Disodium tetrachloropalladate

Endpoint summary

Description of key information

With its relatively low molecular weight (~295 g/mol) and, more critically, high water solubility (622 g/L), it is highly likely that disodium tetrachloropalladate will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of disodium tetrachloropalladate is conservatively set at 100%.

Although not expected to reach the lungs in appreciable quantities (based on particle size distribution data), as a highly water soluble substance with a relatively low molecular weight, any disodium tetrachloropalladate reaching the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.

Disodium tetrachloropalladate, with water solubility in excess of 10 g/L, may be unable to cross the lipid-rich environment of the stratum corneum, especially considering the low dermal penetration expected for metals. Moreover, disodium tetrachloropalladate lacks skin irritation potential (which could, in theory, disrupt skin barrier function). As such, predicted dermal absorption is set at 10%.

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

100

Absorption rate - dermal (%):

10

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 (~295 g/mol) and, more critically, the high estimated water solubility (622 g/L; Winde, 2011) are indicative of a high bioavailability of disodium tetrachloropalladate by this route. A health‑precautionary assumption is that the ions will be absorbed from the gastro-intestinal tract. As such, predicted oral absorption of disodium tetrachloropalladate is set at 100%.

 

The acute oral toxicity test on disodium tetrachloropalladate saw no overt signs of toxicity (Middleton and Husband, 1978) and provides no insights into oral absorption. Adverse findings in a combined repeated dose and reproductive/developmental toxicity dietary study in rats using disodium tetrachloropalladate included reductions in body weight, growth, food consumption and relative weights of various organs (Szaloki, 2022). These findings indicate a degree of oral absorption of the test substance and suggest that absorption of disodium tetrachloropalladate could also occur.

 

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 disodium tetrachloropalladate having a high melting point (decomposition from approximately 395°C with no definitive signs of melting below 450°C; Walker, 2011). Particle size distribution (PSD) data, on the substance as a dry dispersion, indicates that only a small proportion (<10%) of disodium tetrachloropalladate is <100 μm, based on average 10th, 50th and 90th percentile particle sizes of 115, 597 and 1293 μm, respectively, in the <2 mm fraction (Potthoff, 2015). Dustiness testing, a more energetic PSD measurement, with various palladium compounds (not including disodium tetrachloropalladate) returned mass median aerodynamic diameter (MMAD) values in the range of 24.1-38.2 μm. An MMAD value <100 μm indicates that a significant proportion of a substance is likely to be inhalable. However, respiratory tract deposition modelling with the dustiness data for each of the palladium species yielded output values in the range of 40.0-52.5, 0.12-0.41 and 0.08-0.64% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. Hence, for all of the tested palladium species, very little airborne substance (<1%) 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. Similar behaviour is anticipated for disodium tetrachloropalladate.

 

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 for disodium tetrachloropalladate. However, as a highly water soluble substance (622 g/L), any disodium tetrachloropalladate 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 disodium tetrachloropalladate 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 high water solubility of disodium tetrachloropalladate (~622 g/L), it is unlikely to be able to cross the lipid-rich environment of the stratum corneum. In spite of this, 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). Further, disodium tetrachloropalladate is not classified for skin irritation. This is based on the lack of irritation potential observed in rabbits (Middleton, 1978a). Given the low penetration expected from metals, the high water solubility (and, thus, low expected lipophilicity), and the lack of skin irritation potential (which could, in theory, disrupt skin barrier function and facilitate dermal penetration), 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 disodium tetrachloropalladate.

 

No clinical toxicity was seen in in vivo skin irritation and skin sensitisation studies on disodium tetrachloropalladate (albeit these were limited in their assessment of systemic effects). These studies offer little or no insight into the extent of dermal absorption of the substances.

 

Distribution/Metabolism

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

 

In a combined repeated dose and reproductive/developmental toxicity dietary study in rats on disodium tetrachloropalladate, reductions in the relative weight of adrenal glands, thyroid/parathyroid glands, seminal vesicles, ovaries, liver, brain and heart, but these were considered not biologially relevant or due to excessive toxicity (dosing in excess of MTD) and were histologically considered as non adverse or incidental (Szaloki 2022).

 

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).

 

Disodium tetrachloropalladate has characteristics favourable for rapid excretion: low molecular weight (below 300 g/mol) and 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, disodium tetrachloropalladate is considered to have only a low potential for bioaccumulation based on its predicted physico-chemical properties (i.e. water solubility > 10,000 mg/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, disodium tetrachloropalladate 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 powder with a lack of skin irritation potential. Although bioavailability by the inhalation route is anticipated to be low (based on particle size distribution data) inhalation absorption is considered a possibility based on its low molecular weight and high water solubility. Proposed predicted absorption figures for the oral, dermal and inhalation routes are 100, 10 and 100%, respectively.