Diamminedichloropalladium

Endpoint summary

Description of key information

With its relatively low molecular weight (~210 g/mol) and moderate water solubility (630 mg/L), it is likely that diamminedichloropalladium will be absorbed (as the ions) from the gastro intestinal tract. As such, predicted oral absorption of diamminedichloropalladium is conservatively set at 100%.


  

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




Diamminedichloropalladium, despite having a water solubility of 630 mg/L, may be unable to cross the lipid-rich environment of the stratum corneum, given the low dermal penetration expected for metals. Moreover, diamminedichloropalladium lacks skin irritation potential (which could, in theory, disrupt skin barrier function). As such, predicted dermal absorption is conservatively set at 10%.




Once absorbed, distribution and excretion of ions are expected to be rapid, with little or no bioaccumulation occurring, due to the water solubility. 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, the relatively low molecular weight (~210 g/mol) and, more critically, the moderate estimated water solubility (630 mg/L; Gregory, 2014) are indicative of a high bioavailability of diamminedichloropalladium (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 diamminedichloropalladium is set at 100%.

Adverse necropsy findings in the lungs and pancreas in an acute oral toxicity test on diamminedichloropalladium (Robertson, 2012) are indicative of at least partial absorption. In a combined repeated dose and reproductive/developmental toxicity dietary study on diamminedichloropalladium in rats, the reductions in body weight, growth, food consumption and relative organ weights, as well as histological effects in a range of organs (Török-Bathó, 2015) were also suggestive of at least partial oral absorption.

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 diamminedichloropalladium having a high melting point (decomposition at 323°C with no definitive signs of melting below 450°C; Walker, 2011b). Particle size distribution (PSD) data, as measured by simple sieving, indicates that a significant proportion (96.8%) of the compound is <100 μm (Walker, 2011c). Dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 24.9 μm (Parr, 2011; Selck and Parr, 2011), indicating 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 52.2, 0.29 and 0.44% 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 1% is likely capable of reaching the alveoli. Thus, inhalation will not be a significant route of exposure. However, as a relatively water soluble substance (630 mg/L), any diamminedichloropalladium 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 diamminedichloropalladium 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. Given the moderate water solubility of diamminedichloropalladium (630 mg/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). Further, diamminedichloropalladium 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, 2012b). Given the low penetration expected from metals and the lack of skin irritation potential (which could, in theory, disrupt skin barrier function and facilitate dermal penetration), 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 diamminedichloropalladium.

No clinical toxicity was seen in an acute dermal toxicity test on diamminedichloropalladium (Kiss, 2012a) or in the existing in vivo skin sensitisation study (Pooles, 2012) (albeit the latter was limited in its assessment of systemic effects). Given that toxicity was seen following oral exposure, this suggests that the substance is not well-absorbed dermally.

Distribution/Metabolism

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

In the acute oral toxicity test on diamminedichloropalladium, necropsy of deceased animals revealed findings in the lungs and pancreas (Robertson, 2012), suggesting possible distribution to these organs. A combined repeated dose and reproductive/developmental toxicity dietary study in rats on diamminedichloropalladium led to reductions in the relative weight of the liver, thymus, uterus, seminal vesicle and prostate, as well as histological effects in the majority of examined organs, possibly indicative of wide distribution of the ions. Inflammation of the stomach was also apparent, though this was considered to reflect a local irritant effect of the test substance rather than systemic toxicity (Török-Bathó, 2015).

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).

Diamminedichloropalladium has characteristics favourable for rapid excretion: low molecular weight (<300 g/mol) and moderate 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, diamminedichloropalladium is considered to have only a low potential for bioaccumulation based on its predicted physico-chemical properties (i.e. water solubility of 630 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, diamminedichloropalladium 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 and unlikely to disrupt the skin barrier function (due to a lack of skin irritation potential). 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 relatively high water solubility. Proposed predicted absorption figures for the oral, dermal and inhalation routes are 100, 10 and 100%, respectively.

 

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.