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Administrative data

Description of key information

In a guideline study, to GLP, daily oral (gavage) administration of tetraammineplatinum(II) hydrogen carbonate to rats for 28 days had effects at doses of 150 and 300 mg/kg bw/day. With the exception of reduced absolute brain weights in high-dose males, these effects were not considered to be toxicologically significant. A NOAEL of 150 mg/kg bw/day was established (Wragg et al., 1997).

 

In an OECD Test Guideline 421 reproductive/developmental toxicity screening study, to GLP, in rats with tetraammineplatinum(II) dinitrate, the general systemic toxicity NOAEL for females was 250 mg/kg bw/day on the basis of reduced growth at the highest tested dose (1000 mg/kg bw/day). No adverse effects were observed in males at any dose (Hansen, 2015).

 

No repeated dose toxicity studies by the inhalation or dermal route were identified, or are required.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14-Aug-1996 to 26-Nov-1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
to GLP
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
yes
Remarks:
Functional observations in 4th week omitted
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Sourced from study sponsor. Batch number JF0177.
- Expiration date of the lot/batch: not specified.
- Purity test date: not specified.

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, shielded from light.
- Stability under test conditions: formulations prepared daily and dosed within one hour of preparation.
Species:
rat
Strain:
other: Sprague-Dawley Crl:CD (R) BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent
- Age at study initiation: ~5-6 weeks
- Weight at study initiation: males 127-146 g, females 117-137 g
- Housing: 5/cage (no mixed-sex cages), polypropylene grid-floor cages
- Diet: pelleted, Rat and Mouse SQC Expanded Diet No. 1, Special Diet Services Ltd, ad libitum
- Water: mains water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/-2
- Humidity (%): 55 +/- 15 ("occasional" deviations were considered not to have affected study purpose or integrity)
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test substance prepared (vortex mixed) at the appropriate concentrations as a suspension in arachis oil; used within one hour of preparation, since homogeneity could not be maintained over prolonged periods.

VEHICLE
- Concentration in vehicle: 0, 7.5, 75 and 150 mg/ml
- Amount of vehicle (if gavage): 2 ml/kg bw
- Purity: no data (BP grade)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
High performance liquid chromatography (HPLC) using an external standard technique; performed on test substance formulations extracted with water to give theoretical concentrations of 0.5 mg/ml. Test material formulations were sampled and analysed on the day of their preparation.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Vehicle (arachis oil) control.
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: range-finding study (14-day study)
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily. Immediately before dosing and 1 hour after dosing; also 5 hours after dosing on 5 days/week.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: days 0 (day prior to start of treatment), 7, 14, 21 and 28

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): food consumption recorded weekly for each cage group

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes, but calculated as group mean bodyweight gain in g/rat/week divided by group mean food consumption in g/rat/week

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Water consumption recorded from day 15 onwards (because daily visual inspection during first half of treatment period indicated possible differences between treated and control animals).

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 28 (and repeat sample obtained prior to necropsy on day 29)
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all animals from each test and control group (10/group)
- The following parameters were examined: Haemoglobin (Hb), Erythrocyte count (RBC), Haematocrit (Hct), Erythrocyte indices - mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), Total leucocyte count (WBC), Differential leucocyte count (neutrophils (Neut), lymphocytes (Lymph), monocytes (Mono), eosinophils (Eos), basophils (Bas)), Platelet count (PIT), Clotting (prothrombin) time (CT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 28 (and repeat sample obtained prior to necropsy on day 29)
- Animals fasted: No
- How many animals: all animals from each test and control group (10/group)
- The following parameters were examined. Urea, Glucose, Total protein (Tot.Prot.), Albumin, Albumin/Globulin ratio (by calculation) (A/G), Sodium (Na+ ), Potassium (K+ ), Chloride (CI ), Calcium (Ca++), Inorganic phosphorus (P), Aspartate aminotransferase (ASAT), Alanine Aminotransferase (ALAT), Alkaline phosphatase (AP), Creatinine (Creat), Total bilirubin (Bili), Cholinesterase (CHE),

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

- Samples of the following tissues removed and preserved in formalin: Adrenals, Aorta (thoracic), Bone & bone marrow (femur including stifle joint), Bone & bone marrow (sternum), Brain, Caecum, Colon, Duodenum, Eyes, Gross lesions, Heart, lleum, Jejunum, Kidneys, Liver, Lungs (with bronchi), Lymph nodes (cervical and mesenteric), Muscle (skeletal), Oesophagus, Ovaries, Pancreas, Pituitary, Prostate, Rectum, Salivary glands (submaxillary), Sciatic nerve, Seminal vesicles, Skin (hind limb), Spleen, Stomach, Testes (with epididymides), Thymus, Thyroid/parathyroid, Trachea, Urinary bladder, Uterus

HISTOPATHOLOGY: Yes

- The following tissues from all top dose and control animals were prepared, sectioned, stained and examined microscopically: Adrenals, Heart, Kidneys, Liver, Spleen, Testes
- also Liver and Spleen from all animals from the low- and mid-dose groups
- also all macroscopic lesions; kidneys of the low- and mid-dose animals were also examined microscopically

ORGAN WEIGHTS: Adrenals, Heart, Kidneys, Liver, Spleen, Gonads, Brain
Other examinations:
Full external and internal examination for macroscopic abnormalities performed on all animals.
Statistics:
Absolute and relative organ weights and haematological and serum chemistry parameters: one way analysis of variance, incorporating ‘F-max’ test for homogeneity of variance; if heterogeneous variance, Kruskal-Wallis non-parametric analysis of variance and Mann Whitney U-test.

