Tetraammineplatinum (II) diacetate

Endpoint summary

Description of key information

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. Based on experimental rat data on a related soluble platinum salt, an oral absorption figure of 0.5% is proposed.

 

Although 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.

 

A high 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.

 

Once 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.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

0.5

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Absorption

Limited 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.].

 

Experts 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 (ICH, 2014).

 

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.

 

Laboratory 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).

 

Tetraammineplatinum(II) 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.

 

While 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 taken forward.

No 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.

 

Specific 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).

 

Overall, 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.

 

Distribution/Metabolism

Once 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.

 

In Moore’s 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).

 

Elimination (and Bioaccumulation)

In rats 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).

 

“Total net 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 mg/L).

 

Conclusion

Experimental 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.

Absorption 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.

 

References not included elsewhere:

ECHA (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. http://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf

 

ECHA (2014). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 2.0. November 2014.

 

Franken A, 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.

 

Franken A, Eloff FC du Plessis J, Badenhorst CJ and Du Plessis JL (2015). In vitro permeation of platinum through African and Caucasian skin. Toxicology Letters 232, 566-572.

 

ICH (2014). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Guideline. Guideline for elemental impurities. Q3D Current Step 4 version dated 16 December 2014.

 

ICMM (2007). International Council on Mining & Metals. Health risk assessment guidance for metals. September 2007.

 

Lown BA, 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. 

 

Moore W, Jr, Malanchuk M, Crocker W, Hysell D, Cohen A and Stara JF (1975a). Whole body retention in rats of different 191Pt compounds following inhalation exposure. Environmental Health Perspectives 12, 35-39.

 

Moore W, Hysell D, Hall L, Campbell K and Stara J (1975b). Preliminary studies on the toxicity and metabolism of palladium and platinum. Environmental Health Perspectives 10, 63-71.

 

Moore W, Jr, Hysell D, Crocker W and Stara J (1975c). Biological fate of a single administration of 191Pt in rats following different routes of exposure. Environmental Research 9, 152-158.

 

Schierl R, Fries HG, van de Weyer C and Fruhmann G (1998). Urinary excretion of platinum from platinum industry workers. Occupational and Environmental Medicine 55, 138-140.

 

US EPA (2009). United States Environmental Protection Agency. Toxicological review of halogenated platinum salts and platinum compounds in support of summary information on the Integrated Risk Information System (IRIS). January 2009 Draft. EPA/635/R-08/018. https://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=513625