Dihydrogen hexahydroxyplatinate

Endpoint summary

Description of key information

Dihydrogen hexahydroxyplatinate 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 exposure by the inhalation route is anticipated to be low, based on limited experimental data inhalation absorption is potentially extensive. In line with ECHA guidance, a conservative assumption of 100% inhalation absorption is proposed.

 

Significant bioavailability after dermal exposure is unlikely, notably as demonstrated by experimental dermal penetration data (human in vitro studies) for a closely-related surrogate. A value of 10% dermal absorption is proposed.

 

Once absorbed, distribution and excretion are expected to be rapid, with little or no bioaccumulation anticipated. 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 platinum compounds is very low following oral exposure. Seventy-one fasted male rats were administered a dose of radiolabelled191Pt (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.].

 

Absorption of platinum from the normal diet was estimated by measuring the levels of platinum in various foods (from a hypothetical diet) and comparing to the concentration of platinum in the urine of 21 individuals. From this the investigators estimated that 42-60% of the dietary platinum was absorbed. US EPA reports the authors of this study as having presented the hypothesis that the approximately 50-fold difference between this estimate and the measured oral absorption in rodents may be a reflection of the greater bioavailability of dietary sources of platinum. Further, this estimate of absorption is based on dietary estimates from a ‘hypothetical diet’ and that more reliable conclusions on absorption would require measurements from subjects receiving diets with known platinum concentrations (US EPA, 2009). Also, differences between the rat and human absorption figures are likely an artefact of differences in the exposures – absolute dietary Pt content is very low compared to the gavage (bolus) 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 from an oral exposure to 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 and exposure 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 platinum 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 platinum 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 (Moore et al., 1975a).

 

Particle size distribution (PSD) data, as measured by simple sieving, indicate that a significant proportion (62.1%) of the compound is <100 μm (Walker and White, 2011b). Dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 12.3 μm (Selck and Parr, 2011). In agreement with the granulometry data, an MMAD value <100 μm indicates that a significant proportion of the substance is likely to be inhalable. However, respiratory tract deposition modelling with the dustiness data yielded output values of 66.4, 1.10 and 2.40% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. This indicates that little airborne substance (<4%) will be deposited in the lower regions of the human respiratory tract, i.e. the TB or pulmonary regions via oronasal normal augmenter breathing.

 

Most of the inhaled fraction is likely to be retained in the head region and therefore would be cleared by ingestion, along with that deposited in the TB region, and oral bioavailability will again predominantly determine systemic uptake. Around 2% is likely capable of reaching the alveoli. Thus, inhalation will not be a significant route of exposure.

 

While it is very unlikely that dihydrogen hexahydroxyplatinate 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 dihydrogen hexahydroxyplatinate were identified. The low water solubility (<10 mg/L; Gregory, 2014) suggests that the substance may be able to cross the lipid-rich environment of the stratum corneum to a “low to moderate” extent, indicating that the appropriate default value for dermal absorption is 100% in this case (ECHA, 2014). However, 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]. In contrast, 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 dihydrogen hexahydroxyplatinate 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 dihydrogen hexahydroxyplatinate, considering its relatively low water solubility (and thus its 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 hydrogen and hexahydroxyplatinate ions throughout the body is expected based on a relatively low molecular weight (~300 g/mol).

 

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 platinum 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, dihydrogen hexahydroxyplatinate is considered to have only a low potential for bioaccumulation.

 

Conclusion 

Experimental data suggest that dihydrogen hexahydroxyplatinate 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 (based on respiratory tract deposition modelling data), based on limited experimental data absorption could be extensive. A high dermal bioavailability is unlikely.

 

Absorption values of 0.5%, 100% and 10% are proposed for the oral, inhalation and dermal routes, respectively, and are considered health-precautionary for use in the calculation of DNEL values.

 

 

 

References (for which an ESR has not been created in IUCLID):

 

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.

 

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