Dihydrogen tetrachloropalladate(2-)

Endpoint summary

Description of key information

With its relatively low molecular weight (~250 g/mol) and, more critically, high water solubility (>10,000 mg/L), it is likely that dihydrogen tetrachloropalladate will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of dihydrogen tetrachloropalladate 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 dihydrogen tetrachloropalladate that does reach the lungs is likely to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.

Dihydrogen tetrachloropalladate, with water solubility in excess of 10,000 mg/L, may be unable to cross the lipid-rich environment of the stratum corneum. However, the compound is classified for skin corrosion in sub-category 1A. 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 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 (~250 g/mol) and, more critically, the high estimated water solubility (>10,000 mg/L; Gregory, 2014) are indicative of a high bioavailability of dihydrogen tetrachloropalladate 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 dihydrogen tetrachloropalladate is set at 100%.

 

In the acute oral toxicity test on dihydrogen tetrachloropalladate, the liver, abdominal cavity and kidney findings at necropsy, as well as a general reduction in body weight and a variety of clinical signs of toxicity (van Huygevoort, 2003a), are indicative of at least partial oral absorption. Effects in a combined repeated dose and reproductive/developmental toxicity dietary study in rats, on the a category ("tetraamminepalladium salts") member disodium tetrachloropalladate, included reductions in body weight, growth, food consumption and relative weights of various organs (Szaloki 2022). These results are indicative of a potential for some oral absorption of the test substances (and thus possibly of dihydrogen tetrachloropalladate).

 

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 the substance is an aqueous solution of an inorganic salt and the vapour pressure is similar to that of the solvent. 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 dihydrogen tetrachloropalladate 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 dihydrogen tetrachloropalladate 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 dihydrogen tetrachloropalladate (>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, dihydrogen tetrachloropalladate is classified as corrosive (to skin) sub-category 1A. This is based on a mean breakthrough time of about 3 minutes in an in vitro membrane barrier test (Lehmeier, 2013). 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 dihydrogen tetrachloropalladate due to its classification as corrosive to the skin in an in vitro membrane barrier test (Lehmeier, 2013). The existing in vivo skin sensitisation study (van Huygevoort, 2003b), albeit limited in its assessment of systemic effects, did not lead to overt systemic toxicity. Given the toxicity observed following ingestion, this is a limited indication that the substance will not be well-absorbed dermally.

 

Distribution/Metabolism

Once absorbed, distribution of hydrogen/hydroxonium ions and tetrachloropalladate ions throughout the body is expected based on a relatively low molecular weight.

 

In the acute oral toxicity test on dihydrogen tetrachloropalladate, necropsy of deceased animals revealed findings in the liver, abdominal cavity and kidneys (van Huygevoort, 2003a), suggesting possible distribution to these tissues.

In a combined repeated dose and reproductive/developmental toxicity dietary study in rats on disodium tetrachloropalladate, a category member substance, reductions in the relative weight of adrenal glands, thyroid/parathyroid glands, seminal vesicles, ovaries, liver, brain and heart, but these were considered not biologially relevant or due to excessive toxicity (dosing in excess of MTD) and were histologically considered as non adverse or incidental (Szaloki 2022).

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).

Dihydrogen tetrachloropalladate has 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, dihydrogen tetrachloropalladate 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, dihydrogen tetrachloropalladate is likely partially bioavailable by the oral route 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), 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.