Dipotassium hexachloropalladate

Endpoint summary

Description of key information

With its relatively low molecular weight (~400 g/mol) and, more critically, relatively high water solubility (3.41 g/L), it is likely that dipotassium hexachloropalladate will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of dipotassium hexachloropalladate is conservatively set at 100%. 


  


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




With a water solubility of 3.41 g/L, dipotassium hexachloropalladate may be unable to cross the lipid rich environment of the stratum corneum, given the low dermal penetration expected from metals. However, dipotassium hexachloropalladate is classified as a skin irritant. This irritant potential may disrupt skin barrier function, facilitating dermal penetration. As such, predicted dermal absorption is conservatively set at 100%.




Once absorbed, distribution and excretion are expected to be rapid, with little or no bioaccumulation occurring, due to its 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 (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Absorption

Good-quality information on absorption of palladium compounds is very limited. In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration. Experts from the IPCS reported that absorption of palladium ions from the gastrointestinal tract is poor, a view based on a study where adult and suckling rats absorbed less than 0.5% and about 5%, respectively, of a single oral dose of radiolabelled (103Pd) palladium dichloride (IPCS, 2002). 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 palladium compounds to a parenteral equivalent (ICH, 2014). Based on expert ECHA guidance, the relatively low molecular weight (~400 g/mol) and, more critically, the relatively high estimated water solubility (3.41 g/L; Gregory, 2014) are indicative of a high bioavailability of dipotassium hexachloropalladate (as ions) by this route. A health-precautionary assumption is that the ions will be well-absorbed from the gastro-intestinal tract. As such, predicted oral absorption of dipotassium hexachloropalladate is set at 100%.

In the acute oral toxicity test on dipotassium hexachloropalladate, findings in the lungs and spleen at necropsy (Zechel, 1990) indicated at least partial oral absorption. No conclusions about absorption could be reached from a 28-day oral study on the structurally related compound diammonium hexachloropalladate, because the adverse findings (histological inflammation of the stomach and elevated mean white blood cell counts) were considered to reflect a local irritant effect rather than systemic toxicity (Matting, 2015), or from a repeated-dose oral reproduction toxicity study (where similar local effects were observed in the stomach of parental animals) (Török-Bathó, 2015).

No good-quality data were found regarding absorption of palladium compounds following inhalation. One Expert Group noted that, following a single intratracheal or inhalation (7.2 mg/m3; aerodynamic diameter around 1 µm) exposure to 103Pd-radiolabeled palladium dichloride in rats, absorption/retention was higher than was observed for oral administration (i.e. >5%) but did not differentiate between absorption and mere retention in the respiratory tract (IPCS, 2002). Vapour pressure testing was waived on the basis of dipotassium hexachloropalladate having a high melting point (no signs of melting at up to 450°C; Tremain, 2011b). Particle size distribution (PSD) data indicates that a significant proportion of the compound is <100 μm, based on average 10th, 50th and 90th percentile particle sizes of 15.0, 34.4 and 56.8 μm, respectively, and an average mean particle size of 35.16 μm (CILAS, 2008a,b). Further, dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 25.7 μm (Parr, 2011; Selck and Parr, 2011), indicating 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 52.5, 0.17 and 0.15% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. This indicates that very little airborne substance (<1%) 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. Less than 1% is likely capable of reaching the alveoli. Thus, inhalation will not be a significant route of exposure. However, as a relatively water soluble substance (3.41 g/L), any dipotassium hexachloropalladate reaching the lungs is likely to be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract. Overall, while it is very unlikely that dipotassium hexachloropalladate will be available to a high extent via the lungs, it is considered health precautionary to take forward the ECHA default inhalation absorption value of 100%.

No good-quality data were found regarding absorption following dermal exposure to palladium compounds. One Expert Group noted that “palladium was found in all internal organs examined” after dermal treatment of rabbits with “palladium hydrochloride” (formula not specified) or guinea pigs with chloropalladosamine, but quantitative absorption data were not given (IPCS, 2002). 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. However, given the water soluble nature of dipotassium hexachloropalladate (3.41 g/L), it may be able to cross the lipid-rich environment of the stratum corneum to a “moderate to high” extent (ECHA, 2014). In the light of the limited available experimental data, ECHA guidance indicates that a default value of 100% dermal absorption should be used (ECHA, 2014). However, 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). Nevertheless, dipotassium hexachloropalladate is classified as a skin irritant. This is based on the observation of moderate skin irritation in rabbits (Zechel, 1989a). Such irritant potential may disrupt skin barrier function, facilitating dermal penetration. As such, it is considered health precautionary to take forward the ECHA default dermal absorption value of 100%.

No signs of systemic toxicity were seen in an in vivo skin irritation study on dipotassium hexachloropalladate (Zechel, 1989a) following dermal exposure, or in a skin sensitisation study on the structurally related compound diammonium hexachloropalladate (Valiczko, 2013). Given that toxicity was evident after oral exposure, this provides limited support for the conclusion that dipotassium hexachloropalladate will not be well absorbed dermally.

Distribution/Metabolism

Once absorbed, distribution of potassium and hexachloropalladate ions throughout the body is expected based on a relatively low molecular weight.

In the acute oral toxicity test on dipotassium hexachloropalladate, necropsy of deceased animals revealed findings in the lungs and spleen (Zechel, 1990), suggesting possible distribution to these organs.

When rats were given potassium hexachloropalladate in the drinking water at 0, 10, 100 or 250 mg/L for 90 days, absorbed Pd was found mainly in the kidneys and it did not accumulate in liver, lung, spleen or bone tissue (Iavicoli et al., 2010). IPCS noted that, after single oral, intravenous or intratracheal doses of palladium salts or complexes to rats, rabbits or dogs, the highest palladium concentrations were found in kidney, liver, spleen, lymph nodes, adrenal gland, lung and bone (IPCS, 2002).

Elimination

In rats given potassium hexachloropalladate in the drinking water at up to 250 mg/L for 90 days, elimination was rapid and primarily through the faecal route, although small amounts were found in the urine at the highest dose level (Iavicoli et al., 2010).

Despite having a molecular weight above 300 g/mol (molecular weights below this figure are considered to be associated with favourable excretion in the rat (ECHA, 2014)), rapid excretion is likely based on a relatively high water solubility. 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, dipotassium hexachloropalladate is considered to have only a low potential for bioaccumulation based on its predicted physico-chemical properties (i.e. water solubility of 3.41 g/L).

Conclusion

Based on the physico-chemical properties, the chemical structure, molecular weight and the results of toxicity studies, as well as limited toxicokinetic data on other palladium compounds, dipotassium hexachloropalladate is likely partially bioavailable by the oral route and rapidly excreted once absorbed. A high dermal bioavailability is unlikely, particularly as the substance is an inorganic solid. Nevertheless, its irritant potential may disrupt skin barrier function, facilitating dermal penetration. Although bioavailability by the inhalation route is anticipated to be low (based on respiratory tract deposition modelling data, inhalation absorption is considered a possibility based on its low molecular weight and relatively high water solubility. Proposed predicted absorption figures for the oral, dermal and inhalation routes are all conservatively set at 100%.