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Genetic toxicity: in vivo

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Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 Feb 2020 - 20 May 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 Feb 2020 - 20 May 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Version / remarks:
29 July 2016
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of assay:
mammalian erythrocyte micronucleus test
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch number of test material: 9005448302.
- Expiration date of the lot/batch: 16 September 2021.
- Purity test date: CoA issued 10 January 2020.

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Refrigerated (2 - 8 °C).

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: None.
- Final preparation of a solid: Test item was suspended in corn oil.

FORM AS APPLIED IN THE TEST (if different from that of starting material)
: Suspension.
Species:
rat
Strain:
Wistar
Details on species / strain selection:
The Wistar Han rat was the species and strain of choice because it is a readily available rodent which is commonly used for genotoxicity testing, with documented susceptibility to a wide range of toxic items. Moreover, historical control background data has been generated with this strain.
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: 6 weeks.
- Weight at study initiation: 137 ± 8.6 g (Mean body weight ± SD).
- Assigned to test groups randomly: Yes.
- Fasting period before study: No.
- Housing: Up to 5 animals of the same sex and in the same dosing group were housed together.
- Diet: Commercial pellets ad libitum, except during designated procedures.
- Water: Tap water, ad libitum.
- Acclimation period: At least 6 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C.
- Humidity (%): 40 to 70%.
- Air changes (per hr): ≥ 10.
- Photoperiod: 12 hrs light/12 hrs dark, except during designated procedures.

IN-LIFE DATES:
From: Approx. 04 Feb 2020 (6 weeks before experimental start date).
To: 16 Apr 2020.
Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil.
- Source of vehicle: Fagron Farmaceuticals, Capelle a/d IJssel, the Netherlands.
Duration of treatment / exposure:
Three consecutive days.
Frequency of treatment:
Daily.
Post exposure period:
Tissue samples taken 3 - 4 hours after administration of final dose.
Dose / conc.:
25 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Test item-related clinical signs of toxicity were observed in a preliminary dose range finding study in which three male and three female rats received three consecutive daily doses of 100 mg/kg bw. This highest dose could only be administered split into two doses of 50 mg/kg bw administered 2 hours apart.
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
Cyclophosphamide.
- Route of administration: Gavage.
- Doses / concentrations: A single dose of 19 mg/kg bw, dissolved in physiological saline.
Tissues and cell types examined:
Bone marrow from the femur.
Details of tissue and slide preparation:
The femurs were flushed with foetal calf serum and the cell suspension centrifuged. The supernatant was removed and a drop of the remaining cell suspension was spread across a clean slide and fixed with methanol. The slides were automatically stained with Giemsa using the Wright Stain Procedure.

The number of micronucleated polychromatic erythrocytes was initially counted in at least 4000 polychromatic erythrocytes (with a maximum deviation of 5%). Subsequently, a further 4000 cells were counted. Slides were scored at a magnification of 1000x.

The ratio of polychromatic to normochromatic erythrocytes was determined by counting and differentiating at least the first 1000 erythrocytes at the same time. Micronuclei were only counted in polychromatic erythrocytes.
Evaluation criteria:
The test item was considered positive if all of the following criteria were met:
a) at least one treatment group showed a statistically significant increase in frequency of micronucleated polychromatic erythrocytes.
b) the increase was dose related.
c) the results were outside the 95% confidence limits of the historical control data.

If none of the above criteria were met, and bone marrow exposure to the test item occurred, the substance was considered negative.

The incidence of micronuclei was assessed in 8000 polychromatic erythrocytes per animal.

cfr table under section 'Any other information on results incl. tables'
Statistics:
ToxRat Professional v 3.2.1 (ToxRat Solutions® GmbH, Germany) was used for statistical
analysis of the data.

A test item is considered positive in the micronucleus test if all of the following criteria are
met:
a) At least one of the treatment groups exhibits a statistically significant (one-sided,
p < 0.05) increase in the frequency of micronucleated polychromatic erythrocytes
compared with the concurrent negative control
b) The increase is dose related when evaluated with a trend test.
c) Any of the results are outside the 95% control limits of the historical control data range.

A test item is considered negative in the micronucleus test if:
a) None of the treatment groups exhibits a statistically significant (one-sided, p < 0.05)
increase in the frequency of micronucleated polychromatic erythrocytes compared with
the concurrent negative control.
b) There is no concentration-related increase when evaluated with a trend test.
c) All results are within the 95% control limits of the negative historical control data range.

cfr table under section 'Any other information on results incl. tables'
Key result
Sex:
male
Genotoxicity:
negative
Remarks:
cfr table under section 'Any other information on results incl. tables'
Toxicity:
no effects
Vehicle controls validity:
valid
Positive controls validity:
valid
Additional information on results:
Platinum was quantifiable in plasma samples from high-dose (100 mg/kg bw/day) satellite animals 1, 3, 6 and 12 hours after completing the second day of treatment. Moreover, platinum was quantifiable in plasma samples from all high-dose animals taken at necropsy approximately 3 hours after the third dose. Therefore it was confirmed that the bone marrow was exposed to the test item. No test item was detected in the animals dosed with vehicle.

