LD50 values for palladium compounds ranged, depending on compound and route tested, from 3 to >4900 mg/kg body weight, the most toxic compound being palladium(II) chloride, the least toxic, palladium(II) oxide. Oral administration caused the least toxicity. There were very similar intravenous LD50 values for palladium(II) chloride, potassium tetrachloropalladate(II) (K2PdCl4) and ammonium tetrachloropalladate(II) ((NH4)2PdCl4). Marked differences among the different routes of administration were demonstrated with palladium(II) chloride, showing in Charles-River CD1 rats LD50 values of 5 mg/kg body weight for the intravenous, 6 mg/kg body weight for the intratracheal, 70 mg/kg body weight for the intraperitoneal and 200 mg/kg body weight for the oral route. A higher oral LD50 value has been found in Sprague-Dawley rats.
Effects recorded in rodents and rabbits after short-term exposure to various palladium compounds refer mainly to changes in biochemical parameters (e.g., decrease in activity of hepatic microsomal enzymes or yield of microsomal protein). Clinical signs were sluggishness, weight loss, haematoma or exudations. Changes in absolute and relative organ weights and anaemia also occurred. One compound (sodium tetrachloropalladate(II) complexed with egg albumin) caused deaths in mice. Effective concentrations were in the milligram per kilogram body weight range. Histopathological effects have been observed in liver, kidney, spleen or gastric mucosa of rats 28 days after daily oral administration of 15 or 150 mg tetraammine palladium hydrogen carbonate ([Pd(NH3)4](HCO3)2)/kg body weight. Additionally, an increase in absolute brain and ovary weights at the 1.5 and 15 mg/kg body weight doses has been found.
A 28-day study in rats focusing on histopathological end-points (treatment-related abnormalities in liver, spleen, kidney and gastric epithelium of rats after oral dosing) reported a NOAEL of 1.5 mg tetraammine palladium hydrogen carbonate/kg body weight per day (corresponding to 0.54 mg palladium/kg body weight per day). However, absolute organ weight changes occurred at this dose level.
No mutagenic activity of palladium salts has been found in bacterial test systems. However, one compound (tetraammine palladium hydrogen carbonate) produced a weak clastogenic response with human lymphocytes. Interactions with DNA have been observed . An inhibition of DNA synthesis has been demonstrated both and .
Hueso-Urena F, Moreno-Carretero MN, Salas-Peregrín JM, & Alvarez de Cienfuegos-López G (1991) Palladium, platinum, cadmium, and mercury complexes with neutral isoorotic and 2-thioisoorotic acids: IR and NMR spectroscopies, thermal behavior and biological properties. J Inorg Biochem, 43: 17-27.
A case has been reported of occupational rhinoconjunctivitis and asthma due to an isolated sensitization to palladium in a worker of the electronics industry (Daenen et al., 1997, 1999). About 30 min after a brief exposure to the fumes of an electrolysis bath containing palladium, used to coat electronic parts, a previously healthy, non-smoking, non-atopic, 26-year-old male developed (transient) symptoms of conjunctivitis, rhinitis, chest tightness and dyspnoea. Pulmonary function tests (peak flow records) confirmed the existence of asthma. Usual causes of allergy were not found in this worker. He was also exposed to other metal baths (nickel, tin, lead, gold), but not to platinum, whose salts are well known to cause asthma. Skin prick tests with tetraammine palladium(II) chloride (0.001%) as well as a bronchial provocation test to aerolized tetraammine palladium(II) chloride (0.0001-0.001%, several times for 5-180 s) were positive. The latter gave an early reaction (forced expiratory volume in 1 s [FEV1] 35%) and no late change in histamine PC20 (1.2 mg/ml; provocation concentration that causes a 20% fall in FEV1). Exposure of a control asthmatic subject to tetraammine palladium(II) chloride gave no reaction. Skin prick tests carried out with solutions of sodium hexachloroplatinate(IV) (Na2PtCl6), ammonium tetrachloroplatinate(II) ((NH4)2PtCl4) and palladium(II) chloride were negative for the platinum salts (up to 1%) and possibly positive for palladium(II) chloride (0.1%). In a second series of skin prick tests (performed more than 1 year later), the positive response to tetraammine palladium(II) chloride was confirmed. Tests with other salts (nickel chloride, cobalt chloride, ammonium hexachlororhodanate ((NH4)3RhCl6), platinum salts, ammonium tetrachloropalladate(II) and ammonium hexachloropalladate(IV)) were negative, surprisingly including the two additional palladium compounds (Daenen et al., 1999).
