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Administrative data

Description of key information

The acute oral LD50 value of tetraammineplatinum(II) hydrogen carbonate was determined to exceed 2150 mg/kg bw in 5 male and 5 female rats (Berthold, 1997a). In an earlier rat study, the acute oral LD50 value of tetraammineplatinum(II) hydrogen carbonate was determined to be >200 mg/kg bw (in the main study; 5/sex) but <2000 mg/kg bw (in the range-finder; 1 sex/dose). No evidence of systemic toxicity was observed at the limit dose of 200 mg/kg bw in the main study (Dreher, 1989).

 

In an OECD guideline study, to GLP, the acute dermal LD50 value (24-hour semi-occlusive application) for tetraammineplatinum(II) hydrogen carbonate was >2000 mg/kg bw in rats (Allen, 1997).

 

No relevant acute inhalation toxicity data were identified (or are required).

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:
7 to 25 July 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline study (OECD, EU) to GLP
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Dates of QA inspection of systemic toxicity studies are 6, 14, 15 and 27 June 1989. General facilities audit performed on 29 June 1989. Therefore no specific QA inspections of this particular project were carried out.
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Bantin and Kingman Ltd, Grimston, Aldborough, Hull, UK
- Age at study initiation: 5-8 weeks old
- Weight at study initiation: males 120-144 g; females 120-130 g
- Fasting period before study: overnight (plus 2 hr after dosing)
- Housing: 5/sex/solid-floor cage with sawdust bedding
- Diet: ad libitum conventional laboratory diet
- Water: ad libitum drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 68-78
- Air changes (per hr): approx 15
- Photoperiod: 12 hrs dark / 12 hrs light
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
Doses:
200 mg/kg
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: observed 1 and 4 hr after dosing, then daily for 14 days. Body weights recorded prior to dosing and on days 7 and 14
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Mortality:
None
Clinical signs:
No adverse observations
Body weight:
All animals showed expected gain in body weight over the study period.
Gross pathology:
No abnormalities
Other findings:
None
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute oral LD50 value of tetraammineplatinum(II) hydrogen carbonate in rats was determined to be >200 mg/kg bw (in the main study; 5/sex) but <2000 mg/kg bw (in the range-finder; 1 sex/dose). No evidence of systemic toxicity was observed at the limit dose of 200 mg/kg bw in the main study.
Executive summary:

The acute oral toxicity of tetraammineplatinum(II) 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 four animals died at the top two doses. In the main study, rats (5/sex) were gavaged with the test material at a limit 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.

 

Based on the results of the range-finding study, tetraammineplatinum(II) hydrogen carbonate should be considered for classification for acute toxicity (category 4) according to EU CLP criteria (EC 1272/2008).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
300 mg/kg bw
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:
key study
Study period:
9 to 23 January 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline study (OECD) to GLP
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley CD (Crl : CD ® BR)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited
- Age at study initiation: 8-12 weeks old
- Weight at study initiation: males 209-236 g; females 206-227 g.
- Fasting period before study: none
- Housing: Housed individually during the 24-hr exposure period, then in groups of five by sex in suspended polypropylene cages on woodflakes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-21
- Humidity (%): 41-55
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks
- % coverage: 10% of total body surface area
- Type of wrap if used: surgical gauze and self-adhesive bandage, secured with “Blenderm” latex- free, hypoallergenic, surgical tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with cotton wool moistened in distilled water
- Time after start of exposure: 24 hr

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: yes, powder moistened with distilled water

VEHICLE
- Amount(s) applied (volume or weight with unit): not stated
Duration of exposure:
24 hr
Doses:
2000 mg/kg bw

No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed at 0.5, 1, 2 and 4 hrs after dosing, then daily for 14 days; weighed before treatment then weekly for 2 weeks.
- Necropsy of survivors performed: yes
- Other examinations performed: behavioural and clinical signs, body weight changes.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: CL not applicable
Mortality:
None
Clinical signs:
None
Body weight:
Nine of the 10 rats showed normal gain in body weight. One female lost weight during the first week and then showed expected weight gain in second week.
Gross pathology:
No abnormalities
Other findings:
- Other observations: No dermal reactions, including erythema and oedema, were seen during the 14-day period.
Interpretation of results:
GHS criteria not met
Conclusions:
In an OECD guideline study, to GLP, the acute dermal LD50 value (24-hour semi-occlusive application) for tetraammineplatinum(II) hydrogen carbonate was >2000 mg/kg bw in rats.
Executive summary:

In an OECD Test Guideline 402 study, Sprague-Dawley CD rats (5/sex) were given a single 24-hour, semi-occlusive application of tetraammineplatinum(II) 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.

 

Based on the results of this study, classification for acute dermal toxicity under the EU CLP regulation is not required.

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.

 

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(II) 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, 1997a).

 

The acute oral toxicity of tetraammineplatinum(II) 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 limit 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).

 

In an OECD Test Guideline 402 study, Sprague-Dawley CD rats (5/sex) were given a single 24-hour, semi-occlusive application of tetraammineplatinum(II) 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).

 

No acute inhalation toxicity data were identified. However, the compound is not expected to reach the lungs in appreciable quantities (based on vapour pressure data). Thus, inhalation will not be a significant route of exposure.

Justification for classification or non-classification

Based on the results of the most recent acute oral rat study, tetraammineplatinum(II) hydrogen carbonate does not require classification for acute oral toxicity according to EU CLP criteria (EC 1272/2008). However, the previously conducted study indicates that a category 4 classification is more appropriate. Moreover, tetraammineplatinum(II) hydrogen carbonate has a harmonised classification for acute toxicity by the oral route (category 4) according to Annex VI of the CLP regulation. As such, this classification is adopted here.

 

No classification for acute dermal toxicity is required, based on the results of the available and reliable acute dermal rat study with tetraammineplatinum(II) hydrogen carbonate.

 

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