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Description of key information

No relevant acute toxicity data were identified for tetraammineplatinum dinitrate.

 

In a reliable guideline GLP study, the acute oral LD50 value of tetraammineplatinum hydrogen carbonate was determined to exceed 2150 mg/kg bw in rats (5/sex/dose) (Berthold, 1997). In an earlier rat study, the acute oral LD50 value of tetraammineplatinum hydrogen carbonate was determined to be >200 mg/kg bw but <2000 mg/kg bw. No evidence of systemic toxicity was observed at the dose of 200 mg/kg bw in the main study (5/sex/dose) but both tested animals (1/sex) died in the range-finder at 2000 mg/kg bw/day (Dreher, 1989). The acute oral LD50 value of tetraammineplatinum dichloride was reported to exceed 15 g/kg bw in rats (Jones, 1977a).

 

In a guideline study, to GLP, the acute dermal LD50 value of tetraammineplatinum diacetate, following 24-hour occlusive application in rats, was reported to exceed 2000 mg/kg bw (Beerens-Heijnen, 2006). In rats, the acute dermal LD50 value (24-hour semi-occlusive application) for tetraammineplatinum hydrogen carbonate was >2000 mg/kg bw(Allen, 1997).

 

No relevant acute inhalation toxicity data were identified, or are required at this tonnage.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
23 June 1997 to 15 July 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Conducted according to GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: HsdCpb: WU
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, D-33176 Borchen
- Age at study initiation: males 7 weeks; females 9 weeks
- Weight at study initiation: males 156-166 g; females 151-173 g
- Fasting period before study: 16 hours
- Housing: 1 animal/Macrolon cage, type II; soft wood granulate bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-21.6
- Humidity (%): 41-73
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
Trade name TylopurR C 1000 P; 0.5% aqueous CMC: trade name Tylose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 215 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: test substance given as a suspension
- Lot/batch no. (if required): E 114 30100

DOSAGE PREPARATION: test substance suspended immediately before dosing using a homogenizer and magnetic stirrer
Doses:
2150 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Continuous observations for 4-6 hr after dosing, then once per day. Weighed at start of study and day 7 and 14 (or after death if this occurred earlier).
- Necropsy of survivors performed: yes
Statistics:
Not applicable, LD50 higher than the dose administered
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 150 mg/kg bw
Mortality:
One male and one female died on days 5 and 6, respectively.
Clinical signs:
Surviving animals:
Males (n=4): 2 had no symptoms, 2 showed slightly reduced movement, staggered gait and sunken sides (lasting 1-4 days).
Females (n=4): 4 had diarrhoea, 2 had staggered gait, 2 had sunken sides, 1 had reduced movement.

Deceased animals:
Male (n=1): slightly reduced movement, stilted and staggered gait, clonic convulsions, diarrhoea, piloerection, sunken sides, red crusted nose, emaciation.
Female (n=1): slightly reduced movement stilted and staggered gait, diarrhoea, sunken sides.

Body weight:
Males: 156-160 g before treatment; 223-242 g on day 14. Mean body weight gain 71 g. (Deceased male, 166 g before treatment; 125 g at death on day 5.)
Females: 151-173 g before treatment; 172-207 g on day 14. Mean body weight gain 31 g. (Deceased female 154 g before treatment; 100 g at death on day 6.)
Gross pathology:
No gross abnormalities detected.
Other findings:
No other findings reported
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 value of tetraammineplatinum hydrogen carbonate was determined to exceed 2150 mg/kg bw in male and female rats.
Executive summary:

In an acute oral toxicity test, conducted in accordance with OECD Test Guideline 401 (withdrawn in 2002) and to GLP, HsdCpb: WU rats (5/sex) were gavaged with tetraammineplatinum hydrogen carbonate (as a suspension in aqueous carboxymethyl cellulose) at a limit dose of 2150 mg/kg bw and observed for 14 days.

 

Three males showed reduced movement, staggered gait and sunken sides starting 75 minutes after dosing and lasting until day 1 or 4 after dosing. One of these males additionally showed clonic convulsions, diarrhoea, piloerection, stilted gait, red crusted nose and emaciation, and subsequently died (on day 5 after dosing). The other two males showed no signs of toxicity during the observation period.

