Registration Dossier

Diss Factsheets

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Description of key information

No relevant skin or respiratory tract sensitisation data were identified for tetraammineplatinum dinitrate.

 

In guideline studies with closely-related surrogates, no sensitisation was reported with tetraammineplatinum diacetate in a LLNA (Beerens-Heijnen, 2004), tetraammine platinous chloride in a GPMT (Jones, 1977b), or tetraammineplatinum hydrogen carbonate in a Buehler test (Berthold, 1998) or a GMPT (Jones, 1989).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
22 September 2004 to 18 October 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Conducted according to GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
yes
Remarks:
deviations in levels of relative humidity, deviations in minimum temperature and deviations in mouse strain [OECD recommends CBA/Ca or CBA/J mice] were not thought to affect study integrity
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River France, l'Arbresle Cedex, France
- Age at study initiation: approximately 11 weeks
- Weight at study initiation: within 20% of the sex mean
- Housing: individual
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.4 to 21.7 [OECD recommends a minimum temperature of 19 °C]
- Humidity (%): 29 to 94 [OECD specifies 30 to 70%, ideally 50 to 60%]
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: no data
Vehicle:
propylene glycol
Concentration:
Concentrations of 25 and 50% were used in the preliminary irritation study. Concentrations of 5, 25 and 50% were used in the subsequent local lymph node assay.
No. of animals per dose:
Preliminary irritation study: 1
Local lymph node assay: 5
Details on study design:
RANGE FINDING TESTS:
- Compound solubility: no data
- Irritation: two mice were treated with a dermal dose of platinum(2+) tetraammine (SP-4-1) diacetate at either 25 or 50% on each ear over three consecutive days. Ears were examined four hours after the last exposure and graded.
- Lymph node proliferation response: no data

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: local lymph node assay
- Criteria used to consider a positive response: a substance may be regarded as a skin sensitiser if the results indicate a stimulation index of at least 3

TREATMENT PREPARATION AND ADMINISTRATION:
INDUCTION (days 1, 2 and 3)
25 µl of the test substance was applied to the dorsum surface of both ears at 5%, 25% or 50% at approximately the same time each day. Controls recieved vehicle alone.

TREATMENT (day 6)
Animals were injected via the tail vein with 0.25 ml sterile phosphate buffered saline (PBS) containing 20 µCi of 3H-methyl thymidine. Approximately five hours later, animals were sacrificed by an overdose of pentobarbital via intraperitoneal injection. A gross macroscopic examination was perfomed. The draining lymph node of each ear was excised, nodes were examined visually and any abnormalities were recorded.
For each animal, a single cell suspension of lymph node cells was prepared. DNA was precipitated and processed for radioactivity.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
no data
Positive control results:
Historical lab data performed in July/August 2004 involved the treatment of groups of female mice treated with alpha-hexylcinnamicaldehyde (tech. 85%) at concentrations of 5, 10 or 25%, using a similar procedure. SI values of 1.0, 3.2 and 7.1 were recorded, and an EC3 value of 9.5% was calculated.
Parameter:
SI
Remarks on result:
other: Group 1 - propylene glycol (vehicle control): SI +/- SD = 1.0 Group 2 - 5% test substance: SI +/- SD = 1.4 Group 3 - 25% test substance: SI +/- SD = 1.3 Group 4 - 50% test substance: SI +/- SD = 1.4
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: see Remark
Remarks:
Group 1 - propylene glycol (vehicle control): 700, 197, 151, 337 and 571 (five animals). Median DPM/animal value = 337. Group 2 - 5% test substance: 381, 362, 525, 482, 618 (five animals). Median DPM/animal value = 482. Group 3 - 25% test substance: 645, 285, 466, 377 (four animals - an anomalous value of 4766 was recorded for a further mouse, but rejected based on abnormalities in the right eye and an extremely large right lymph node). Median DPM/animal value = 422. Group 4 - 50% test substance: 805, 1555, 4020, 738, 416. Median DPM/animal value = 805.

Skin irritation reactions were graded 0 (corresponding to "no erythema" and "no oedema") for all tested animals at all doses.

Interpretation of results:
GHS criteria not met
Conclusions:
In a guideline LLNA, to GLP, platinum(2+) tetraammine (SP-4-1) diacetate was non-sensitising at concentrations of up to 50%.
Executive summary:

In a guideline local lymph node assay, conducted to GLP, 25µl platinum(2+) tetraammine (SP-4-1) diacetate in propylene glycol was applied once daily to the skin of both ears of female CBA mice (5/group), at 0, 5, 25 or 50%, for three consecutive days. Mice were monitored for mortality and overt signs of toxicity, as well as changes in body weight. Skin irritation was assessed and graded three to four hours after the final dose (on day three). Three days after this induction period (on day six), mice were given tail vein injections of radiolabelled thymidine, and were sacrificed after approximately five hours. Lymph nodes were excised and processed for radioactivity.

