the
relatively high density of the substance, an estimate of the mass median
aerodynamic diameter (MMAD) from the measured d50 would exceed the
threshold of 100 µm for the inhalable fraction.
it is very unlikely that tetraammineplatinum(II) diacetate will be
available to a high extent via the lungs, ECHA guidance notes that “that
if data on the starting route (oral) are available these should be used,
but for the end route (inhalation), the worst case inhalation absorption
should still be assumed (i.e. 100%)”. Therefore, the
health-precautionary figure of 100% as recommended by ECHA has been
substance-specific data on dermal uptake of tetraammineplatinum(II)
diacetate were identified. Given the low partition coefficient (<-3.94;
Mekelburger, 2004d) and high water solubility (799 g/L; Mekelburger,
2004e), it is unlikely to be able to cross the lipid-rich environment of
the stratum corneum. Furthermore, REACH guidance states that a
reasonable default assumption is that dermal absorption will not be
greater than by the oral route (ECHA, 2012) [i.e. <1% in this case].
However, two in vitro permeation studies on a related soluble platinum
salt, dipotassium tetrachloroplatinate, showed a greater degree of
absorption [about 5-8%] than this default process would assume. Using a
K2PtCl4 solution (0.3 mg Pt/ml in synthetic sweat) and full thickness
skin from six donors (three African and three Caucasian), 4.8 and 2.3%,
respectively (as mean values), diffused into the skin in 24 hr;
the receptor solutions contained a further 3.4 and 0.5%, respectively
(Franken et al., 2015). A slightly earlier publication reported mean
skin diffusion and receptor solution percentages of 2.2% and 2.3%,
respectively, in similar studies on full thickness skin from four
Caucasian females (Franken et al., 2014). Apart from these studies, very
little information appears to be available regarding dermal absorption
of platinum compounds.
expert guidance on the health risk assessment of metals states that
“inorganic compounds require dissolution involving dissociation to metal
cations prior to being able to penetrate skin by diffusive mechanisms”
and, as such, dermal absorption might be assumed to be very low (values
of 0.1 and 1.0% are suggested for dry and wet media, respectively)
(ICMM, 2007). Furthermore, there is no evidence that
tetraammineplatinum(II) diacetate causes skin irritation (which could
facilitate a greater degree of dermal uptake).
the default values are somewhat conflicting. Absorption in the range of
that indicated by oral studies (i.e. <1%), as suggested by ECHA guidance
and ICMM (2007), seems to be too low when considering the in vitro
studies on human skin (Franken et al., 2014, 2015). However, care must
be taken not to overestimate the dermal absorption potential of
tetraammineplatinum(II) diacetate, considering its low log Pow and high
water solubility (and thus its low potential to penetrate the stratum
corneum). With particular reference to the Franken et al. studies, and
considering the lack of evidence of skin irritation, a value of 10%
dermal absorption is proposed.
absorbed, distribution of tetraammineplatinum and acetate ions
throughout the body is expected based on a relatively low molecular
weight (~380 g/mol) and high water solubility.
study (1975b), platinum was found in the liver and kidney of rats
gavaged with radiolabelled-PtCl4, although levels in other organs were
not significantly above background. Other investigators have detected Pt
in the liver, kidney, spleen, lung and testis following gavage
administration (Lown et al., 1980). A range of other studies, summarised
by the US EPA, concur with these findings, with the kidney clearly the
most significant site of deposition. A similar pattern was observed
following inhalation (US EPA, 2009).
given gavage doses of radiolabelled-platinum compounds, absorbed
platinum was found to be predominantly excreted in the faeces, with only
a small amount excreted in the urine (Moore et al., 1975b). Given that
oral absorption was so low, faecal excretion of unabsorbed platinum
during the first 1-2 days after administration contributed substantially
to the detected levels (US EPA, 2009). Most of the radiolabelled
platinum in rats administered a range of salts by inhalation appeared in
the faeces (Moore et al., 1975a), presumably reflecting mucociliary
clearance and a lack of significant absorption from the gastrointestinal
tract (US EPA, 2009).
gastrointestinal excretion was extremely high”, with less than 1% of the
administered dose retained after 3 days (Moore et al., 1975b).
Similarly, clearance of radiolabelled platinum after inhalation exposure
to platinum metal and various (soluble and insoluble) platinum salts was
rapid (20-40% retained after 1 day; approximately 10-15% after 4 days)
(Moore et al., 1975a). Accordingly, tetraammineplatinum(II) diacetate is
considered to have only a low potential for bioaccumulation, as expected
based on its physico-chemical properties (i.e. water solubility >10,000
data suggest that tetraammineplatinum(II) diacetate is likely to be
poorly absorbed after administration by the oral route; what small
proportion of the substance is taken up is likely to be rapidly
excreted. Although inhalation is not anticipated to be a significant
route of exposure (on the basis of vapour pressure data), based on
limited experimental data absorption could be extensive. A high dermal
bioavailability is unlikely.
values of 0.5%, 10% and 100% are proposed for the oral, dermal and
inhalation routes, respectively, and are considered health-precautionary
for use in the calculation of DNEL values.
not included elsewhere:
(2012). European Chemicals Agency. Guidance on information requirements
and chemical safety assessment. Chapter R.8: Characterisation of dose
[concentration]-response for human health. Reference: ECHA-2010-G-19-EN.
Version 2.1. November 2012.
(2014). European Chemicals Agency. Guidance on information requirements
and chemical safety assessment. Chapter R.7c: endpoint specific
guidance. Version 2.0. November 2014.
Eloff FC, du Plessis J, Badenhorst CJ, Jordaan A and Du Plessis JL
(2014). In vitro permeation of platinum and rhodium through Caucasian
skin. Toxicology in Vitro 28, 1396 1401.
Eloff FC du Plessis J, Badenhorst CJ and Du Plessis JL (2015). In vitro
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International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use. ICH Harmonised Guideline.
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(2007). International Council on Mining & Metals. Health risk assessment
guidance for metals. September 2007.
Morganti JB, Stineman CH, D’Agostino RB and Massaro EJ (1980). Tissue
organ distribution and behavioral effects of platinum following acute
and repeated exposure of the mouse to platinum sulfate. Environmental
Health Perspectives 34, 203-212.
Jr, Malanchuk M, Crocker W, Hysell D, Cohen A and Stara JF (1975a).
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Hysell D, Hall L, Campbell K and Stara J (1975b). Preliminary studies on
the toxicity and metabolism of palladium and platinum. Environmental
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Fries HG, van de Weyer C and Fruhmann G (1998). Urinary excretion of
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Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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