Diammineplatinum(II) nitrite

Endpoint summary

Description of key information

In a guideline study, to GLP, no irritation potential was observed when 0.5 g dinitrodiammine-platinum(II) was applied (under occlusion for 4 hr) to the clipped, intact skin of three rabbits (Zechel, 1989a).

In a guideline study, to GLP, instillation of dinitrodiammine-platinum(II) into the conjuctival sac of the left eye of three rabbits caused moderate irritation according to the Draize scale. However, the test substance caused severe and sometimes irreversible effects (especially on the cornea). As such, the study authors conclude that dinitrodiammine-platinum(II) should be classified as a severe eye irritant in this test system (Zechel, 1989b).

No relevant respiratory tract irritation data were identified.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4 to 7 April 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study, to GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

other: White Russian (albino)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Breeder: ASTA Pharma AG, D-4800 Bielefeld 14
- Age at study initiation: Male 10 months, females 11 and 12 months
- Weight at study initiation: Male 2.75 kg, females 2.58 and 3.02 kg
- Housing: Stainless steel cages with grating floor, one animal/cage
- Diet (e.g. ad libitum): Approx. 120 g/day standard diet
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5-23.5
- Humidity (%): 45-60
- Photoperiod (hrs dark / hrs light): 12 hrs natural light-dark-rhythm (6 pm to 6 am)/ 12 hrs artificial lighting

Type of coverage:

occlusive

Preparation of test site:

other: clipped free of hair one day before treatment

Vehicle:

water

Controls:

yes, concurrent vehicle

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

VEHICLE
- Concentration (if solution): about 3 g/ml (moistened with 0.17 mL demineralised water)

Duration of treatment / exposure:

4 hours

Observation period:

Inspection of the skin occurred 1, 24, 48 and 72 hrs after removal of the patches

Number of animals:

Three (one male and two females)

Details on study design:

TEST SITE
- Area of exposure: The site of application was covered with a linen cloth (approx. 6.25 cm2) which adhered to a synthetic film glue
- Type of wrap if used: A bandage (Acrylastic No. 2408, width 8 cm) wrapped several times around the trunk provided complete occlusion

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After removal of the patch, remaining test material “was gently washed off as far as possible”
- Time after start of exposure: about 4 hours

SCORING SYSTEM: The treated skin area was qualitatively and quantitatively assessed using the Draize method at 1, 24, 48, and 72 hrs following removal of the patches. The irritation index is given by the sum of the mean values for erythema (and eschar) formation, and edema, following a modified method according to Gilman et al. 1983:
Index ranges Gradation
0-0.5 non-irritant
0.6-3 slightly irritant
3.1-5 moderately irritant
5.1-8 severely irritant
In addition, attention was paid to the occurrence of further reactions on the skin (including corrosive effects) and to clinical symptoms (systemic toxic effects).

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1, 24, 48, and 72 hrs

Score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1, 24, 48, and 72 hrs

Score:

0

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 1, 24, 48, and 72 hrs

Score:

0

Irritant / corrosive response data:

No erythema or edema (Draize score of 0) was seen on the skin of the animals within the 3 day observation period.

Other effects:

Systemic toxic effects did not occur and the general condition of the rabbits was not affected by treatment.

Interpretation of results:

GHS criteria not met

Conclusions:

In a guideline study, to GLP, no irritation potential was observed when 0.5 g dinitrodiammine-platinum(II) was applied (under occlusion for 4 hr) to the clipped, intact skin of three rabbits.

Executive summary:

In an OECD Test Guideline 404 study, conducted according to GLP, dinitrodiammine-platinum(II) (0.5 g, moistened with 0.17 mL water) was applied (occluded) to the clipped intact skin of 3 White Russian rabbits. After 4 hours, the dressings were removed and the treated skin sites were washed and subsequently observed for erythema and oedema at 1, 24, 48 and 72 hours.

 

No skin reactions were recorded at any time point in any animal during the 72 -hr observation period. The primary dermal irritation index was therefore 0, and dinitrodiammine-platinum(II) was classified as a non-irritant to rabbit skin under the conditions of the test. Systemic toxic effects were not detected and the general condition of the rabbits was unaffected by treatment.

 

No skin classification, according to EU CLP criteria (EC 1272/2008), is required on the basis of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 April – 24 August 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study, to GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

other: White Russian (albino)

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Origin/breeder: ASTA Pharma AG, D-4800 Bielefeld 14
- Age at study initiation: 8-11 months
- Weight at study initiation: 2.78-2.98 kg
- Housing: Stainless steel cages with grating floor, one animal/cage
- Diet (e.g. ad libitum): Approx. 120 g/day standard diet
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-23
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12 hrs natural light-dark-rhythm (6 pm to 6 am) / 12 hrs artificial lighting

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated eye of each of the three rabbits was used as the control.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g of test material applied to the conjuctival sac of the left eye

Duration of treatment / exposure:

Both lids were briefly closed by gentle finger pressure

Observation period (in vivo):

Inspection of the eyes occurred 1, 24, 48 and 72 hrs after application and then daily until day 21. An additional examination was performed on day 124.

