Diamminedichloropalladium

Endpoint summary

Description of key information

In an OECD Test Guideline 423 study, to GLP, the acute oral LD50 of diamminedichloropalladium was determined to be between 300 and 2000 mg/kg bw (Robertson, 2012).


  


In an OECD Test Guideline 402 study, to GLP, there were no deaths over a 2-week observation period following application of neat diamminedichloropalladium for 24 hours under occlusion at a limit dose of 2000 mg/kg bw to the skin of groups of 5 male and 5 female rats (Kiss, 2012a). 




No relevant acute inhalation toxicity data were identified. 

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:

key study

Study period:

16 March 2012 - 10 August 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline study, to GLP. Occasional deviations from protocol were not considered to impact the integrity or outcome of the study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

occasional humidity variations outwith protocol limits and daily-post dose observations made less frequently than protocol required were not considered to impact the integrity or outcome of the study

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Sprague-Dawley Crl:CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Margate, UK
- Age at study initiation: 8-12 weeks old
- Weight at study initiation: 222.9-250.0 g
- Fasting period before study: overnight
- Housing: In groups of 3 (except when reduced by mortality) in appropriately sized solid-bottomed polycarbonate cages with stainless steel mesh tops, suspended on movable racks
- Bedding: wood shavings
- Diet: ad libitum PMI Nutrition International Certified Rodent Diet No. 5CR4 (14% protein)
- Water: ad libitum from the public supply
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): daily average temperatures approx 20-21
- Humidity (%): range of daily average relative humidity approx. 43-49%; on several occasions humidity was intermittently below 40%, the actual minimum humidity was approx. 22% but, on that day, the daily mean humidity was approx. 43%
- Air changes (per hr): Minimum of 10
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

IN-LIFE DATES: From: 27 March 2012 To: 10 April 2012

Route of administration:

oral: gavage

Vehicle:

other: high viscosity hydroxypropyl methylcellulose in Milli-Q water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Amount of vehicle (if gavage): 0.5% (w/v)
- Justification for choice of vehicle: Not given
- Lot/batch no. (if required): DT200527
- Purity: Not given

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual): A weighed amount of hydroxypropyl methylcellulose (HPMC) was blended with a measured volume of Milli-Q water. The blender was rinsed with more Milli-Q water and the vehicle was then made up to a final volume in a volumetric flask. The required amount of test item was weighed into a mortar bowl and approx. 70% of the vehicle gradually added and the mixture homogenized then transferred to a suitable container that held the remaining 30% of vehicle. Formulations were magnetically stirred until an orange-coloured formulation was obtained. Analysis of prepared formulations with regard to stability, concentration and homogeneity was not conducted however, examination of the formulation records indicated that all preparations had been prepared correctly.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The starting dose was selected following review of the documentation of the test item supplied by the Sponsor

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

6 females/low dose, 3 females/high dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals observed daily for clinical effects (although signs seen in all Group 1 animals were not recorded on days 5 and 6 and only recorded for 2 of the animals on day 13), twice daily for viability, and body weights recorded before dosing on day 1 and on days 8 and 15 for the low dosed animals and daily until day 9 and on days 13 and 15 for the survivors of th ehigh-dose group .
- Necropsy of survivors performed: yes (all animals were necropsied)
- Necropsy parameters: examination of cranial, thoracic and abdominal organs and tissues
- Other examinations performed: clinical signs, body weight, other: mortality/moribundity

Statistics:

No formal statistical analysis was conducted.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: CL not applicable

Mortality:

There were no deaths amongst animals treated at a dose of 300 mg/kg bw. However 2 of the 3 animals were euthanised on days 9 and 13 with 2000 mg/kg bw.

Clinical signs:

other: All animals treated with 300 mg/kg bw displayed subdued behaviour for a short period after dosing. Full recovery was seen within 3 hours. At 2000 mg/kg bw, all animals displayed subdued behaviour, laboured breathing, piloerection and partial closure of

Gross pathology:

There were no macroscopic abnormalities at 300 mg/kg bw.

At 2000 mg/kg bw, lesions to the stomachs of all 3 animals were noted and included thickening of the non-glandular stomach and abnormal (black) stomach contents in one animal, distention of the stomach and filing with brown liquid in another, and distention of the stomach, dark pink discolouration of the glandular serosa, black discolouration of the glandular mucosa, thickening of the glandular stomach and thinness of the non-glandular stomach in the third animal. Other macroscopic abnormalities included pale discolouration of the lobes of the lungs in one animal and abnormal (green) contents of the oesophagus and dark red dicolouration of the pancreas in another.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In an OECD Test Guideline 423 study, to GLP, the acute oral LD50 of diamminedichloropalladium was determined to be between 300 and 2000 mg/kg bw

Executive summary:

In an acute oral toxicity test, conducted according to OECD Test Guideline 423 and to GLP, groups of 6 and 3 female rats were given a single oral intubation of 300 and 2000 mg/kg bw, respectively, and observed for 14 days.

No deaths were reported in any of the 6 animals at the lower dose and there were no effects on body weight gain and no macroscopic abnormalities. At 2000 mg/kg bw, unscheduled deaths were reported in 2 (euthanasia on days 9 and 13, respectively) of the 3 animals, with all animals showing overt signs of toxicity and (likely local) effects in the non-glandular stomach.