No statistically significant increase in the frequency of micronucleated polychromatic erythrocytes was observed.

Treated animals showed no decrease in the PCE:NCE ratio, indicating a lack of toxicity to the bone marrow.











































































































































































































































































































































































































































































































































































































































































































Mean Number of Micronucleated Polychromatic Erythrocytes and Ratio of Polychromatic/Normochromatic  Erythrocytes (scoring of 4000 initial cells for all groups including the positive control) 
grouptreatmentDose
(mg/kg body weight)
animal numberNumber of
micronucleated
polychromatic
erythrocytes (number per animal)
Number of micronucleated
polychromatic erythrocytes
(mean +/- SD) (1,2)
ratio polychromatic/
normochromatic erythrocytes
(mean +/- SD) (1,3)
1vehicle control0101.2± 1.31.11± 0.04
   22    
   33    
   40    
   51    
2test item25612.0± 1.01.12± 0.04
   71    
   83    
   92    
   103    
3test item501102.2± 1.81.06± 0.10
   122    
   135    
   142    
   152    
4test item1001601.8± 2.61.08± 0.08
   171    
   184    
   193    
   201    
6Cyclophosphamide19262526.0± 8.2 (4)0.54± 0.25
   2727    
   2838    
   2915    
   3025    
Legend(1) Five animals per treatment group.     
 (2) At least 4000 polychromatic erythrocytes were evaluated with a maximum deviation of 5%.  
 (3) The ratio was determined from at least the first 1000 erythrocytes counted.   
 (4) Significantly different from corresponding control group (Students t test, P < 0.001).  
         
         
Mean Number of Micronucleated Polychromatic Erythrocytes and Ratio of Polychromatic/Normochromatic Erythrocytes (including scoring of 4000 additional cells for all groups except the positive control)
grouptreatmentDose
(mg/kg body weight)
animal numberNumber of
micronucleated
polychromatic
erythrocytes (number per animal)
Number of micronucleated
polychromatic erythrocytes
(mean +/- SD) (1,2,3)
ratio polychromatic/
normochromatic erythrocytes
(mean +/- SD) (1,4)
1vehicle control0143.8± 1.91.25± 0.17
   23    
   37    
   42    
   53    
2test item25685.2± 1.81.22± 0.06
   73    
   85    
   95    
   105    
3test item501134.4± 1.71.12± 0.15
   123    
   137    
   144    
   155    
4test item1001623.6± 1.81.23± 0.16
   173    
   186    
   195    
   202    
6Cyclophosphamide19262526.0± 8.2 (5)0.54± 0.25
 (no additional scoring!)2727    
   2838    
   2915    
   3025    
legend(1) Five animals per treatment group.     
 (2) At least 8000 polychromatic erythrocytes were evaluated with a maximum deviation of 5%, except for the  
 positive control were at least 4000 polychromatic erythrocytes were evaluated with a maximum deviation of  
 5%.       
 (3) Between brackets are the number of micronuclei in the vehicle control and test item groups converted to  
 number of micronuclei per 4000 polychromatic erythrocytes    
 (4) The ratio was determined from at least the first 2000 erythrocytes counted   
 (5) Significantly different from corresponding control group (Students t test, P < 0.001).  

 




















































































Dose-response relationship & statistics  
Micronucleus test (Evaluation of initial 4000 cells) 
Test item: Comparison with the corresponding vehicle control group by using the Dunnett’s test, no significant
differences
positive control: p-value (one sided) <0.001, significantly different from the corresponding vehicle control group by using the Student t-test
    
Micronucleus test (Evaluation of data including additional scoring)
Test item: Comparison with the corresponding vehicle control group by using the Dunnett’s test, no significant
differences
positive control: p-value (one sided) <0.001, significantly different from the corresponding vehicle control group by using the Student t-test
    
Distribution historical  control data from experiments performed between November 2016 and November 2019.
  negative control datapositive control data
 mean number of
micronucleated cells
per 4000 cells
3.945.2
 Standard deviation1.031.8
 number of obsevations2929
 lower control limit
(95% control limits)
2*-17
 upper control limit
(95% control limits)
6108
 legend: * Rounded value; unrounded value is 1.895
Conclusions:
Dipotassium tetrachloroplatinate did not induce an increase in micronucleated polychromatic erythrocytes in rats administered up to 100 mg/kg bw/day by gavage on three consecutive days.
Executive summary:

The in vivo clastogenicity and aneugenicity of dipotassium tetrachloroplatinate, as evaluated by its ability to induce micronuclei in polychromatic erythrocytes, was assessed in a study following OECD 474 and according to GLP. Male Wistar rats (5/group) were given gavage doses of 25, 50 or 100 mg/kg bw/day of the test item on three consecutive days, or a vehicle control. The concurrent positive control group received a single dose of cyclophosphamide. Bone marrow was harvested from the femurs and assessed for micronuclei.

