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EC number: 262-819-1 | CAS number: 61495-96-3
In an OECD Test Guideline 421 reproductive/developmental toxicity screening study, to GLP, in rats with tetraamminepalladium dichloride, the general systemic toxicity NOAEL for males was the lowest tested dose (4 mg/kg bw/day), on the basis of reduced growth at 20 and 100 mg/kg bw/day (Török-Bathó, 2015). The critical oral NOAEL for tetraamminepalladium dichloride (4 mg/kg bw/day) equates to NOAELs of 1.76 and 5.45 mg/kg bw/day for palladium and tetraamminepalladium diacetate, respectively (based on MWt ratios).
In a GLP guideline study (EU Method B.7), rats were gavaged with tetraamminepalladium hydrogen carbonate for 28 days. A NOAEL of 15 mg/kg bw/day was obtained based on microscopic changes in the spleen in high-dose animals (150 mg/kg bw/day) (Wragg et al., 1997).
No repeated dose toxicity studies by the inhalation or dermal route were identified, or are required.
In a OECD Test Guideline 421 reproductive/developmental toxicity study, conducted according to GLP, rats (12/sex/group) received a solution of tetraamminepalladium dichloride by gavage at doses of 0, 4, 20, or 100 mg/kg bw/day for at least 28 days (males were dosed for 28-days in total, while females received treatment for a longer period of time [incorporating the gestation period and proceeding up until postpartum day 4, i.e. around 7-8 weeks]). This reproductive and developmental screening assay, has some limitations compared to a standard repeated dose assay for assessing general systemic toxicity. Notably, no haematology, clinical chemistry or urinalysis. Histopathology was limited to the high dose group and focused on the reproductive organs and gross lesions.
Effects on the glandular stomach (including discolouration, inflammation, and congestion) were seen in the high-dose animals, and likely reflects a local effect of treatment. These effects in the glandular stomach may have contributed to the significantly reduced body weight gain seen in males at 20 and 100 mg/kg bw/day (growth of females was unaffected). The NOAEL for systemic toxicity was 4 mg/kg bw/day on the basis of reduced growth in males at 20 and 100 mg/kg bw/day.
No relevant human data were identified. However, a reliable reproduction/developmental screening toxicity study and a 28-day oral gavage repeated dose toxicity (both in rats) have been conducted with tetraamminepalladium dichloride and tetraamminepalladium hydrogen carbonate, respectively.
Tetraamminepalladium dichloride and hydrogen carbonate are considered to fall within the scope of the read-across category "tetraamminepalladium salts". See IUCLID section 13 for full read-across justification report.
In the first of these, in a OECD Test Guideline 421 reproductive/developmental toxicity study, conducted according to GLP, rats (12/sex/group) received a solution of tetraamminepalladium dichloride by gavage at substance doses of 0, 4, 20, or 100 mg/kg bw/day for at least 28 days (males were dosed for 28 days in total, while females received treatment for a longer period of time [incorporating the gestation period and proceeding up until postpartum day 4, i.e. around 7-8 weeks]). This reproductive and developmental screening assay has some limitations compared to a standard repeated dose assay for assessing general systemic toxicity (e.g. no haematology, clinical chemistry or urinalysis, and histopathology was limited to the high dose group). Effects on the glandular stomach (including discolouration, inflammation, and congestion) were seen in the high-dose animals, and likely reflect a local effect of treatment. These effects in the glandular stomach may have contributed to the significantly reduced body weight gain seen in males at 20 and 100 mg/kg bw/day (growth of females was unaffected). Although likely a consequence of local effects on the stomach, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 4 mg/kg bw/day on the basis of reduced growth in males at 20 and 100 mg/kg bw/day (Török-Bathó, 2015). [This NOAEL of 4 mg/kg bw/day is used as the health-precautionary critical point of departure for DNEL derivation purposes.] The critical oral NOAEL for tetraamminepalladium dichloride (4 mg/kg bw/day) equates to NOAELs of 1.76 and 5.45 mg/kg bw/day for palladium and tetraamminepalladium diacetate, respectively (based on MWt ratios).
In support, the repeated dose toxicity of tetraamminepalladium hydrogen carbonate was assessed in a 28-day oral GLP study conducted according to EU Method B.7. Groups of Sprague-Dawley rats (5/sex) were given a daily gavage administration of tetraamminepalladium hydrogen carbonate at 0 (distilled water), 1.5, 15 or 150 mg/kg bw/day for 28 days. Throughout the study, animals were observed daily for mortality and other overt clinical signs of toxicity. Body weight and food and water consumption were monitored. At the end of the study, blood samples were taken for haematological and clinical chemistry assessments, and animals were killed and subject to gross necropsy. The major organs of all animals were weighed, and the adrenals, heart, kidneys, liver, spleen, stomach and testes of high-dose and control animals were examined microscopically. Having been identified as possible target organs, the liver, spleen, kidneys and stomach were subsequently examined microscopically in all treated and control animals. No unscheduled deaths or treatment-related overt clinical signs of toxicity were seen over the course of the study. During study week 3, growth was reduced in high-dose males and females, and high-dose males demonstrated reduced food consumption and food efficiency – but these effects were not seen during week 4. High-dose males demonstrated reduced haemoglobin, erythrocyte count, haematocrit and mean corpuscular volume, with two rats having unusually high reticulocyte counts. A slight but significant rise in eosinophil levels was seen in high-dose females. At necropsy, absolute and relative kidney weights were increased in high-dose females. One high-dose male had a pale liver, kidney and glandular gastric epithelium, while one high-dose female had a reddened glandular gastric epithelium. A draft commentary on the report notes that the "degree of pigment deposition in the spleen varies marked in rats" and that the "absence of pigment deposition is indicative of a toxicologic effect". However, "slight variations of pigment deposition are normal and do not have any physiological, pathological, or toxicological significance". Therefore, the overall NOAEL was considered to be 15 mg/kg bw/day, with the critical effect being microscopic changes in the spleen (no haemosiderin deposition in 5/5 males and 2/5 females, compared to 0 controls) in high-dose animals. Changes seen in the stomach have been considered indicative of local irritation (Wragg et al., 1997).
According to REACH Annex VIII (EC 1907/2006), repeated dose toxicity studies only need to be conducted on one species taking into consideration the most appropriate route of administration regarding human exposure. The compound is not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data). Thus, inhalation will not be a significant route of exposure. Similarly, skin contact during production and/or use is expected to be negligible. As the oral route of exposure is considered the most appropriate, repeated dose toxicity studies were not carried out for the dermal or inhalation routes.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: Reliable reproductive/developmental screening study involving repeated dosing of the parental animals for at least 28 days and assessment for systemic toxicity, conducted to OECD guidelines and GLP, with a lower critical effect level (NOAEL) than determined in the 28-day (read-across) study.
No significant systemic effects sufficient for classification were seen in reliable guideline studies (28-day oral repeated dose and a reproductive/developmental screening assay) with tetraamminepalladium hydrogen carbonate and tetraamminepalladium dichloride, respectively. The adverse effects seen at 150 mg/kg bw/day in the repeated dose study and (reduced growth) at 20 and 100 mg/kg bw/day in the reproductive/developmental screening assay are likely the result of local toxicity in the gastrointestinal tract, and are not considered sufficient for classification as STOT-RE. As such, the results of these studies indicate that classification as STOT-RE is not required, according to EU CLP criteria (EC 1272/2008).
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