Palladium dinitrate

Endpoint summary

Description of key information

With its relatively low molecular weight (~230 g/mol) and, more critically, high water solubility (>10,000 mg/L), it is likely that palladium dinitrate will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of palladium dinitrate is conservatively set at 100%. 
Although not expected to reach the lungs in appreciable quantities (since the substance is marketed as a solution and the concept of vapour pressure is irrelevant for this compound), as a highly water soluble substance with a relatively low molecular weight, any palladium dinitrate reaching the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.
Palladium dinitrate, with water solubility in excess of 10,000 mg/L, may be unable to cross the lipid-rich environment of the stratum corneum. However, palladium dinitrate is classified for skin corrosion in sub-category 1B. This corrosive 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 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 (%):

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 (~230 g/mol) and, more critically, the high estimated water solubility (>10,000 mg/L; Gregory, 2014) are indicative of a high bioavailability of palladium dinitrate 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 palladium dinitrate is set at 100%.

Overt toxicity and (at necropsy) tissue changes in the caecum and thymus seen in rats in an acute oral toxicity test on palladium dinitrate (van Huygevoort, 2003a) indicate a degree of absorption. Similarly, a combined repeated dose and reproductive/developmental toxicity dietary study on another palladium (II) species, palladium dihydroxide, found increases in liver weight in females and decreases in seminal vesicle weight in males (Török-Bathó, 2015), findings suggestive of absorption.

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 that such a concept does not apply for palladium dinitrate: it is unlikely that the substance could exist in molecular form in the gas phase due to its solid state structure, while the dissolved form (ions) cannot evaporate. 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 palladium dinitrate 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 palladium dinitrate 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 transdiamminedichloropalladium (DDP, described in the citing source as "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 palladium dinitrate (>10,000 mg/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). Nevertheless, palladium dinitrate is classified as corrosive (to skin) sub-category 1B. This is based on mean breakthrough times of about 14 and 3-6 minutes in in vitro membrane barrier tests with palladium dinitrate hydrate (solid) and palladium dinitrate solution type H, respectively (Lehmeier, 2013a, b). Such corrosive 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 acute dermal toxicity or in vivo skin irritation tests were conducted on palladium dinitrate due to its classification as corrosive to the skin in two in vitro membrane barrier tests (Lehmeier, 2013a,b). No overt systemic toxicity was seen in an in vivo skin sensitisation study on palladium dinitrate (van Huygevoort, 2003b). Given that oral exposure caused overt toxicity, this is limited evidence that palladium nitrate will not be well-absorbed dermally.

Distribution/Metabolism

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

In an acute oral toxicity test on palladium dinitrate, changes in the caecum and thymus (van Huygevoort, 2003a) might possibly indicate distribution to these organs. A combined repeated dose and reproductive/developmental toxicity dietary study on another palladium (II) species, palladium dihydroxide, noted increases in liver weight in females and decreases in seminal vesicle weight in males (Török-Bathó, 2015), which might suggest distribution to those 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).

Palladium and nitrate ions have 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, palladium dinitrate 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, palladium dinitrate is likely partially bioavailable by the oral route (as ions) and rapidly excreted once absorbed. A high dermal bioavailability is anticipated on the basis that its corrosive potential may disrupt skin barrier function, facilitating dermal penetration. Although bioavailability by the inhalation route is anticipated to be low (since the substance is marketed as a solution), absorption of any inhaled substance is considered likely based on its low molecular weight and high water solubility. Proposed predicted absorption figures for the oral, dermal and inhalation routes are all conservatively set at 100%.