 

There was no increase in the number of micronucleated polychromatic erythrocytes in any treatment group. On that basis, dipotassium tetrachloroplatinate was concluded to be non-genotoxic under the conditions of this assay.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)
Version / remarks:
29 July 2016.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of assay:
mammalian comet assay

Test material

Constituent 1
Chemical structure
Reference substance name:
Dipotassium tetrachloroplatinate
EC Number:
233-050-9
EC Name:
Dipotassium tetrachloroplatinate
Cas Number:
10025-99-7
Molecular formula:
Cl4Pt.2K
IUPAC Name:
dipotassium tetrachloroplatinate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): potassium chloroplatinite
- Substance type: red powder
- Physical state: solid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: 031435
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: stored in sealed grey plastic container
- Other:

Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch number of test material: 9005448302.
- Expiration date of the lot/batch: 16 September 2021.
- Purity test date: CoA issued 10 January 2020.

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Refrigerated (2 - 8 °C).

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: None.
- Final preparation of a solid: Test item was suspended in corn oil.

FORM AS APPLIED IN THE TEST (if different from that of starting material)
: Suspension.

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
The Wistar Han rat was the species and strain of choice because it is a readily available rodent which is commonly used for genotoxicity testing, with documented susceptibility to a wide range of toxic items. Moreover, historical control background data has been generated with this strain.
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: 6 weeks.
- Weight at study initiation: 137 ± 8.6 g (Mean body weight ± SD).
- Assigned to test groups randomly: Yes.
- Fasting period before study: No.
- Housing: Up to 5 animals of the same sex and in the same dosing group were housed together.
- Diet: Commercial pellets ad libitum, except during designated procedures.
- Water: Tap water, ad libitum.
- Acclimation period: At least 6 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C.
- Humidity (%): 40 to 70%.
- Air changes (per hr): ≥ 10.
- Photoperiod: 12 hrs light/12 hrs dark, except during designated procedures.

IN-LIFE DATES:
From: Approx. 04 Feb 2020 (6 weeks before experimental start date).
To: 16 Apr 2020.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil.
- Source of vehicle: Fagron Farmaceuticals, Capelle a/d IJssel, the Netherlands.
- Justification for choice of solvent/vehicle: corn oil is a widely used standard vehicle for in vivo animal experiments.
- Concentration of test material in vehicle: analytical verification confirmed that the measured test item concentrations in vehicle were 97% and 104% of the nominal values for group 2 and group 3 (i.e. 25 and 50 mg/kg(bw) respectively). Accuracy and homogeneity (coefficient of variation
≤ 10%) of the test item in vehicle was confirmed. Note that group 4 (100 mg/kg(bw) was dosed split-dose using the group3 dosing formulation with a 2-hour interval.
- Amount of vehicle (if gavage or dermal): 10 mL/kg bw except group 4 that was dosed split-dose and received 20 ml/kg. Also the vehicle control group was dosed split-dose and received 20 mL/kg.
- Stability of test item in vehicle: stability of test item suspended in vehicle demonstrated for 4 hours at room temperature under normal laboratory conditions(sufficient for the dosing of all test animals), after which unused test item formulations were discarded.
Duration of treatment / exposure:
Three consecutive days.
Frequency of treatment:
Daily.
Post exposure period:
Tissue samples taken 3 - 4 hours after administration of final dose.
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Test item-related clinical signs of toxicity were observed in a preliminary dose range finding study in which three male and three female rats received three consecutive daily doses of 100 mg/kg bw. This highest dose could only be administered split into two doses of 50 mg/kg bw administered 2 hours apart.
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
Ethyl methanesulphonate.
- Route of administration: Gavage.
- Doses / concentrations: 200 mg/kg bw, dissolved in physiological saline, administered twice.

Examinations

Tissues and cell types examined:
Cells were isolated from the liver, glandular stomach, duodenum and kidney.
Details of tissue and slide preparation:
Minced liver or kidney tissue was added to collagenase and dissolved in HBSS (saline). This suspension was shaken and centrifuged. The cell pellet was resuspended in HBSS and kept on ice prior to preparation of the slides.

Tissue from the glandular stomach and duodenum was stored on ice in "mincing buffer incomplete" (HBSS + EDTA). The surface epithelium of both the glandular stomach and duodenum was discarded as it contains a high proportion of apoptotic cells which distort the comet analysis. The cells, suspended in the buffer, were filtered though a 100 µm cell strainer and stored on ice prior to preparation of the slides.

