Registration Dossier

Administrative data

Description of key information

In two in vivo OECD guideline skin irritation studies, no irritant or corrosive reactions were observed following 4-hr application of tetraamminepalladium dichloride (under occlusion) or tetraamminepalladium hydrogen carbonate (semi-occlusion) to the intact shaved skin of three New Zealand white rabbits in each case (Allen, 1995b; Driscoll, 1981).

 

In an in vitro OECD guideline study, conducted to GLP, tetraamminepalladium diacetate was found to be non-irritating to isolated chicken eyes (Hargitai, 2014). However, in two previously conducted OECD guideline eye irritation studies with New Zealand white rabbits, moderate to severe irritation was seen following instillation of undiluted tetraamminepalladium dichloride (Driscoll and Collier, 1981) or tetraamminepalladium hydrogen carbonate (Allen, 1995c).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 to 21 November 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study, on closely-related surrogate.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
no
Remarks:
individual experimental studies were not inspected for GLP compliance. Inspections of skin irritation studies were reported to be carried out 19-20 February 1981
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Nottingham University
School of Agriculture
Sutton Bonington
Leicestershire
UK
- Age at study initiation: no data
- Weight at study initiation: 2.34-3.19 kg
- Housing: Individually in suspended metal cages
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): no data
- Air changes (per hr): 20
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
other: no concurrent control site
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg moistened with water to make a paste


VEHICLE
no data

Duration of treatment / exposure:
4 hr
Observation period:
72 hr with an additional 7 day observation period if irritation was still apparent at 72 hr
Number of animals:
Three
Details on study design:
TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- % coverage: no data
- Type of wrap if used: absorbent lint covered with polythene, secured by adhesive tape. The trunk of each rabbit was wrapped in an elasticated bandage (Tubigrip)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): cotton wool soaked in warm water
- Time after start of exposure: 4 hr

SCORING SYSTEM: assessed at 1, 24, 48 and 72 hr. Scored using the method of Draize (1959) for erythema/eschar formation and edema at all time points and the total scores were divided by 12 to hive the primary irritation index.
Primary irritation index Classification
0 non-irritant
> 0-2 mild irritant
> 2-5 moderate irritant
> 5-8 severe irritant

Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: Mean of 1, 24, 48 and 72 hr time points
Score:
0
Max. score:
8
Reversibility:
other: no irritation observed
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: Mean of 1, 24, 48 and 72 hr time points
Score:
0
Max. score:
8
Reversibility:
other: no irritation observed
Irritation parameter:
edema score
Basis:
mean
Time point:
other: Mean of 1, 24, 48 and 72 hr time points
Score:
0
Max. score:
8
Reversibility:
other: no irritation observed
Irritant / corrosive response data:
None seen at any time point
Other effects:
No indication of whether systemic effects were assessed

Very slight yellowing staining of the test site which did not interfere with the assessment of irritation

Interpretation of results:
GHS criteria not met
Conclusions:
In a guideline study, no irritation potential was observed when tetraammine palladous chloride was applied (under occlusion for 4 hr) to the intact shaved skin of three rabbits.
Executive summary:

In an OECD Test Guideline 404 study, tetraammine palladous chloride (0.5 g, moistened) was applied (occluded) to the clipped but intact skin of three New Zealand white rabbits. After 4 hours, the dressings were removed and the skin sites assessed for signs of irritation (oedema and erythema/eschar) and corrosion at 1, 24, 48 and 72 hours.

No irritation (erythema/eschar formation or erythema) or corrosion of the skin was seen at any time point during the 72 hr study period. The primary irrational index was therefore 0, and tetraammine palladous chloride is classified as non-irritating.

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

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
OECD guideline study, on closely-related surrogate. However, any possible deviations could not be fully assessed as the study report appears to have some pages omitted. These pages may contain important information, including details on exposure (concentration of the test material), preparation of the test site (shaved?), use of vehicle, further details on the test animal and environmental conditions.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.6 and 2.71 kg (females) and 2.69 kg (male)
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%):no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data
Type of coverage:
semiocclusive
Preparation of test site:
other: intact
Vehicle:
not specified
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): no data
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3 (2 females and 1 male)
Details on study design:
TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: no data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

