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EC number: 237-489-7 | CAS number: 13815-17-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- repeated dose toxicity: oral
- Remarks:
- other: Reproduction/Developmental Toxicity Screening Test
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 June - 09 August 2014 (last necropsy)
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Guideline study, conducted to GLP. However, as a reproducitve and developmental screening assay, it has some limitations compared to a standard repeated dose assay assessing general systemic toxicity (e.g. no haematology, clinical chemistry or urinalysis was conducted, and histopathology was limited to the high dose group).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Tetraamminepalladium dichloride
- IUPAC Name:
- Tetraamminepalladium dichloride
- Reference substance name:
- Tetraamminepalladium(2+) dichloride
- EC Number:
- 237-489-7
- EC Name:
- Tetraamminepalladium(2+) dichloride
- Cas Number:
- 13815-17-3
- Molecular formula:
- H8Cl2N4Pd
- IUPAC Name:
- tetraaminopalladiumbis(ylium) dichloride
- Test material form:
- other: solid
- Details on test material:
- - Name of test material (as cited in study report): Tetraamminepalladium(2+) dichloride
- Physical state: solid
- Analytical purity: Pd content: 41.69%
- Impurities (identity and concentrations): 15 ppm Pt; <2 ppm Ru, <5 ppm Rh; <10 ppm Ir; 4 ppm Au; 7 ppm Ag; 3 ppm Al; 1 ppm Ca; <2 ppm Co; <1 ppm Cr; 13 ppm Cu; <2 ppm Fe; <2 pmm Mg; <5 ppm Mn; <1 ppm Ni; <2 ppm Pb; <10 ppm Sb; <10 ppm Si; <5 ppm Sn; 18 ppm Zn.
- Isomers composition: not applicable
- Purity test date:
- Lot/batch No.: 10214
- Expiration date of the lot/batch: 13 January 2015
- Stability under test conditions: The test item solution in aqueous ammonium-chloride buffer was stable over 7 days at room temperature and for 14 days when refrigerated (2-8ºC).
- Storage condition of test material: Controlled room temperature (15-25 deg C, below 70 RH%), protected from humidity
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633, from SPF colony
- Age at study initiation: Young adult rats, at least 10 weeks old at starting and at least 12 weeks at mating.
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study: no data
- Housing: Type II and III polycarbonate cages. Lignocel® Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH+Co.KG (Holzmühle 1, D-73494 Rosenberg, Germany).
- Diet (e.g. ad libitum): ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany offered ad libitum
- Water (e.g. ad libitum): tap water from municipal supply as for human consumption from 500 ml bottle ad libitum
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-23.8 °C (target range 22±3°C)
- Humidity (%): 40 - 70 % (target range 30-70%)
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.
IN-LIFE DATES:
Start of experiment (start of treatment): 24 June 2014
End of treatment: 22 July 2014 (males); 08 August 2014 (females)
End of experiment: 09 August 2014 (last necropsy)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: an aqueous ammonium-chloride buffer (NH4Cl/NH4OH) was selected as the vehicle. The vehicle allowed formulation of a stable solution of the test item, considered suitable for the study purpose.
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Aqueous ammonium-chloride buffer (NH4Cl/NH4OH) was used as the dosing vehicle.
The buffer was prepared as follows:
2.68 g ammonium chloride (Batch/Lot No.: BCBM5575V, Supplier: Sigma-Aldrich, Expiry: March 2015) was dissolved in 1000 ml distilled water (Batch/Lot No.: 0271113, Supplier: TEVA Pharmaceutical Works PLtd., Expiry: November 2016).
The pH was adjusted to 9 by adding approximately 1650-1850 µL of 29.1% ammonium hydroxide (Batch/Lot No.: SZBD2260V, Supplier: Sigma-Aldrich, Expiry: August 2015).
The first preparation was used for 7 consecutive days and was kept at room temperature. The next preparations were used for periods of up to 14 days, following confirmation of the stability, and the stock solution was kept refrigerated (2-8ºC). Dose solutions for treatment were diluted from the stock solution with aqueous ammonium-chloride buffer to the concentrations of 4.0 and 0.8 mg/mL, daily just before the treatment. The stock solution was prepared four times during the study.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on the results of the preliminary formulation trial and pilot DRF study (CiToxLAB study code: 13/195-100PE), an aqueous ammonium-chloride buffer (NH4Cl/NH4OH) was selected as the vehicle. The vehicle allowed formulation of a stable solution of the test item, considered suitable for the study purpose.
- Concentration in vehicle: The test item was formulated in the aqueous ammonium-chloride buffer as a stock solution at the concentration of 20 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw/day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability of the test item in the vehicle was assessed in the concentration range of 5 mg/mL-200 mg/mL by Fourier-transformation infrared spectroscopy (FT-IR). According to the results the test item solution in aqueous ammonium-chloride buffer was stable over 7 days at room temperature and for 14 days when refrigerated (2-8ºC). (CiToxLAB Study code: 13/195-929AN).
