Platinum

Endpoint summary

Description of key information

Platinum metal is likely to be poorly absorbed after administration by the oral route, based on a low water solubility and a lack of appreciable bio-elution in simulated gastric fluid; what small proportion of the substance is taken up is likely to be rapidly excreted. Based on experimental rat data on a soluble platinum salt, an absorption figure of 0.5% is considered to represent a worst-case approach for platinum metal.

 

Although not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data), as a relatively low molecular weight substance, any platinum reaching the lungs has the potential to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.

 

Significant bioavailability after dermal exposure is unlikely, notably as demonstrated by a lack of appreciable bio-elution in simulated dermal fluid. A value of 10% dermal absorption is proposed.

Once absorbed, distribution and excretion of platinum ions are expected to be rapid, with little or no bioaccumulation occurring. 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

Good-quality information on absorption of platinum and its compounds is very limited. Indeed, most toxicokinetic data on platinum comes from studies of platinum complexes (IPCS, 1991). Several of these complexes have aqueous solubilities far in excess of platinum metal itself and, as such, use of this data represents a worst-case scenario for the consideration of potential oral bioavailable of platinum metal. Furthermore, the proportion of metal release (from total metal content) in simulated gastric fluid was 2 x 10^-4 % for platinum sponge after 2 hours (Rodriguez, 2012). This indicates a very low potential for absorption after oral exposure to platinum metal.

 

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 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., 1975a,b). 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. ECHA guidance is clear that the preferred approach is to undertake route-to-route extrapolation within one species as the first step. Thus, 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.

 

No good-quality data were found regarding absorption of platinum metal following inhalation, and limited information is available on platinum compounds.

Particle size distribution (PSD) data indicates that a reasonable proportion of platinum metal is <100 μm, based on average 10th, 50th and 90th percentile particle sizes of 55, 286 and 811 μm, respectively (Potthoff, 2012). Dustiness testing, a more energetic PSD measurement, returned a mass median aerodynamic diameter (MMAD) value of 31.4 μm for platinum sponge (Selck and Parr, 2012). An MMAD value <100 μm indicates that a significant proportion of a substance is likely to be inhalable. However, respiratory tract deposition modelling using the dustiness data yielded output values of 43.9, 0.098 and 0.053% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively, for platinum sponge. Hence, very little airborne substance (0.2%) is expected to deposit 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, based on a low water solubility (<0.1 mg/L), could be coughed or sneezed out of the body or swallowed, with systemic uptake being determined predominantly by subsequent oral bioavailability. The insoluble nature of the substance would limit any diffusion/dissolution into the mucus lining the respiratory tract. However, any platinum which is able to migrate into the mucus has the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. At most only around 1% of the inhaled fraction is capable of reaching the alveoli. Thus, absorption via the lungs will not be a significant route of exposure. Any platinum reaching the lungs would mainly be engulfed by alveolar macrophages and translocated out of the respiratory tract by absorption.

 

Overall, while it is very unlikely that platinum will be available to a high extent via inhalation, it is considered health precautionary in the light of the lack of specific absorption data, to take forward the ECHA default inhalation absorption value of 100%.

 

No good-quality data were found regarding absorption following dermal exposure to platinum metal. Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Partition coefficient testing was waived on the basis of the inorganic nature of substance. Given the insoluble nature of platinum (<0.1 mg/L), dermal uptake is likely to be low. Furthermore, specific guidance on the health risk assessment of metals indicates that molecular weight and log Pow considerations do not apply to these substances (“as inorganic compounds require dissolution involving dissociation to metal cations prior to being able to penetrate skin by diffusive mechanisms”) and tentatively proposes dermal absorption figures: 1.0 and 0.1% following exposure to liquid/wet media and dry (dust) respectively (ICMM, 2007).

 

In bio-elution tests with platinum sponge, the proportion of metal release (from total metal content) in simulated dermal fluid was 6 x 10^-5 % and 1 x 10^-4 % after 24 and 168 hours, respectively (Rodriguez, 2012), indicating a low dermal bioavailability of the compound. Given the low penetration expected for metals, and the low water solubility (and, thus, low expected dermal bioavailability), it is suitably health precautionary to take forward the lower of the two ECHA default values for dermal absorption, of 10%, for the safety assessment of platinum.

 

Distribution/Metabolism

Once absorbed, distribution of platinum ions (the anticipated form of the metal in vivo) throughout the body is expected based on water solubility of the cationic form (and a relatively low molecular weight).

 

In Moore’s study (1975a), 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

In rats given gavage doses of radiolabelled-platinum compounds, absorbed Pt was found to be excreted in the urine and faeces (Moore et al., 1975a). However, given that oral absorption was so low, faecal excretion of unabsorbed Pt during the first 1-2 days after administration contributed substantially to the detected levels (US EPA, 2009).

 

It is noted that certain metals and ions may interact with the matrix of the bone, causing them to accumulate within the body (ECHA, 2014). However, any absorbed platinum will likely be in the form of platinum ions, and the potential for bioaccumulation is considered to be low, based on a low anticipated affinity for the lipophilic tissues.

 

Conclusion

Experimental data suggest that platinum metal is not likely to be bioavailable 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), 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.

 

 

References not included elsewhere:

 

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

 

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

 

IPCS (1991). International Programme on Chemical Safety. Platinum. Environmental Health Criteria 125. WHO, Geneva.

 

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, Hysell D, Hall L, Campbell K and Stara J (1975a). 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 (1975b). Biological fate of a single administration of 191Pt in rats following different routes of exposure. Environmental Research 9, 152-158.

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