SCORING SYSTEM: Individual scores for erythema/eschar and oedema were made for the three rabbits according to the Draize classification scheme at the 1, 24, 48 and 72-hr readings. The mean of the scores at the 24 and 72-hr observations were summed, and divided by 6 to give the primary irritation index.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 1, 24, 48 and 72-hour observations
Score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
No irritation or corrosive effects seen during the study.
Other effects:
Yellow-staining was noted at all treated sites at 1, 24, 48 and 72-hr observations.
Interpretation of results:
GHS criteria not met
Conclusions:
In an OECD guideline study, a 4-hr semi-occluded application of an unspecified amount of tetraamminepalladium hydrogen carbonate to the intact shaved skin of three rabbits produced no irritant or corrosive reactions.
Executive summary:

In a study conducted to OECD Test Guideline 404, a 4-hr semi-occluded application of an unspecified amount of tetrammine palladium hydrogen carbonate was made to the intact skin (details on preparation of test site not known) of 2 female and 1 male rabbit. Yellow-staining was noted at all treated skin sites at 1, 24, 48 and 72 hrs. No erythema/eschar or oedema were seen at any of the four observation points. The test material produced a primary irritation index of 0 and was classified as non-irritant to rabbit skin according to the Draize classification system. No corrosive effects were noted. The test material did not meet the criteria for classification as irritant or corrosive according to EU labelling regulations.

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:
21 to 28 December 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD Guideline study, to GLP, on closely-related surrogate
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.36-3.16 kg
- Housing: metal cages
- Diet (e.g. ad libitum): conventional; ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): no data
- Air changes (per hr): 20
- Photoperiod (hrs dark / hrs light): 12/12


Vehicle:
unchanged (no vehicle)
Controls:
other: yes, concurrent no treatment; other eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg


Duration of treatment / exposure:
After 30 seconds (“with rinsing” group) or throughout observation period ("without rinsing” group)
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 in the “without rinsing” group; 3 in the “with rinsing” group
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes in one group
- Time after start of exposure: 30 seconds with 100 ml sterile distilled water at 37oC (one group)

SCORING SYSTEM: According to the numerical evaluation of Draize. For each tissue the total score was calculated as follows:
Total score for conjunctivae = (redness + chemosis + discharge) x 2
Total score for iris = any changes x 5
Total score for cornea = (degree of opacity x area of opacity) x 5

TOOL USED TO ASSESS SCORE: no data

Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1, 24, 48 and 72 hr, and 7 days
Score:
27
Reversibility:
not fully reversible within: 7 days in two of the three animals
Irritation parameter:
maximum mean total score (MMTS)
Remarks:
with rinsing
Basis:
mean
Time point:
other: 1, 24, 48 and 72 hr, and 7 days
Score:
31
Reversibility:
not fully reversible within: 7 days in two of the rabbits
Irritant / corrosive response data:
Without washing: One hour after treatment irritation showed as iridial congestion, conjunctival reness and severe chemosis. By seven days post treatment minimal chemosis was present in one animal and minimal chemosis and redness in another.

With washing: One hour following treatment irritation was exhibited as slight corneal opacity and iridial congestion in two rabbits, and slight to moderate conjunctival redness and moderate to severe chemosis in all three animals, which had not improved by 72 hours. By day 7 significant irritation was still persistent in the cornea and conjunctivae of two rabbits.
Other effects:
There is no indication that clinical signs of systemic toxic effects were evident.
Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
In an OECD Guideline study, to GLP, instillation of undiluted tetraamminepalladium dichloride to one eye of each of three rabbits without washing caused moderate to severe irritation and severe irritation in three rabbits when the eye was rinsed after 30 seconds.
Executive summary:

In an OECD Test Guideline 405 study, to GLP, undiluted tetraamminepalladium dichloride (100 mg, powdered) was instilled into the right eye of each of six New Zealand white rabbits. The contralateral eye remained untreated and was used for control purposes. In half of the animals, the eyes were rinsed after 30 seconds with 100 ml of sterile distilled water.

Moderate to severe irritation was observed in the ‘non-rinsed group’, which (although had reduced in severity) was not fully reversible in two of the 3 rabbits within seven days after treatment. When the eyes were rinsed after a 30-second exposure, the test substance caused severe eye irritation in all three rabbits which (although reduced in severity) still persisted at day 7 in two of the animals. No clinical signs of systemic toxic effects were reported. Tetraamminepalladium dichloride caused severe irritation to the eye of rabbits observed for a 7-day period.

