Diammonium hexachloropalladate

Endpoint summary

Description of key information

With its relatively low molecular weight (MWt ~355 g/mol) and, more critically, high water solubility (>10,000 mg/L), it is likely that diammonium hexachloropalladate will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption is conservatively set at 100%. 


  


Although not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data), as a highly water soluble substance with a relatively low MWt, any diammonium hexachloropalladate reaching the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.




Diammonium hexachloropalladate, with water solubility in excess of 10,000 mg/L, may be unable to cross the lipid-rich environment of the stratum corneum. However, it is classified as a skin irritant. This irritant 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 the 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 (~355 g/mol) and, more critically, the high estimated water solubility (>10,000 mg/L; Gregory, 2014) are indicative of a high bioavailability of diammonium hexachloropalladate, as ions, 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 diammonium hexachloropalladate is set at 100%.

Findings in the lungs, liver and kidneys of rats in the acute oral toxicity test on diammonium hexachloropalladate (Dreher, 1989) indicated at least partial oral absorption. No conclusions can be reached about absorption from a 28-day oral study on diammonium hexachloropalladate in rats (where histological inflammation of the stomach of both sexes and elevated mean white blood cell counts in males were seen) (Matting, 2015) or from a repeated-dose and reproduction toxicity study (where similar effects were observed in the stomach of parental animals) (Török-Bathó, 2015) because these findings were considered to reflect a local irritant effect of the test substance rather than systemic 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 diammonium hexachloropalladate having a high melting point (decomposition at 250°C; Tremain, 2011b). Particle size distribution (PSD) data, as measured by simple sieving, indicate that only a small proportion (0.1%) of the compound is <100 μm (Tremain, 2011c). Dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 28.6 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. However, respiratory tract deposition modelling with the dustiness data yielded output values of 48.0, 0.11 and 0.062% 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 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 0.1% is likely capable of reaching the alveoli. Thus, inhalation will not be a significant route of exposure. However, as a highly water soluble substance (>10,000 mg/L), any diammonium hexachloropalladate 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 diammonium hexachloropalladate 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 high water solubility of diammonium hexachloropalladate (>10,000 mg/L), it is unlikely to be able to cross the lipid-rich environment of the stratum corneum. 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, diammonium hexachloropalladate is classified as a skin irritant. This is based on the observation of moderate skin irritation in rabbits (Guest, 1989a). 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 overt toxicity was seen in an in vivo skin irritation (Guest, 1989a) or skin sensitisation (Valiczko, 2013) studies (albeit the latter was limited in assessment of systemic effects). Given that adverse effects were seen after oral exposure, this suggests that the substance will not be well-absorbed dermally.

Distribution/Metabolism

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

An acute rat oral toxicity test on diammonium hexachloropalladate led to tissue changes in the lungs, liver and kidneys) (Dreher, 1989), 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 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 a 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, diammonium hexachloropalladate 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).

In the acute oral toxicity test on diammonium hexachloropalladate, necropsy of deceased animals revealed findings in various organs including the kidneys (Dreher, 1989), which is potentially indicative of renal excretion of the substance and/or metabolites.

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, diammonium hexachloropalladate 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, 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 all conservatively set at 100%.

 

References not included elsewhere:

ECHA (2014). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 2.0. November 2014.

Iavicoli I, Bocca B, Fontana L, Caimi S, Bergamaschi A and Alimonti A (2010). Distribution and elimination of palladium in rats after 90-day oral administration. Toxicology and Industrial Health 26, 183-189.

ICH (2014). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Guideline. Guideline for elemental impurities. Q3D Current Step 4 version dated 16 December 2014.

ICMM (2007). International Council on Mining & Metals. Health risk assessment guidance for metals. September 2007.

IPCS (2002). International Programme on Chemical Safety. Palladium. Environmental Health Criteria 226. WHO, Geneva.