Tetraamminepalladium(2+) dichloride

Endpoint summary

Description of key information

With its relatively low molecular weight (~240 g/mol) and, more critically, high water solubility (327 g/L), it is likely that tetraamminepalladium dichloride will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of tetraamminepalladium dichloride is conservatively set at 100%.

Although not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data), as a highly water soluble substance with a relatively low molecular weight, any tetraamminepalladium dichloride reaching the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.
Tetraamminepalladium dichloride, 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 from metals. Moreover, tetraamminepalladium dichloride lacks skin irritation potential (which could, in theory, disrupt skin barrier function). As such, predicted dermal absorption is conservatively set at 10%.

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 (%):

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 (~240 g/mol) and, more critically, the high estimated water solubility (327 g/L; Gregory, 2014) are indicative of a high bioavailability of tetraamminepalladium dichloride 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 tetraamminepalladium dichloride is set at 100%.

No acute oral toxicity test was conducted on tetraamminepalladium dichloride, but the lung, liver and kidney effects seen in an acute oral study on the structurally related tetraamminepalladium hydrogen carbonate in rats (Allen, 1995) indicated at least partial oral absorption. Slower growth in rats in a repeated-dose reproduction toxicity study on tetraamminepalladium dichloride (Török-Bathó, 2015) was possibly indicative of absorption, as were the reductions in body weight, growth, food consumption, changes in blood parameters (in males) and kidney weight, as well as histological effects in the spleen, liver and kidneys of rats given tetraamminepalladium hydrogen carbonate, a member of the "tetraamminepalladium salts" category, by gavage for 28 days (Wragg, 1997).

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 tetraamminepalladium dichloride having a high melting point (decomposition from approximately 300°C with no definitive signs of melting below 450°C; Atwal, 2011b). Particle size distribution data indicate that only a small proportion (16.2%) of the compound is <100 μm (Atwal, 2011c). Dustiness testing with the compound returned a mass median aerodynamic diameter (MMAD) value of 25.7 μm (Parr, 2011; Selck and Parr, 2011). In contradiction 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 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 highly water soluble substance (327 g/L), any tetraamminepalladium dichloride 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 tetraamminepalladium dichloride 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 tetraamminepalladium dichloride (327 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, tetraamminepalladium dichloride is not classified for skin irritation. This is based on the lack of irritation potential observed in rabbits (Driscoll, 1981). 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 tetraamminepalladium dichloride.

No overt signs of toxicity were seen in an acute dermal toxicity test on the structurally related tetraamminepalladium hydrogen carbonate (Allen, 1997), or in the in vivo skin irritation (Driscoll, 1981) and skin sensitisation (Allen, 2000) studies on tetraamminepalladium dichloride. Though these latter two studies were limited in their assessment of systemic effects, the data overall provide limited evince that the substance will not be well-absorbed dermally.

Distribution/Metabolism

Once absorbed, distribution of tetraamminepalladium and chloride ions throughout the body is expected based on ion water solubility and relatively low molecular weights.

An acute oral study on the structurally related tetraamminepalladium hydrogen carbonate found changes in the lungs, liver, kidneys and small intestine (Allen, 1995), suggesting possible distribution to these tissues. Histological effects in the spleen, liver and kidneys of rats gavaged with tetraamminepalladium hydrogen carbonate for 28 days (Wragg, 1997) might indicate 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).

Tetraamminepalladium dichloride has characteristics favourable for rapid excretion: low molecular weight (<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, tetraamminepalladium dichloride 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, tetraamminepalladium dichloride 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 respiratory tract deposition modelling 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.