Palladium (II) di(4-oxopent-2-en-2-oate)

Endpoint summary

Description of key information

Despite having only slight water solubility (11.1 mg/L), this compound’s relatively low molecular weight (~305 g/mol), moderate partition coefficient (2.6) and appreciable bio-elution in simulated gastric fluid indicate a high degree of oral availability. It is likely that palladium di(4 oxopent-2-en-2-oate) will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of palladium di(4 oxopent-2-en-2-oate) is conservatively set at 100%.
Although not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data), as a relatively lipophilic compound, any palladium di(4 oxopent-2-en-2-oate) deposited in the upper regions of the respiratory tract has the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. As such, the predicted inhalation absorption is conservatively set at 100%.

Palladium di(4-oxopent-2-en-2-oate), despite having an optimal partition coefficient for dermal absorption, may not exhibit appreciable uptake by this route, given its slight water solubility and, more critically, the low dermal penetration expected from metals. Moreover, palladium di(4-oxopent-2-en-2-oate) lacks 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. The organic 4-oxopent-2-en-2-oate moiety is likely to undergo metabolism, and the palladium excreted. 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, while palladium di(4‑oxopent-2-en-2-oate) has a relatively low estimated water solubility (11.1 mg/L; Gregory, 2014), it has a moderate partition coefficient (log Pow; between -1 and 4) (2.6; Winkler, 2015) which is favourable for absorption by passive diffusion. Moreover, in a bio-elution test with the compound, the proportion of metal ion release (from total metal content) in simulated gastric fluid was 22.6% after 2 hours, indicating a significant oral availability of the compound. The relatively low molecular weight (~305 g/mol) of palladium di(4 oxopent-2-en-2-oate) is also aligned with a high bioavailability 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 di(4-oxopent-2-en-2-oate) is set at 100%.

In the acute oral toxicity test in rats, palladium di(4-oxopent-2-en-2-oate) caused clinical signs of toxicity, lower body weight, and (at necropsy of deceased animals) changes in the lungs (Matting, 2013). In a combined repeated dose and reproductive/developmental toxicity dietary study, the source substance palladium dihydroxide induced increases in liver weight in females and decreases in seminal vesicle weight in males. Macroscopic and microscopic effects were also seen in a number of organs (including stomach, ileum, caecum, colon and rectum), but these could have reflected local toxicity (Török-Bathó, 2015). Overall, these studies indicate that absorption of the test substance can be expected.

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 di(4-oxopent-2-en-2-oate) has a very low predicted vapour pressure (8.2x10E-5 Pa; Nau, 2015), indicating that only a small proportion of the substance may be available for inhalation as a vapour. Further, 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 dry dispersion, the 10th, 50th and 90th percentile average particle sizes for palladium di(4 oxopent-2-en-2-oate) were 0.66, 2.1 and 5.4 μm, respectively (Potthoff, 2012), suggesting that a significant proportion of the substance may reach the alveolar region of the respiratory tract (particle sizes <15 μm). Moreover, dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 38.2 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 40.0, 0.14 and 0.26% 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 slight water solubility (11.1 mg/L) could be coughed or sneezed out of the body or swallowed, with systemic uptake being determined predominantly by oral bioavailability. The relatively low water solubility of the compound would limit any diffusion/dissolution into the mucus lining the respiratory tract. However, as a moderately lipophilic substance (log Pow >0), any palladium di(4‑oxopent-2-en-2-oate) 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 di(4-oxopent-2-en-2-oate) 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 di(4-oxopent-2-en-2-oate) 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. Given the slight water solubility (11.1 mg/L) of palladium di(4-oxopent-2-en-2-oate), dermal uptake is likely to be low. However, the compound has an optimal log Pow (2.6) for absorption through the skin. 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 di(4-oxopent-2-en-2-oate) is not classified for skin irritation. This is based on the inability of the compound to reduce skin cell viability by more than 50% in vitro (Kiss, 2012a). Moreover, in a bio-elution test with palladium di(4-oxopent-2-en-2-oate), the proportion of metal release (from total metal content) in simulated dermal fluid was 0.57 and 1.90% after 24 and 168 hours respectively, indicating a low dermal availability of the compound. Given the low penetration expected from metals, the relatively low water solubility (and, thus, low expected dermal bioavailability), and the mixed organic/inorganic nature it is appropriate to take forward the lower of the two ECHA default values for dermal absorption, of 10%, for the safety assessment of palladium di(4-oxopent-2-en-2-oate).

No overt toxicity was seen in an acute dermal toxicity study) (Matting, 2014) or an in vivo skin sensitisation study (Váliczkó, 2014) on palladium di(4-oxopent-2-en-2-oate (albeit the latter would be limited in its assessment of systemic effects). Given that toxicity was seen in the acute oral study, this suggests that the substance will not be well-absorbed dermally.

Distribution/Metabolism

Once absorbed, wide distribution of palladium ions, 4-oxopent-2-en-2-oate ions and metabolites of the latter is expected based on water solubility and/or relatively low molecular weights. Distribution into cells is likely as the compound is moderately lipophilic (log P >0). Intracellular concentration may exceed extracellular concentration, particularly in fatty tissues.

The organic part of the compound is likely to undergo metabolism to simpler substances.

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 only slight water solubility, bio-elution test data indicate that an appreciable proportion of the metal is released in simulated gastric fluid. As such, rapid excretion is likely based on a relatively high water solubility and low 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). Additionally, the potential for accumulation in the lungs and adipose tissue is recognised, based on a moderate log Pow value (2.6). However, the respiratory tract deposition modelling data indicate that an insignificant proportion of the compound penetrates the lower regions of the respiratory tract and hence the alveolar accumulation potential is anticipated to be low. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissue as a result of the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Gradual elimination would ensue upon termination of the exposure (ECHA, 2014). Moreover, excretion or utilisation of oxidative metabolites of the organic moiety is expected.

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 di(4-oxopent-2-en-2-oate) 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 moderate lipophilicity. Proposed predicted absorption figures for the oral, dermal and inhalation routes are 100, 10 and 100%, respectively. Bioaccumulation is unlikely; palladium ions will undergo excretion and the organic moiety will presumably undergo metabolism and excretion.