Tetraamminepalladium(2+) diacetate

Endpoint summary

Description of key information

With its relatively low molecular weight (~330 g/mol) and, more critically, high water solubility (100 g/L), it is likely that tetraamminepalladium diacetate will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of tetraamminepalladium diacetate is conservatively set at 100%.

Although not expected to reach the lungs in appreciable quantities (since the substance is marketed as a solution with a low predicted vapour pressure [for the organic component of the substance]), as a highly water soluble substance with a relatively low molecular weight, any tetraamminepalladium diacetate reaching the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.
Tetraamminepalladium diacetate, with water solubility in excess of 10,000 mg/L, may be unable to cross the lipid-rich environment of the stratum corneum, especially considering the low dermal penetration expected for metals as well as the low partition coefficient of -0.17 [for the organic component of the substance]. Moreover, tetraamminepalladium diacetate 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 (~330 g/mol) and, more critically, the high estimated water solubility (100 g/L) are indicative of a high bioavailability of tetraamminepalladium diacetate by this route. Moreover, the partition coefficient (log Pow) of acetic acid, representative of the organic component of tetraamminepalladium diacetate, is -0.17 (Hansch, 1995) which is favourable (between -1 and 4) for absorption by passive diffusion. A health-precautionary assumption is that the ions will be absorbed from the gastro-intestinal tract. As such, predicted oral absorption of tetraamminepalladium diacetate is set at 100%.

In an acute oral study on the structurally related tetraamminepalladium hydrogen carbonate, necropsy revealed changes in the lungs, liver, kidneys and small intestine (Allen, 1995a), indicating a degree of oral absorption. In a 28-day gavage toxicity study on the same "tetraamminepalladium salts" category member (source substance), various of the toxic effects, which included reductions in body weight, growth, food consumption and kidney weight, as well as changes in blood parameters (in males) and histological effects in the spleen, liver and kidneys (Wragg, 1997), were indicative of absorption. Slower growth in rats in a repeated-dose reproduction toxicity study on tetraamminepalladium dichloride, a different source substance (Grosz, 2015) also indicated absorption. Overall, absorption is expected for ingested tetraamminepalladium diacetate.

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). Palladium diacetate has the same organic component as tetraamminepalladium diacetate, and has a very low QSAR‑predicted vapour pressure (0.00239 Pa at 25°C; USEPA, 2010), indicating that only a small proportion of the latter substance may be available for inhalation as a vapour. Particle size distribution testing was waived as the substance is marketed in a “non-solid or granular form” (as a solution). Accordingly, inhalation is not considered to be a significant route of exposure. However, as a highly water soluble substance (>10,000 mg/L), any tetraamminepalladium diacetate reaching the lungs is likely to be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract by absorption. Overall, while it is very unlikely that tetraamminepalladium diacetate 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. Given the high water solubility of tetraamminepalladium diacetate (100 g/L), it is unlikely to be able to cross the lipid-rich environment of the stratum corneum. Moreover, dermal penetration is likely to be limited by the poor lipophilicity of the organic portion of the molecule, as represented by acetic acid (log Pow <0). 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 diacetate is not classified for skin irritation. This is based on the lack of irritation potential observed in rabbits with the structurally related compounds tetraamminepalladium dichloride and tetraamminepalladium hydrogen carbonate (Allen, 1995b; 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 diacetate.

No overt toxicity was seen in rats in an acute dermal study on the structurally related compound tetraamminepalladium hydrogen carbonate (Allen, 1997a). Effects were similarly absent in in vivo skin irritation (Allen, 1995b; Driscoll, 1981) and skin sensitisation (Allen, 1997b, 2000) studies on the source substances tetraamminepalladium dichloride and tetraamminepalladium hydrogen carbonate (though these are limited in their assessment of systemic effects). Overall, there is limited evidence to suggest that the substance will not be well-absorbed dermally.

Distribution/Metabolism

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

Rats given the structurally related compound tetraamminepalladium hydrogen carbonate showed alterations in the lungs, liver, kidneys and small intestine) (Allen, 1995a), which might suggest distribution to these sites. In a 28‑day gavage toxicity study on the category member, tetraamminepalladium hydrogen carbonate, there were histological effects in the spleen, liver and kidneys of rats (Wragg, 1997), possibly indicative of distribution to these tissues.

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 high water solubility of the substance and ions. 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 diacetate 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 diacetate is likely partially bioavailable by the oral route and rapidly excreted once absorbed. A high dermal bioavailability is unlikely, particularly as the substance is anticipated to be highly water soluble and poorly lipophilic with a lack of skin irritation potential. Although bioavailability by the inhalation route is anticipated to be low (since the substance is marketed as a solution and has low predicted vapour pressure), 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.