The acute oral median lethal dose (LD50) of diamminedichloropalladium was determined to be between 300 and 2000 mg/kg bw. Based on the results of this study, diamminedichloropalladium should be classified for acute oral toxicity (category 4) according to EU CLP criteria (EC 1272/2008).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

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:

01-15 August 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline study, to GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

other: Acute dermal toxicity study: limit test

Limit test:

yes

Species:

rat

Strain:

other: CRL:(WI) rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Hygienic level at arrival: SPF
- Age at study initiation: Not reported
- Weight at study initiation: Between 222 g and 247 g
- Fasting period before study: None
- Housing: "Standard housing conditions": Individual caging; Type II. polypropylene/polycarbonate cage; Laboratory bedding:
Lignocel(R) Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH&Co.KG
- Diet (e.g. ad libitum): Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany ad libitum,
- Water (e.g. ad libitum): tap water from the municipal supply, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Remarks:

But "Sufficient water to damp the material was used to ensure good contact with the skin."

Details on dermal exposure:

TEST SITE
- Area of exposure: the back
- % coverage: approximately 10 % area of the total body surface
- Type of wrap if used: sterile gauze, held in place with a patch of adhesive hypoallergenic plaster, wrapped with semi occlusive plastic wrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with water at body temperature
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Paste formed: presumably yes - "Sufficient water to damp the material was used to ensure good contact with the skin."

Duration of exposure:

24 hours (occlusive contact)

Doses:

2000 mg/kg bw only

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: on the day of treatment at 1 and 5 hours after application of the test item, and once each day thereafter. Observations included the skin and fur, eyes and mucous membranes, the respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Frequency of weighing: The body weights were recorded on Day 0 (before test item administration) and on Days 7 and 14.
- Necropsy of survivors performed: yes. Macroscopic examination was performed on all animals. All surviving animals were anaesthetised with Euthasol®40% and exsanguinated. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. All macroscopic changes were recorded.

Statistics:

None reported.

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: CL not applicable

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:

other: No adverse clinical signs were observed after the treatment with the test item or during the 14-day observation period.

Gross pathology:

There were no macroscopic abnormalities in any animals

Other findings:

No signs of dermal irritation were observed following patch removal or during the 14 day observation period.

There were no control animals; the benchmark by which there was considered to be no effect on body weights is not clear from the study report.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In an OECD Test Guideline 402 study, to GLP, there were no deaths over a 2-week observation period following application of neat diamminedichloropalladium for 24 hours under occlusion at a limit dose of 2000 mg/kg bw to the skin of groups of 5 male and 5 female rats.

Executive summary:

In an acute toxicity test by the dermal route, conducted according to OECD Test Guideline 402 and to GLP, groups of 5 male and 5 female rats were dermally exposed to neat diamminedichloropalladium for 24 hours (under occlusion).

There were no deaths, clinical signs, gross pathological effects or indications of skin irritation in any of the animals over a 2 -week post-dose observation period. The acute dermal median lethal dose (LD50) of diamminedichloropalladium is greater than 2000 mg/kg bw in rats.

Based on the results of this study, diamminedichloropalladium does not need classification 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.

In an acute oral toxicity test, conducted according to OECD Test Guideline 423 and to GLP, groups of 6 and 3 female rats were given a single oral intubation of 300 and 2000 mg/kg bw, respectively, and observed for 14 days. No deaths were reported in any of the 6 animals at the lower dose and there were no effects on body weight gain and no macroscopic abnormalities. At 2000 mg/kg bw, unscheduled deaths were reported in 2 (euthanasia on days 9 and 13, respectively) of the 3 animals, with all animals showing overt signs of toxicity. The acute oral median lethal dose (LD50) of diamminedichloropalladium was determined to be between 300 and 2000 mg/kg bw (Robertson, 2012). Based on the results of this study, diamminedichloropalladium should be classified for acute oral toxicity (category 4) according to EU CLP criteria (EC 1272/2008).

In an acute dermal toxicity test, conducted according to OECD Test Guideline 402 and to GLP, groups of 5 male and 5 female rats were dermally exposed to neat diamminedichloropalladium for 24 hours (under occlusion). There were no deaths, clinical signs, gross pathological effects or indications of skin irritation in any of the animals over a 2 -week post-dose observation period. The acute dermal LD50 of diamminedichloropalladium is greater than 2000 mg/kg bw in rats (Kiss, 2012a). In support, the existing in vivo skin sensitisation study (Pooles, 2012), albeit limited in its assessment of systemic effects, indicates a lack of acute systemic toxicity following dermal exposure.

No acute inhalation toxicity data were identified. However, 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 selection of acute toxicity – oral endpoint
OECD guideline study, to GLP, and the only acute oral toxicity study available.

Justification for selection of acute toxicity – dermal endpoint
GLP, OECD guideline study, and the only acute dermal toxicity study available.

Justification for classification or non-classification

Based on the results of the available and reliable acute oral rat study, diamminedichloropalladiumshould be classified for acute oral toxicity (category 4) according to EU CLP criteria (EC 1272/2008).

No classification for acute dermal toxicity is required, based on the results of the available and reliable acute dermal rat study with diamminedichloropalladium.

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