Analysis of test item formulations was performed at the Test Site using a validated ICP method (ICP-AES) to determine the palladium content. The concentration measurements were performed on all preparations of the stock solutions and at the same time, from samples of diluted dose solutions. The sampling occasions coincided with the preparation of the stock solution.
Samples were taken from the test item formulations (including control) for concentration measurements. One set of samples was collected for analysis and one set retained as a back-up, for possible confirmatory analysis. Similarly, one sample was taken on each occasion in duplicate from the Group 1 (control) solution to confirm the absence of the test item. No confirmatory analysis was required.
The measured concentrations of palladium in the formulations varied between 95.0 % and 111.9 % of the nominal. These results were within the range of acceptable values (85% - 115%). - Duration of treatment / exposure:
- Males were dosed for 28 days (14 days pre-mating and 14 days mating/post- mating period). They were then euthanized and subjected to necropsy examination.
Females were dosed for 14 days pre-mating, for up to 7 days mating period, through gestation and up to and including the day before necropsy (at least 4 days post-partum dosing). The day of birth (viz. when parturition was complete) is defined as Day 0 post-partum. - Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
4 mg/kg bw/day
Basis:
other: nominal dose
- Remarks:
- Doses / Concentrations:
20 mg/kg bw/day
Basis:
other: nominal dose
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/day
Basis:
other: nominal dose
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected by the Sponsor in consultation with the Study Director, based on available data, including the results of a dose range finding study (CiToxLAB study code 13/195-100PE), with the aim of inducing toxic effects but no death or suffering at the highest dose and a NOAEL at the lowest dose.
- Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
Adult (parental) animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day). General clinical observations were made once a day.
All animals were monitored for pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity including mortality. The changes were recorded including onset, degree and duration of signs as applicable.
DETAILED CLINICAL OBSERVATIONS: Yes
More detailed examinations were performed once prior to first treatment (to allow for within-subject comparisons), and once a week thereafter. The animals were examined outside the home cage in a standard arena and at similar times on each occasion. The animals were monitored for changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern), or changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. self-mutilation, walking backwards); special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
BODY WEIGHT: Yes
All adult animals were weighed with an accuracy of 1 g for randomization purposes, then on Day 0, twice a week thereafter and prior to necropsy.
Adult females were weighed on gestation Days GD0, 7, 14 and 20 and on postpartal Days PPD0 (within 24 hours after parturition) and PPD4 (before necropsy).
The body weights of the females were also recorded on GD4, 10 and 17 in order to give accurate treatment volumes, however, these data were not evaluated statistically.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption was determined by re-weighing the non-consumed diet with a precision of 1 g on Day 7 and then weekly thereafter.
FOOD EFFICIENCY: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data (gavage study)
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- SACRIFICE
- Male animals: All animals were sacrificed on test day 29, after a dosing period of 28 days.
- Maternal animals: Dams were sacrificed following at least 4 days post-partum dosing.
GROSS NECROPSY
- Gross necropsy consisted of external appearance. The cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed macroscopically. Special attention was paid to the organs of the reproductive system. The number of implantation sites and the number of corpora lutea were recorded. Any abnormality was recorded with details of the location, colour, shape and size, as appropriate.
HISTOPATHOLOGY / ORGAN WEIGHTS
Detailed histological examination was performed on testes, epididymides and ovaries in the control and high dose groups. In addition, gross lesions (the stomachs of 9 males and 5 females from the High Dose) were also examined microscopically. The stomachs of two control males and females were also examined for comparison.
Special attention was paid to evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments as well as the epithelial capsule and ovarian stroma. - Statistics:
Numerical data obtained during the conduct of the study were subjected as appropriate to calculation of group means and standard deviations.
The statistical evaluation of appropriate data was performed with the statistical program package SPSS PC+4.0. The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences. When Bartlett’s test was significant, the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test.
Chi2 test was performed when feasible.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Slight growth reductions in the two highest dose groups (slight transient body weight loss in the highest dose group)
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Discolouration of the glandular stomach and epididymis were apparent in the highest tested dose group
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Effects on the glandular stomach apparent in the highest tested dose group
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY: There were no clinical signs related to treatment. All animals were clinically normal.
BODY WEIGHT AND WEIGHT GAIN: Mean body weights of males treated at 100 mg/kg/day were slightly lower than controls from Week 1 onwards. This was due in part to the higher mean body weight for the control group. The differences from control attained statistical significance (p<0.01 on Days 7, 14, 21). Compared to the controls, mean value was approximately 7% lower on Day 27, and the difference was statistically significant (p<0.05).