Number of animals or in vitro replicates:

3 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated eye was not rinsed

SCORING SYSTEM: Signs of irritation on the cornea, iris and conjunctiva were assessed quantitatively and qualitatively using the Draize scale (see attachment 5 for details) assessed at 1, 24, 48, and 72 hrs following application of the test material into the eye. The irritation index is given by the sum of these scores, following a modified method according to Gilman et al. 1983:
Index ranges Gradation
0-10 non-irritant
11-25 slightly irritant
26-56 moderately irritant
57-110 severely irritant

TOOL USED TO ASSESS SCORE: Cliptrix pencil light

Irritation parameter:

overall irritation score

Basis:

other: irritation index is the sum of the scores from the cornea, iris and conjuctiva

Time point:

other: 72 hrs

Score:

39

Reversibility:

not fully reversible within: 3 months after application

Other effects:

There were no systemic toxic effects observed.

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

In a guideline study, to GLP, instillation of dinitrodiammine-platinum(II) into the conjuctival sac of the left eye of three rabbits caused moderate irritation according to the Draize scale. However, the test substance caused severe and sometimes irreversible effects, especially on the cornea, and therefore should be classified as Category 1 (irreversible effects on the eye) under EU CLP criteria.

Executive summary:

In an OECD Test Guideline 405 study, conducted according to GLP, dinitrodiammine-platinum(II) was investigated for irritant effects on the rabbit eye and associated mucous membranes following instillation of 0.1 g into the conjuctival sac of the left eye of each of three animals.

No systemic toxic effects were detected, and the untreated control eyes showed no changes. Following application of the test material, slight partial or moderate circumcorneal hyperaemia was seen in the iris. Regarding the conjuctival sac, diffuse crimson discolouration, white foci, single haemorrhages and eye lid swelling were observed, of which some were considered severe effects. The cornea was particularly affected, with changes including diffuse opacity or opaque areas and diffuse capacity or easily discernable translucent areas, obscured iris and vessel ingrowth. The cornea lesions persisted in two rabbits when examined 3 months after application of the test material. After the 72 hr observation period, the primary index irritation index was 39, indicating a moderate eye irritant. However, as the test substance caused severe and sometimes irreversible effects (notably) on the cornea, the study authors conclude that dinitrodiammine-platinum(II) should be classified as a severe eye irritant in this test system.

 

According to EU CLP criteria (EC 1272/2008), dinitrodiammine-platinum(II) should be classified as Category 1 (irreversible effects on the eye).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No relevant irritation/corrosion human data were identified.

 

In an OECD Test Guideline 404 study, conducted according to GLP, dinitrodiammine-platinum(II) (0.5 g, moistened with 0.17 mL water) was applied (occluded) to the clipped intact skin of 3 White Russian rabbits. After 4 hours, the dressings were removed and the treated skin sites were washed and subsequently observed for erythema and oedema at 1, 24, 48 and 72 hours. No skin reactions were recorded at any time point in any animal during the 72-hr observation period. The primary dermal irritation index was therefore 0, and dinitrodiammine-platinum(II) was classified as a non-irritant to rabbit skin under the conditions of the test. Systemic toxic effects were not detected and the general condition of the rabbits was unaffected by treatment (Zechel, 1989a).

 

In an OECD Test Guideline 405 study, conducted according to GLP, dinitrodiammine-platinum(II) was investigated for irritant effects on the rabbit eye and associated mucous membranes following instillation of 0.1 g into the conjuctival sac of the left eye of each of three animals. No systemic toxic effects were detected, and the untreated control eyes showed no changes. Following application of the test material, slight partial or moderate circumcorneal hyperaemia was seen in the iris. Regarding the conjuctival sac, diffuse crimson discolouration, white foci, single haemorrhages and eye lid swelling were observed, of which some were considered severe effects. The cornea was particularly affected, with changes including diffuse opacity or opaque areas and diffuse capacity or easily discernable translucent areas, obscured iris and vessel ingrowth. The cornea lesions persisted in two rabbits when examined 3 months after application of the test material. After the 72 hr observation period, the primary index irritation index was 39, indicating a moderate eye irritant. However, as the test substance caused severe and sometimes irreversible effects (notably on the cornea), the study authors conclude that dinitrodiammine-platinum(II) should be classified as a severe eye irritant in this test system (Zechel, 1989b).

 

No respiratory tract data were identified.

Justification for classification or non-classification

Based on the results of the available reliable skin and eye irritation studies (in rabbits), diammineplatinum dinitrite need not be classified for skin irritation, but should be classified for ‘irreversible effects on the eye’ (category 1), according to EU CLP criteria (EC 1272/2008).