 

No skin irritation was seen as a result of treatment with platinum(2+) tetraammine (SP-4-1) diacetate. Lymph nodes were a normal size, with the exception of one animal given the test substance at 25% and showing eye abnormalities. The anomalous results for this animal were subsequently discounted. No mortality or substance-related toxicity was observed over the course of the experiment.

 

Median disintegrations per minute/animal values were 337, 482, 422 and 805 for groups of mice given platinum(2+) tetraammine at concentrations of 0, 5, 25 and 50% respectively. SI values were 1.4, 1.3 and 2.4 for animals given respective concentrations of 5%, 25% and 50%. An SI value of over three was judged to be indicative of a substance being sensitising. Hence, under the conditions of this assay, platinum(2+) tetraammine (SP-4-1) diacetate was considered non-sensitising.

 

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No relevant human skin sensitisation data were identified for tetraammineplatinum dinitrate or closely-related surrogates, and no laboratory animal data for tetraammineplatinum dinitrate. No in vitro skin sensitisation studies were identified, or are required, as adequate in vivo studies are already available.

 

In an OECD Test Guideline 429 local lymph node assay (LLNA), conducted to GLP, 25 µl tetraammineplatinum diacetate in propylene glycol was applied once daily to the skin of both ears of female CBA mice (5/group), at 0, 5, 25 or 50%, for three consecutive days. Mice were monitored for mortality and overt signs of toxicity, as well as changes in body weight. Skin irritation was assessed and graded three to four hours after the final dose (on day three). Three days after this induction period (on day six), mice were given tail vein injections of radiolabelled thymidine, and were sacrificed after approximately five hours. Lymph nodes were excised and processed for radioactivity. No skin irritation was observed and lymph nodes were a normal size, with the exception of one animal given the test substance at 25% and showing eye abnormalities. The anomalous results for this animal were subsequently discounted. No mortality or substance-related toxicity was observed over the course of the experiment. SI values were 1.4, 1.3 and 2.4 for animals given respective concentrations of 5%, 25% and 50%. An SI value of over 3 was judged to be indicative of a substance being sensitising. Hence, under the conditions of this assay, tetraammineplatinum diacetate was considered non-sensitising (Beerens-Heijnen, 2004).

 

The skin sensitising potential of tetraammine platinous dichloride was investigated in a guinea pig maximisation test (GPMT) conducted according the method of Magnusson and Kligman (as described in OECD Test Guideline 406). A group of ten male animals were treated in the shoulder area by intradermal injection with 5% of the test compound, followed 7 days later by a 48-hr topical occluded application of the neat substance. A challenge dose of the neat substance was applied topically to the flank region 14 days later and examined for sensitisation reactions after 24 and 48 hr. No positive reactions were evident. Hence, tetraammine platinous chloride did not induce sensitisation in this test (Jones, 1977b).

 

The skin sensitisation potential of tetraammineplatinum hydrogen carbonate was evaluated using a Buehler test in guinea pigs, in accordance with OECD Test Guideline 406. Animals (10/sex) received three 6 -hr epicutaneous applications of the test material at 50% in 1% aqueous carboxymethyl cellulose (CMC) during a 2-week induction period .There were no skin responses to an epicutaneous occlusive challenge exposure to an identical concentration (50% in 1% aqueous CMC) 2 weeks later (Berthold, 1998).

 

The skin sensitisation potential of tetraammineplatinum hydrogen carbonate was assessed in an OECD Test Guideline 406 GPMT using groups of 20 test and 10 control animals. Guinea pigs were induced with a suspension of 25% test material in arachis oil by intradermal injection (in combination with a preparation of Freund’s complete adjuvant), followed one week later by a second induction by topical application of 75% of the test substance in arachis oil under a 48-hr occlusive patch. Control animals were similarly treated but without the test substance. Two weeks after the topical inductions, a challenge dose of 75% was applied under a 24-hr occlusive patch to both test and control animals. These doses were selected after a preliminary range-finding study. No positive reactions were observed in the test or control animals on examination at 24 and 48 hr after removal of the challenge patches. Tetraammineplatinum hydrogen carbonate was not a contact sensitiser in this GPMT (Jones, 1989).

Tetraammineplatinum diacetate, 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.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

No respiratory tract sensitisation data are available. A new study was not conducted as no standard and validated test method is available and it is not a REACH Standard Information Requirement.

Justification for classification or non-classification

Based on the lack of skin sensitisation apparent in studies with and tetraammineplatinum diacetate (LLNA), tetraammineplatinum dichloride (GPMT) and tetraammineplatinum hydrogen carbonate (Buehler and GPMT), tetraammineplatinum dinitrate also does not require classification for skin sensitisation according to EU CLP criteria (EC 1272/2008).