Compared to the control, significantly lower body weight gain was noted for High dose males during Weeks 1 (p<0.01) and 3 (not statistically significant) resulting in lower overall (Days 0-27) gain value by 25% (p<0.05). In 5 of 12 males at 100 mg/kg/day suppressed body weight gain or slight body weight loss was recorded at the beginning of the treatment period (Days 0-3). For one male no body weight gain or a slight body weight loss was noted during the last week of the treatment. This animal had the most severe changes in the stomach in the form of mild inflammation and ulceration in the glandular stomach.
Body weight of males at 20 mg/kg/day was lower than control mean throughout the entire treatment period by 6-7%, and the differences were statistically significant (p<0.01 on days 7, 14 and p<0.05 on days 21 and 27). The body weight gain values of these males were significantly lower, than control mean during Weeks 1 (p<0.01) and 2 (not statistically significant). The overall (Days 0-27) body weight gain value was lower than the control mean by 22% (p<0.05). The individual body weight gain values were within the control range, with the exception of one male which had consistently suppressed body weight gain or slight body weight loss throughout the entire treatment period.
The mean body weight of males at 4 mg/kg/day did not differ significantly from the control mean.
It should be noted, that the mean body weight of control males was slightly higher (by approximately 2%) on Day 0 and the body weight values were in the higher range. In addition, two control males had overall body weight gain value higher than group mean by 25-30%.
Females at 100, 20 and 4 mg/kg/day had mean body weights and body weight gains comparable to the controls throughout the entire treatment period.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): The average food consumption of males in all test item treated groups was lower, than control during Week 2 by approximately 12-13% at 4 and 100 mg/kg/day, and by 18% at 20 mg/kg/day. The differences attained statistical significance: p<0.01 for Low and Mid dose groups and p<0.05 for High Dose group, but were not clearly treatment related due to the lack of dose-response.
Lower than control mean food consumption was also recorded for all test item treated groups of males from the end of mating period up to Day 21. The differences were statistically significant (p<0.05) and attributed to the higher control value.
There were two males in the control group with food consumption well above the control mean.
The average food consumption in females in all test item treated groups was comparable with the control mean throughout the entire treatment period.
The test item formulations were found to be in the range of 95.0 and 111.9 % of of nominal concentrations and were therefore considered acceptable.
FOOD EFFICIENCY: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not applicable
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOUR: No data
ORGAN WEIGHTS: There were no test item related effects on organ weights. Occasional statistically significant differences in absolute testis and prostate weight were attributed to the lower body weights of the animals and therefore of no toxicologically significance.
GROSS PATHOLOGY: At necropsy, test item-related findings were observed at 100 mg/kg/day (High dose) in the form of focal/multifocal dark red discoloration of the glandular mucosa of the stomach in 9/12 males and 5/12 females.
Unilateral, focal, yellow/green discoloration of the epididymis was noted in 1/12 males in the High dose.
HISTOPATHOLOGY: NON-NEOPLASTIC: Test item-related microscopic findings were observed in the glandular stomach of animals at 100 mg/kg/day (High dose). In all males with macroscopic changes (dark red discoloration), congestion was noted in the glandular mucosa of the stomach (9/9). In addition, 7/9 of these males had minimal to mild, mixed cellular infiltration, and minimal to mild mixed cellular inflammation was observed in 2/9 males. In one animal organizing ulcer in the glandular mucosa was found additionally. In 5/5 all High dose females congestion of the glandular mucosa of the stomach with minimal, mixed cellular infiltration was detected. The observation was in agreement with necropsy finding.
No test item-related microscopic findings were noted in the reproductive system of the males and females from the High dose group. The follicular, luteal and interstitial compartments of the ovary as well as epithelial capsule and stroma were similar histological structure in both Control and High Dose females. The primordial, secondary and tertiary follicles and corpora lutea were also bilaterally present.
The spermatogenic cells, representing different phases of the development and differentiation of the spermatozoons as well as interstitial cell structure were similar in Control and High Dose males.
The unilateral, focal, yellow/green discoloration of the epididymis in 1/12 males in the High dose was microscopically identified as moderate spermatocoele and was regarded as a background observation.
The other microscopic changes were regarded as incidental or background.
HISTOPATHOLOGY: NEOPLASTIC: Not applicable
HISTORICAL CONTROL DATA: Not applicable
OTHER FINDINGS: The spermatogenic cells, representing different phases of the development and differentiation of the spermatozoons as well as interstitial cell structure were similar in Control and High Dose males.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- gross pathology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Dose descriptor:
- NOAEL
- Effect level:
- 4 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Decreased body weight gain at 20 and 100 mg/kg bw/day.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- 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.
- Executive summary:
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.
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