Overall, tetraamminepalladium dichloride caused severe irritation to the eye of rabbits observed for a seven day period. Classification as an eye irritant (category 2), is required on the basis of the findings of this study and according to EU CLP criteria (EC 1272/2008).

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. No in vitro skin or eye irritation studies were identified, or are required, as reliable in vivo studies are already available.

 

In an OECD Test Guideline 404 study, neat tetraamminepalladium dichloride (0.5 g, moistened) was applied (occluded) to the clipped but intact skin of three New Zealand white rabbits. After 4 hours, the dressings were removed and the skin sites assessed for signs of irritation (oedema and erythema/eschar) and corrosion at 1, 24, 48 and 72 hours. No irritation (erythema/eschar formation or erythema) or corrosion of the skin was seen at any time point during the 72-hr study period. The primary irrational index was therefore 0, and tetraamminepalladium dichloride was classified as non-irritating (Driscoll, 1981).

 

In another study conducted to OECD Test Guideline 404, a 4-hr semi-occluded application of an unspecified amount of tetraamminepalladium hydrogen carbonate was made to the intact skin [details on preparation of test site not known] of 2 female and 1 male New Zealand white rabbit. Yellow-staining was noted at all treated skin sites at 1, 24, 48 and 72 hrs. No erythema/eschar or oedema were seen at any of the four observation points. The test material produced a primary irritation index of 0 and was considered as non-irritant to rabbit skin according to the Draize classification system. No corrosive effects were noted (Allen, 1995b).

 

In an in vitro OECD Test Guideline 438 study, conducted according to GLP, tetraamminepalladium diacetate was assessed for potential irritating effects in isolated chicken eyes. One of the eyes was treated with physiological saline (negative control), three eyes with the test item (30 µL) and another three eyes with 5% w/v benzalkonium chloride (positive control). After 10 seconds, the surface of the eyes was rinsed with physiological saline. Corneal thickness, corneal opacity and fluorescein retention were measured and any morphological effects (e.g. pitting or loosening of the epithelium) evaluated. No evidence of treatment-related corrosion or severe irritation to the isolated chicken eyes was observed. The positive and negative controls gave the expected results, confirming the validity of the test (Hargitai, 2014).

 

However, eye irritation was observed in two previously conducted in vivo studies on two closely-related surrogates.

 

In an OECD Test Guideline 405 study, to GLP, undiluted tetraamminepalladium dichloride (100 mg, powdered) was instilled into the right eye of each of six New Zealand white rabbits. The contralateral eye remained untreated and was used for control purposes. In half of the animals, the eyes were rinsed after 30 seconds with 100 ml of sterile distilled water. Moderate to severe irritation was observed in the ‘non-rinsed group’, which (although reduced in severity) was not fully reversible in two of the three rabbits within 7 days after treatment. When the eyes were rinsed after a 30-second exposure, the test substance caused severe eye irritation in all three rabbits which (although reduced in severity) still persisted at day 7 in two of the animals. No clinical signs of systemic toxicity were reported. Tetraamminepalladium dichloride caused severe irritation to the eye of rabbits observed for a 7-day period (Driscoll and Collier, 1981).

 

In another study conducted to OECD Test Guideline 405, to GLP, tetraamminepalladium hydrogen carbonate produced a maximum group mean score of 81.0 [maximum total score possible = 110] at 24 hours and was classified as at least a very severe eye irritant to the rabbit eye according to a modified Kay and Calandra classification system. The animal was killed at 24 hours for humane reasons. Due to the severity of the effects, the test material was considered to be severely irritating to the eyes (Allen, 1995c).

Tetraamminepalladium dichloride and hydrogen carbonate are considered to fall within the scope of the read-across category "tetraamminepalladium salts". See IUCLID section 13 for full read-across justification report.

 

No respiratory tract data were identified. A new study was not conducted as it is not a REACH Standard Information Requirement. Further, the compound is not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data). Thus, inhalation will not be a significant route of exposure.


Justification for classification or non-classification

Based on the results of the available in vivo skin irritation studies on closely-related surrogates, tetraamminepalladium dichloride does need not be classified for skin irritation according to EU CLP criteria (EC 1272/2008).

 

Based on the results of an in vitro eye irritation study with tetraamminepalladium diacetate, no classification is required for such effects. However, eye irritation was observed in two previously conducted in vivo studies on closely-related surrogates. As such, it seems prudent to classify tetraamminepalladium diacetate as an eye irritant (category 2), according to EU CLP criteria (EC 1272/2008).