Palladium dichloride

Endpoint summary

Description of key information

With its relatively low molecular weight (~180 g/mol) and, more critically, relatively high water solubility (4.03 g/L), it is likely that palladium dichloride will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of palladium 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 water soluble substance with a relatively low molecular weight, any palladium dichloride reaching the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.

Palladium dichloride, despite having a water solubility of 4.03 g/L, may be unable to cross the lipid rich environment of the stratum corneum, given the low dermal penetration expected for metals. However, palladium dichloride showed evidence of skin irritation (despite not being classified for this endpoint). This irritant potential may disrupt skin barrier function, facilitating dermal penetration. As such, predicted dermal absorption is very 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 (~180 g/mol) and, more critically, the relatively high estimated water solubility (4.03 g/L; Gregory, 2014) are indicative of a high bioavailability of palladium dichloride by this route. Moreover, as the molecular weight is low (less than 200 g/mol) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. A health-precautionary assumption is that the ions will be absorbed from the gastro-intestinal tract. As such, predicted oral absorption of palladium dichloride is set at 100%.

Necropsy of deceased animals in an acute oral toxicity test on palladium dichloride revealed changes in the lungs, liver, kidneys, stomach and small intestine (Allen, 1994a), at least some of which indicate a degree of absorption. In a combined repeated dose and reproductive/developmental toxicity dietary study, the structurally related compound palladium dihydroxide induced increases in liver weight in females and decreases in seminal vesicle weight in males (Török-Bathó, 2015). [Macroscopic and microscopic effects in the stomach, ileum, caecum, colon and rectum were also seen but could reflect local toxicity.] This study indicates the anticipated potential for oral absorption of the test substance (and thus, possibly, palladium dichloride).

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 palladium dichloride having a high melting point (679°C; Lide, 2008). Particle size distribution (PSD) data, as measured by simple sieving, indicates that a significant proportion (91.8%) of palladium dichloride is <100 μm (O’Connor, 2011). Dustiness testing, a more energetic PSD measurement, with various palladium compounds (not including palladium dichloride) 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. 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 palladium dichloride.

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 is not anticipated to be a significant route of exposure for palladium dichloride. However, as a relatively water soluble substance (4.03 g/L), any palladium 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 palladium 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 water soluble nature of palladium dichloride (4.03 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, palladium dichloride caused moderate skin irritation in rabbits (Allen, 1994b) (despite not being classified for this endpoint). 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 clinical toxicity was seen in in vivo skin irritation (Allen, 1994b; Campbell et al., 1975) and skin sensitisation (Wahlberg and Boman, 1990, 1992; Schuppe et al., 1998) studies on palladium dichloride. While these studies would have been limited in their assessment of systemic effects, the data provide limited evidence that the substance might not be well-absorbed dermally.

Distribution/Metabolism

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

In the acute oral toxicity test on palladium dichloride, necropsy findings in lungs, liver and kidneys (as well as stomach and small intestine) (Allen, 1994a) suggest possible distribution to these organs. In a combined repeated dose and reproductive/developmental toxicity dietary study, the structurally related compound palladium dihydroxide induced increases in liver weight in females and decreases in seminal vesicle weight in males (Török-Bathó, 2015), suggesting possible wide distribution.

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 dichloride has characteristics favourable for rapid excretion: low molecular weight (below 300 g/mol) and 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, palladium dichloride is considered to have only a low potential for bioaccumulation based on its predicted physico-chemical properties (i.e. water solubility of 4.03 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, palladium 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. 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 on various palladium species) 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%.