Palladium dihydroxide

Endpoint summary

Description of key information

Despite a low water solubility (<0.1 mg/L), a high oral availability is anticipated based on significant bio-elution in simulated gastric fluid (cf Rodriguez 2012a,b in section 7.12) and a relatively low molecular weight (~140 g/mol). It is therefore likely that palladium dihydroxide will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of palladium dihydroxide is conservatively set at 100%.

Although not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data - cfr Selck and Parr 2011 in IUCLID section 4.5), as a relatively low molecular weight compound, any palladium dihydroxide reaching the lungs has the potential to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.
Palladium dihydroxide, with water solubility of <0.1 mg/L (cfr. Skaeff 2012 a,b and O'Connor 2011 in IUCLID Section 4.8), may not exhibit appreciable uptake by the dermal route (HERAG Guidance 'Assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds' at https://www.icmm.com/en-gb/guidance/mining-metals/herag), especially considering the low dermal penetration expected from metall. Moreover, palladium dihydroxide is demonstrated to lack 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. 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). While palladium dihydroxide is estimated to be essentially insoluble in water (<0.1 mg/L; Skeaff, 2012), a bio-elution test with the compound showed that the proportion of metal release (from total metal content) in simulated gastric fluid was 77.8% after 2 hours, indicating a high oral availability of the compound. Moreover, based on expert ECHA guidance, as the molecular weight is low (~140 g/mol i.e. 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 dihydroxide is set at 100%.

In an acute oral study on the structurally related compound palladium dichloride, necropsy of deceased animals 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, palladium dihydroxide induced increases in liver weight in females and decreases in seminal vesicle weight in males (Török-Bathó, 2015), again indicating a degree of oral absorption. [Macroscopic and microscopic effects in the stomach, ileum, caecum, colon and rectum were also seen but could reflect local toxicity.]

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 dihydroxide having a high melting point (decomposition at 60°C with no definitive signs of melting below 450°C; Walker, 2011b). Particle size distribution (PSD) data, as measured by simple sieving, indicate that only a small proportion (13.1%) of the compound is <100 μm (Walker, 2011c). However, in another PSD study, on the substance as a liquid dispersion, the 10th, 50th and 90th percentile average particle sizes for palladium dihydroxide were 0.27, 0.67 and 12.1 μm, respectively (Potthoff, 2012). Moreover, dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 29.8 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. Nevertheless, respiratory tract deposition modelling with the dustiness data yielded output values of 46.6, 0.16 and 0.19% 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, based on a low water solubility (<0.1 mg/L) could be coughed or sneezed out of the body or swallowed, with systemic uptake being determined predominantly by oral bioavailability. The insoluble nature of the compound would limit any diffusion/dissolution into the mucus lining the respiratory tract. However, any palladium dihydroxide which is able to migrate into the mucus has the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. Less than 1% of the inhaled fraction is likely capable of reaching the alveoli. Thus, absorption via the lungs will not be a significant type of exposure. Any palladium dihydroxide reaching the lungs would mainly be engulfed by alveolar macrophages and translocated out of the respiratory tract. Overall, while it is very unlikely that palladium dihydroxide will be available to a high extent via inhalation, it is considered health precautionary in the light of the lack of specific absorption data, 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. Given the insoluble nature of palladium dihydroxide (<0.1 mg/L), dermal uptake is likely to be low. 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). Nevertheless, 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, palladium dihydroxide is not classified for skin irritation. This is based on the lack of irritation potential observed both in vitro and in vivo with the structurally related compounds palladium dichloride and palladium monoxide (Allen, 1994b; Campbell et al., 1975). Moreover, in a bio-elution test with palladium dihydroxide, the proportion of metal release (from total metal content) in simulated dermal fluid was 1.045 and 2.60% after 24 and 168 hours respectively, indicating a low dermal availability of the compound. Given the low penetration expected from metals, and the low water solubility (and, thus, low expected dermal bioavailability), 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 palladium dihydroxide.

No clinical signs of toxicity were 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 the "uncomplexed and partially-complexed palladium compounds" category members palladium monoxide and palladium dichloride. While these studies would have been limited in their assessment of systemic effects, the data overall suggest that the substance will not be well-absorbed dermally.

Distribution/Metabolism

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

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

Despite displaying poor water solubility, bio-elution test data indicate that a significant proportion of the metal is released in simulated gastric fluid. As such, rapid excretion is likely based on a high water solubility and low substance molecular weight. 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, as an ionic substance, palladium dihydroxide is considered to have only a low potential for bioaccumulation based on a low anticipated affinity for the lipophilic tissues.

Conclusion

Based on the physico-chemical properties, the chemical structure, molecular weight and the results of toxicity and bio-elution studies, as well as limited toxicokinetic data on other palladium compounds, palladium dihydroxide 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 and unfavourable bio-elution parameters. 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. Proposed predicted absorption figures for the oral, dermal and inhalation routes are 100, 10 and 100%, respectively.