Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline study. However, potential deviations could not be fully assessed as the study report appears to have some pages omitted. On closely-related surrogate.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Tetrammine palladium hydrogen carbonate
- Substance type: no data
- Physical state: no data
- Analytical purity: no data
- Lot/batch No.: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: animals were fasted, but no details on duration of fasting period
- 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

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: no data

DOSAGE PREPARATION (if unusual): no data
Doses:
0.5, 1 and 2 g/kg bw
No. of animals per sex per dose:
Five females/dose, a group of 5 males also treated at 2 g/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed 30 minutes, 1, 2, 4 hours, and then daily and weighed at day 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Statistics:
Acute oral median lethal dose (LD50) and 95% confidence limits of the test material were calculated by the method of Thompson W.R.

Results and discussion

Preliminary study:
In the range finding study, one male and one female received 2 g/kg bw. The male was found dead two days after dosing, the female had no signs of systemic toxicity at day 5 after dosing. Hunched posture, lethargy and pilo-erection were seen in both animals, and ptosis and occasional body tremours were also noted in the male.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
933 mg/kg bw
Based on:
test mat.
95% CL:
664 - 1 310
Mortality:
In the main study, all 5 male and 5 female rats receiving 2 g/kg bw died by day 3, whilst 3 of 5 females died at 1 g/kg bw on days 4 to 6. No deaths were seen in the females receiving 0.5 g/kg bw.
Clinical signs:
Hunched posture, lethargy, decreased respiratory rate, laboured respiration and emaciation were commonly noted in all dose groups during the study. Pilo-erection and ptosis were noted in animals dosed with 1 g/kg bw and above. Ataxia was seen in females dosed with 1 g/kg bw (and higher) and distended abdomen noted at 0.5 and 1 g/kg bw, and in males given 2 g/kg bw. Incidents of diarrhoea, noisy or gasping respiration, red/brown staining around the mouth and snout and occasional body tremours were also noted with isolated incidents of tiptoe or splayed gait, dehydration and increase salivation. Surviving animals had no signs of systemic toxicity within 1 to 9 days after dosing.
Body weight:
Surviving animals showed an “acceptable gain in bodyweight during the study”, except for one female administered 0.5 g/kg bw and one female given 1 g/kg bw who showed a body weight loss during the first and second week, respectively.
Gross pathology:
Haemorrhagic or abnormally red lungs, dark liver, dark or pale kidneys, gaseous distention of the stomach, dark, hardened or thickened gastric mucosa and haemorrhage of the small intestine were noted at necropsy of animals that died during the study. Sloughing of the non-glandular epithelium of the stomach with a raised limiting edge were noted in females receiving 0.5 and 1 g/kg bw killed at the end of the study period. Two female rats were found cannibalised, therefore necropsy was noted performed.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In an OECD guideline study, the acute oral LD50 of tetraamminepalladium hydrogen carbonate in the female rat was reported to be 933 mg/kg bw .
Executive summary:

The acute oral toxicity of tetraamminepalladium hydrogen carbonate was assessed in rats, in a study conducted according to OECD Test Guideline 401.

In the range finding study, one male and one female rat received a single dose of 2000 mg /kg bw by oral gavage. The male was found dead two days after dosing whereas the female had no signs of systemic toxicity at day 5.

Therefore, in the main study, groups of 5 females were administered 500, 1000 or 2000 mg/kg bw of the test material and a group of 5 male rats received 2000 mg/kg bw. All 10 rats receiving 2000 mg/kg bw died by day 3 of the observation period, whilst 3 of 5 females receiving 1000 mg/kg bw died on days 4 to 6. No deaths were seen in the low dose females, following the 14-day observation period. The study authors conclude that the acute oral median lethal dose (LD50) of the test material in females rats is 933 mg/kg bw. “No significant difference in toxicity was noted between male and female animals”.

Based on the results of this study, tetraamminepalladium hydrogen carbonate should be classified for acute oral toxicity (category 4) according to EU CLP criteria (EU 1272/2008).

Tetraamminepalladium hydrogen carbonate is closely related to tetraamminepalladium dihydroxide, and is considered a suitable surrogate for read-across for this endpoint. The proposed read-across is appropriate because it is expected that the target and source substances undergo biotransformation to a common product. In solution, the hydrogen carbonate and hydroxide anions are expected to dissociate from the tetraamminepalladium cation; thus, this can be regarded as the common product and toxicologically-active species of both salts. The hydroxide and hydrogen carbonate counterions would not have an impact on the overall acute toxicity of the target or source substance, respectively. Therefore, it is considered that use of in vivo acute oral toxicity data obtained in a test on tetraamminepalladium hydrogen carbonate to fill a gap in the standard information requirements for tetraamminepalladium dihydroxide is scientifically justified and suitably reliable.