 

All females exhibited diarrhoea, and some showed staggered and/or stilted gait, reduced movement and sunken sides. These effects were evident from 90 minutes after dosing, and lasted for 6 days or, in one animal, until death (on day 6).

 

The acute oral LD50 value was therefore determined to exceed 2150 mg/kg bw in male and female rats.

 

Based on the results of this study, tetraammineplatinum hydrogen carbonate does not require classification for acute oral toxicity according to EU CLP criteria (EC 1272/2008).

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Overall, good-quality database which meets REACH Standard Information Requirements.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
10 May 2006 to 24 May 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Conducted according to GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
both sexes studied, only one dose tested, no data presented on histopathological results
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry, and Fisheries (JMAFF) Guidelines (2000), including the most recent revisions
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: body weight variation did not exceed +/- 20% of the sex mean
- Fasting period before study: no data
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 to 23.3
- Humidity (%): 36 to 68
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: no data
Type of coverage:
occlusive
Vehicle:
water
Remarks:
Milli-U
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 25 cm2 for males, and 18 cm2 for females
- % coverage: 10% total body surface
- Type of wrap if used: a dressing consisting of a surgical gauze patch (Surgy 1D) covered with aluminium foil and a Coban elastic bandage. Micropore tape was additionally used to fix the bandages in females.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed with water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight
- Constant volume or concentration used: no

VEHICLE
- Amount(s) applied (volume or weight with unit): no data
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations, weekly measurements of body weight
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred
Clinical signs:
Hunched posture, chromoacryorrhoea, lethargy, shallow respiration and/or piloerection were noted in the majority of animals on days one and/or two. Treated skin showed general, focal or maculate erythema, scales, scabs, scars and/or necrosis during the observation period.
Body weight:
No body weight changes indicative of toxicity were observed.
Gross pathology:
Post mortem macroscopic examinations showed no abnormalities.
Other findings:
- Organ weights: no data
- Histopathology: no data
- Potential target organs: no data
- Other observations: no data
Interpretation of results:
GHS criteria not met
Conclusions:
In a guideline study, to GLP, the acute dermal LD50 value of platinum(2+)tetraammine(SP-4-1) diacetate, following 24-hour occlusive application in Wistar rats, was reported to exceed 2000 mg/kg bw.
Executive summary:

The acute dermal toxicity of platinum(2+)tetraammine(SP-4 -1) diacetate was investigated in a protocol performed according to OECD Test Guideline 402 and to GLP. 

 

The test substance was applied under occlusion to the skin of Wistar rats (5/sex) at a limit dose of 2000 mg/kg bw for 24 hours. After this period, dressings were removed and the skin was washed with water. Animals were then monitored over the next two weeks for mortality and any clinical signs of toxicity. After this period, any survivors were sacrificed, and subjected to gross necropsy.

 

No mortality occurred during the experiment, and no macroscopic abnormalities were found at post mortem. No body weight changes indicative of toxicity were observed. Clinical signs included hunched posture, bloody tears, lethargy, shallow respiration and piloerection. In the treated skin area, general, focal or maculate erythema, scales, scabs, scars and/or necrosis were apparent.

 

Hence the acute dermal LD50 value of platinum(2+)tetraammine(SP-4 -1) diacetate was determined to exceed 2000 mg/kg bw in rats.

 

Based on the results of this study, no classification is required for acute dermal toxicity according to EU CLP criteria (EC 1272/2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Overall, good-quality database which meets REACH Standard Information Requirements.

Additional information

No relevant acute toxicity human data were identified for tetraammineplatinum dinitrate or closely-related surrogates, and no laboratory animal data for tetraammineplatinum dinitrate.

 

In an acute oral toxicity test, conducted in accordance with OECD Test Guideline 401 (withdrawn in 2002) and to GLP, HsdCpb: WU rats (5/sex) were gavaged with tetraammineplatinum hydrogen carbonate (as a suspension in aqueous carboxymethyl cellulose) at a limit dose of 2150 mg/kg bw and observed for 14 days. Three males showed reduced movement, staggered gait and sunken sides starting 75 minutes after dosing and lasting until day 1 or 4 after dosing. One of these males additionally showed clonic convulsions, diarrhoea, piloerection, stilted gait, red crusted nose and emaciation, and subsequently died (on day 5 after dosing). The other two males showed no signs of toxicity during the observation period. All females exhibited diarrhoea, and some showed staggered and/or stilted gait, reduced movement and sunken sides. These effects were evident from 90 minutes after dosing, and lasted for 6 days or, in one animal, until death (on day 6). The acute oral LD50 value was therefore determined to exceed 2150 mg/kg bw in male and female rats (Berthold, 1997). Based on the results of this study, tetraammineplatinum hydrogen carbonate does not require classification for acute oral toxicity according to EU CLP criteria (EC 1272/2008).