Criteria: p<0.05 significant; p> or equal to 0.05 not significant
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Male rats dosed at 300 mg/kg bw/day showed a lower body weight gain than controls from week 2 onwards, while females in this group showed a lower body weight gain than controls during weeks 1 to 3 inclusive.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Animals of both sexes dosed at 300 mg/kg bw/day showed a lower food efficiency during the periods corresponding with reduced body weight gain.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water intake was increased in females dosed with 150 or 300 mg/kg bw/day, in a dose-related manner. No such dose-response relationship was seen in males, although water intake was also increased at these doses.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
High dose males showed a lower plasma cholinesterase activity than controls.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Male rats dosed with 300 mg/kg bw/day showed a statistically significant decrease in absolute brain weight compared to controls.

Male rats dosed with 150 or 300 mg/kg bw/day showed a slightly increased relative kidney weight relative to controls.

Males dosed with 15 mg/kg bw/day and all females showed no toxicologically significant organ weight changes.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
4/5 high dose females showed a pale liver at study termination.
4/5 high dose and 1/5 mid dose males showed accentuated lobular pattern of the liver.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
High and mid dose males showed a reduced severity of periportal hepatocyte vacuolation.
High (and possibly mid) dose females showed a reduced severity of renal tubular basophilia
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
No treatment-related effects

BODY WEIGHT AND WEIGHT GAIN
300 mg/kg bw/day - lower bw gain in males from wk 2 onwards, lower bw gain in females from wk 1-3 (coincident with reduced feed efficiency)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No treatment-related effects

FOOD EFFICIENCY
300 mg/kg bw/day - lower in males from wk 2 onwards, lower in females from wk 1-3 (coincident with reduced body weight gain)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
150 and 300 mg/kg bw/day - substantially greater in females from day 15 onwards (not measured from day 1-14); equivocal evidence of treatment-related increases in males in all dose groups (no consistent dose-response relationship).

OPHTHALMOSCOPIC EXAMINATION
Not done

HAEMATOLOGY
No toxicologically significant changes (neutrophil counts and clotting time in male rats did not show convincing dose-response relationships).

CLINICAL CHEMISTRY
300 mg/kg bw/day - significantly lower plasma cholinesterase in males only. No other observed changes were considered to be of toxicological significance as no dose-response relationship was evident and/or values were largely within historical normal range and were not accompanied by other changes that would indicate a "true" effect.

URINALYSIS
Not done

NEUROBEHAVIOUR
Not done

ORGAN WEIGHTS
150 and 300 mg/kg bw/day - marginally higher relative kidney weight in males only (said by the investigators to be of equivocal toxicological significance); statistically significant reduction in absolute brain weight in males.

GROSS PATHOLOGY
150 and 300 mg/kg bw/day - accentuated lobular pattern of the liver in 1/5 and 4/5 males respectively; 300 mg/kg bw/day - pale liver in 4/5 females

HISTOPATHOLOGY: NON-NEOPLASTIC
150 and 300 mg/kg bw/day - reduced severity of periportal hepatocyte vacuolation in males only (considered to be adaptive in nature), reduced severity of groups of basophilic renal tubules in females only

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not applicable

HISTORICAL CONTROL DATA (if applicable)
Used for comparison of some observations above (i.e. clinical chemistry) to strengthen authors' conclusion of a lack of toxicological significance.
Dose descriptor:
NOEL
Effect level:
15 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed at this dose level.
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
In a guideline study, to GLP, daily oral (gavage) administration of tetraammineplatinum(II) hydrogen carbonate to rats for 28 days had effects at doses of 150 and 300 mg/kg bw/day. With the exception of reduced absolute brain weights in high-dose males, these effects were not considered to be toxicologically significant. A NOAEL of 150 mg/kg bw/day was established.
Executive summary:

The repeated dose oral toxicity of tetraammineplatinum(II) hydrogen carbonate was evaluated in rats in a GLP study conducted according to EU guideline B7. Sprague-Dawley rats (5/sex/group) were given a daily gavage administration of tetraammineplatinum(II) hydrogen carbonate at doses of 0 (arachis oil vehicle only), 15, 150 or 300 mg/kg bw/day for 28 days.