Palladium-containing alloys tested varied in their cytotoxicity, depending mainly on microstructure and composition of the samples (Kawahara et al., 1968; Kawata et al., 1981; Niemi & Hensten-Pettersen, 1985; Ito et al., 1995; Warocquier-Clerout et al., 1995). Severe effects seem to be triggered by other components (e.g., copper). Exposure of a high-noble alloy (Au58, Ag25, Pd13, Zn4; weight per cent) to human fibroblast-keratinocyte co-cultures resulted in a 87-90% reduction of cell viability (MTT assay), but there was no change in prostaglandin E2 or interleukin-6 levels (Schmalz et al., 1997b, 1998). Differences from controls in fibronectin arrangement and cell proliferation were observed with an alloy containing 78% palladium (Au2, Pt1, Pd78, Ag6, Sn2.5, In1.5, Ga9) in a human fibroblast culture (Grill et al., 1997).
Palladium applied in its metallic form (incubation of small test pieces) showed no cytotoxicity in mouse fibroblasts (Kawahara et al., 1968) or little cytotoxicity in human cell lines (Kawata et al., 1981; Niemi & Hensten-Pettersen, 1985), as evaluated microscopically. In a test system consisting of three-dimensional human fibroblast-keratinocyte co-cultures, palladium did not alter cell viability (measured by mitochondrial dehydrogenase activity, MTT assay) after 24 h of exposure. There was also no influence on prostaglandin E2 release, but a 4-fold increase in interleukin-6 levels compared with untreated controls (Schmalz et al., 1997b, 1998).
Palladium(II) chloride (10 mg deposited on the eye surface) caused corrosive conjunctival lesions and severe inflammation of the cornea and anterior chamber of the eyes of rabbits ( = 6). These effects were observed at 24 h and persisted at 48 and 72 h. At the same dose, no reaction was observed with palladium(II) oxide, and no reaction was noted with either platinum oxide or platinum dichloride, tested according to the same protocol (Hysell et al., 1974). A single application (according to OECD Guideline No. 405) of tetraammine palladium hydrogen carbonate to the non-irrigated eye of one rabbit produced severe lesions in the cornea, conjunctiva and nictitating membrane within 24 h. The substance was classified (according to a modified Kay and Calandra classification system) as at least a very severe irritant to the rabbit eye (Johnson Matthey, 1995c).
Several palladium compounds are capable of eliciting dermal irritation. A series of eight palladium compounds was tested with male albino rabbits ( = 6 per group), according to US National Institute of Occupational Safety and Health procedures and evaluation criteria (adapted from those of US FDA, 1973). Twenty-four and 72 h after application of the substances (0.1 g plus 0.1 ml water) onto intact and abraded dorsolateral skin, skin irritation was noted. Evaluation on the basis of combined worst intact and abraded scores resulted in the following ranking (in decreasing order of severity): (NH4)2PdCl6 > (NH4)2PdCl4 > (C3H5 PdCl)2 (allyl palladium chloride dimer) > K2PdCl6 > K2PdCl4 > PdCl2 > (NH3)2PdCl2 > PdO. The first three compounds (causing erythema, oedema or eschar) were considered as unsafe for skin contact; only the last two turned out to be safe. The middle three were non-irritant to intact skin but caused erythema in abraded skin (Campbell et al., 1975). The degree of irritation may correspond to the solubility of these compounds (see section 2.2.2). In another study, palladium hydrochloride (formula not provided) was applied (5.4 mg/kg body weight per day; 2% aqueous solution) to shaved dorsal skin of rabbits ( = 5) over 8 weeks. Dermatitis was observed beginning on day 7 (Kolpakov et al., 1980). Palladium(II) chloride tested on intact skin of rabbits ( = 3), according to Guideline No. 404 of the Organisation for Economic Co-operation and Development (OECD), produced a primary irritation after 1-72 h of observation and was classified as a moderate irritant to rabbit skin according to the Draize classification scheme. Skin reactions 7 days after treatment were crust formation and desquamation (Johnson Matthey, 1994b). No dermal reactions have been found with tetraammine palladium hydrogen carbonate applied to intact skin of rabbits according to the same protocol (Johnson Matthey, 1995b).
There are two studies (Roshchin et al., 1984; Augthun et al., 1991) available investigating the chronic effects of palladium dust. Daily oral administration of 50 mg palladium powder/kg body weight to rats (strain, sex and number not specified) for 6 months resulted in delayed body weight gain, shortening of the prothrombin clotting time, a decrease in urea and lipoprotein contents and an increase in albumin concentrations in blood serum, and a decreased density of urine (Roshchin et al., 1984). In the second study, 6 months after a single intratracheal application of 50 mg palladium dust (~143 mg/kg body weight), the lungs of rats (Sprague-Dawley, female, = 10) were histopathologically examined. There were several signs of inflammatory responses (peribronchial inflammation, lymphocyte infiltration, interstitial pneumonia, formation of granulomata) observed, but no indications of interstitial fibrosis or carcinogenic changes (Augthun et al., 1991).