 

The acute oral toxicity of tetraammineplatinum hydrogen carbonate was investigated in an OECD Test Guideline 401 study, conducted to GLP. In a range-finding study, Sprague-Dawley rats (1/sex) were gavaged with the test material at 25, 200, 2000 or 5000 mg/kg bw. All animals died at the top two doses. In the main study, rats (5/sex) were gavaged with the test material at a dose of 200 mg/kg bw and observed for 14 days. There were no deaths in the main study and all animals showed expected gain in body weight over the study period. No abnormalities were noted at necropsy. The investigators stated that the acute oral LD50 value was therefore >200 mg/kg bw but <2000 mg/kg bw (Dreher, 1989). Based on the results of the range-finder study, tetraammineplatinum hydrogen carbonate could be considered for classification for acute oral toxicity (category 4) according to EU CLP criteria (EC 1272/2008), as both tested animals died at 2000 mg/kg bw.

 

In a brief report of an acute oral toxicity test, no deaths were reported following administration of a single oral dose of tetraammineplatinum dichloride at 15.1 g/kg bw, to a group of 5 rats/sex. The acute oral LD50 is therefore >15 g/kg bw. No other findings were reported (Jones, 1977a). No classification would be needed on this basis of this study.

 

The acute dermal toxicity of tetraammineplatinum diacetate was investigated in a protocol conducted according to OECD Test Guideline 402 and to GLP. The test substance was applied under occlusion to the skin of Wistar rats (5/sex) at a limit dose of 2000 mg/kg bw for 24 hours. After this period, dressings were removed and the skin was washed with water. Animals were then monitored over the next two weeks for mortality and any clinical signs of toxicity. After this period, any survivors were sacrificed, and subjected to gross necropsy. No mortality occurred during the experiment, and no macroscopic abnormalities were found at post mortem. No body weight changes indicative of toxicity were observed. Clinical signs included hunched posture, bloody tears, lethargy, shallow respiration and piloerection. In the treated skin area, general, focal or maculate erythema, scales, scabs, scars and/or necrosis were apparent. Hence the acute dermal LD50 value of tetraammineplatinum diacetate was determined to exceed 2000 mg/kg bw in rats (Beerens-Heijnen, 2006).

 

In another OECD Test Guideline 402 study, Sprague-Dawley CD rats (5/sex) were given a single 24-hour, semi-occlusive application of tetraammineplatinum hydrogen carbonate to intact skin at a dose level of 2000 mg/kg bw. The animals were observed for 14 days after the day of treatment and were then sacrificed for gross pathological examination. There were no deaths and no signs of systemic toxicity or skin irritation during the study. All rats showed the expected increase in body weight except for one female which showed body weight loss during the first week only. No abnormalities were noted at necropsy. The acute dermal LD50 of the test material in rats was >2000 mg/kg bw (Allen, 1997). Based on the results of this study, classification for acute dermal toxicity under the EU CLP regulation is not required.

 

Tetraammineplatinum dichloride and hydrogen carbonate are 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.

No acute inhalation toxicity data were identified, or are required at this tonnage (1-10 tpa).

Justification for classification or non-classification

Based on the weight of evidence (notably the results of a reliable acute oral rat study with tetraammineplatinum hydrogen carbonate and a study with tetraammineplatinum dichloride in which LD50 values of >2 g/kg bw were determined), tetraammineplatinum dinitrate also does not require classification for acute oral toxicity according to EU CLP criteria (EC 1272/2008).

 

Based on the results of the available and reliable acute dermal studies in rats with tetraammineplatinum diacetate and tetraammineplatinum hydrogen carbonate, tetraammineplatinum dinitrate does not require classification for acute dermal toxicity according to EU CLP criteria (EC 1272/2008).

 

No evidence of specific target organ toxicity was noted. As such, classification for STOT-SE is not considered appropriate.