 

No animals died during the study and there were no adverse clinical signs. Reduced growth - coincident with reduced food efficiency - was observed in the high-dose group males from week 2 onwards and in similarly-treated females during weeks 1 to 3. Water consumption was higher in the 300 and 150 mg/kg bw/day females but no convincing dose-response relationship was seen for males (increases at all three doses), and the toxicological significance of this finding was said to be dubious. Plasma cholinesterase activity and absolute brain weight were significantly lower in high-dose males only. There were effects on the liver and kidneys in both sexes. Pale liver was seen in 4/5 of the high-dose females and there was reduced severity of groups of basophilic renal tubules in females dosed with 300 (and possibly 150) mg/kg bw/day. Accentuated lobular pattern of the liver was seen in 1/5 and 4/5 mid- and high-dose males respectively; slightly raised relative kidney weights (considered to be of equivocal toxicological significance) and, histopathologically, reduced severity of periportal hepatocyte vacuolation (considered to be adaptive in nature) were also observed in these treatment groups. No toxicologically significant changes in haematology were observed in any treatment group.

 

In conclusion, treatment-related changes were seen at doses of 150 and 300 mg/kg bw/day. With the exception of reduced absolute brain weights in high dose males, these were considered by the investigators as not indicative of serious damage to health. A NOAEL of 150 mg/kg bw/day was established.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Overall, good-quality database which meets REACH Standard Information Requirements.
System:
nervous system
Organ:
brain

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

No data identified.

Additional information

No relevant human data were identified. However, a reliable 28-day oral gavage repeated dose toxicity study has been conducted with tetraammineplatinum(II) hydrogen carbonate.

 

The repeated dose oral toxicity of tetraammineplatinum(II) hydrogen carbonate was evaluated in rats in a study performed to EU guideline B7. Sprague-Dawley rats (5/sex/group) were given a daily gavage administration of tetraammineplatinum(II) hydrogen carbonate at doses of 0 (arachis oil vehicle only), 15, 150 or 300 mg/kg bw/day for 28 days. No animals died during the study and there were no adverse clinical signs. Reduced growth - coincident with reduced food efficiency - was observed in the high-dose group males from week 2 onwards and in similarly-treated females during weeks 1 to 3. Water consumption was higher in the 300 and 150 mg/kg bw/day females but no convincing dose-response relationship was seen for males (increases at all three doses), and the toxicological significance of this finding was said to be dubious. Plasma cholinesterase activity and absolute brain weight were significantly lower in high-dose males only. There were effects on the liver and kidneys in both sexes. Pale liver was seen in 4/5 of the high-dose females and there was reduced severity of groups of basophilic renal tubules in females dosed with 300 (and possibly 150) mg/kg bw/day. Accentuated lobular pattern of the liver was seen in 1/5 and 4/5 mid- and high-dose males respectively; slightly raised relative kidney weights (considered to be of equivocal toxicological significance) and, histopathologically, reduced severity of periportal hepatocyte vacuolation (considered to be adaptive in nature) were also observed in these treatment groups. No toxicologically significant changes in haematology were observed in any treatment group. In conclusion, treatment-related changes were seen at doses of 150 and 300 mg/kg bw/day. With the exception of reduced absolute brain weights in high dose males, these were considered by the investigators as not indicative of serious damage to health. Therefore, the no-observed-adverse-effect level (NOAEL) was considered to be 150 mg/kg bw/day (Wragg et al., 1997).

 

In an OECD Test Guideline 421 reproductive/developmental toxicity study, conducted according to GLP, rats (12/sex/group) received a solution of tetraammineplatinum(II) dinitrate by gavage at doses of 0, 50, 250 or 1000 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 post-partum day 3, test day 40-47]). 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; histopathology was limited to the high dose group). The only clinical sign of toxicity was a significantly reduced body weight in high-dose females at the end of the study on post-partum day 4. No adverse effects were observed in males at any dose. There was no impact on food consumption in males or females. Thus, the NOAEL for general toxicity was deemed to be 250 mg/kg bw/day (Hansen, 2015). Tetraammineplatinum dinitrate is considered to fall within the scope of the read-across category "tetraammineplatinum(II) salts". See section 13 in IUCLID for full read-across justification report.

 

The critical oral NOAEL for tetraammineplatinum(II) hydrogen carbonate (150 mg/kg bw/day) equates to an NOAEL of 76 mg/kg bw/day for platinum (based on MWt ratio).

Justification for classification or non-classification

No adverse systemic effects were seen in reliable guideline studies withtetraammineplatinum(II) hydrogen carbonate (28-day oral repeated dose study)and tetraammineplatinum(II) dinitrate (reproductive/developmental screening assay), at up to respective doses of 150 and 250 mg/kg bw/day.The adverse effects seen at 300 mg/kg bw/day in the repeated dose study and reduced growth in the reproductive/developmental screening assay (at 1000 mg/kg bw/day) are not 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).