Low melting point agarose was added to the cell suspensions and layered on a pre-coated comet slide (Trevigen), which was then incubated for 13 - 43 minutes in the refrigerator. Three slides per tissue were prepared.

Slides were kept overnight in the refrigerator, immersed in pre-chilled lysis solution. After rinsing, the slides were placed in freshly-prepared alkaline solution; electrophoresis was performed for 20 minutes (stomach and duodenum) or 30 minutes (liver and kidney). Following another rinse, the slides were immersed in absolute ethanol and allowed to dry, before staining with SYBR Gold fluorescent dye.
Evaluation criteria:
150 comets were examined per sample using an IV image analysis system. Only horizontal comets, oriented with the head on the left and the tail on the right, were scored. Cells that showed overlap or were not sharp were not scored.


A test item was considered positive if all of the following criteria were met:
a) at least one treatment group demonstrated a statistically significant increase in % tail intensity vs. control.
b) the increase was dose-related.
c) any of the results were outside the 95% confidence limits of the historical control data.

If none of the above criteria were met, and direct or indirect evidence supportive of exposure of, or toxicity to, the target tissues was demonstrated, the test item was considered negative. If the data precluded making a conclusion of clearly positive or negative, the result was concluded as equivocal.

cfr table under section 'Any other information on results incl. tables'
Statistics:
ToxRat Professional v 3.2.1 (ToxRat Solutions® GmbH, Germany) was used for statistical
analysis of the comet assay data .

A test item is considered positive in the comet assay if all of the following criteria are met:
a) At least one of the treatment groups exhibits a statistically significant (one-sided, p <
0.05) increase in percentage Tail Intensity is detected compared with the concurrent
negative control.
b) The increase is dose related when evaluated with a trend test.
c) Any of the results are outside the 95% control limits of the historical control data range.

A test item is considered negative in the comet assay if:
a) None of the treatment groups exhibits a statistically significant (one-sided, p < 0.05)
increase in percentage Tail Intensity is detected compared with the concurrent negative
control.
b) There is no concentration-related increase when evaluated with a trend test.
c) All results are within the 95% control limits of the negative historical control data range.

cfr table under section 'Any other information on results incl. tables'

Results and discussion

Test resultsopen allclose all
Key result
Sex:
male
Genotoxicity:
negative
Remarks:
Kidney: no statistically significant increase in % tail intensity. cfr table under section 'Any other information on results incl. tables'
Toxicity:
no effects
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Sex:
male
Genotoxicity:
negative
Remarks:
Liver: no statistically significant increase in % tail intensity. cfr table under section 'Any other information on results incl. tables'
Toxicity:
not examined
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Sex:
male
Genotoxicity:
negative
Remarks:
Glandular stomach: statistically significant increase in % tail intensity in low-dose group only; not dose-related and no significant trend, so considered not biologically relevant cfr table under section 'Any other information on results incl. tables'
Toxicity:
not examined
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Sex:
male
Genotoxicity:
negative
Remarks:
Duodenum: no statistically significant increase in % tail intensity. cfr table under section 'Any other information on results incl. tables'
Toxicity:
not examined
Vehicle controls validity:
valid
Positive controls validity:
valid
Additional information on results:
Platinum was quantifiable in plasma samples from high-dose (100 mg/kg bw/day) satellite animals 1, 3, 6 and 12 hours after completing the second day of treatment. Moreover, platinum was quantifiable in plasma samples from all high-dose animals taken at necropsy approximately 3 hours after the third dose. Therefore it was confirmed that there was systemic exposure to the test item. No test item was detected in the animals dosed with vehicle.

A statistically significant increase in the mean tail intensity (%) was observed in stomach cells of the males in the low-dose (25 mg/kg bw/day) group (6.6%) which also exceeded the upper 95% control limit of the historical negative control database. However, the increase observed was not dose related and no significant trend was observed. Therefore, the findings were considered not biologically relevant.

Any other information on results incl. tables






























































































































































































































































































































































































Group mean % tail DNA for the different tissues analyses (mean and standard deviation)
livertail intensity (%)SD  
vehicle control2.370.53  
test item 25 mg/kg1.770.41  
test item 50 mg/kg1.660.45  
test item 100 mg/kg2.170.83  
EMS 200 mg/kg90.04*0.74  
* significantly different (p<0.001) compared to corresponding vehicle control group 
duodenumtail intensity (%)SD  
vehicle control3.571.09  
test item 25 mg/kg3.901.12  
test item 50 mg/kg3.381.01  
test item 100 mg/kg3.551.08  
EMS 200 mg/kg45.91*7.00  
* significantly different (p<0.001) compared to corresponding vehicle control group 
stomachtail intensity (%)SD  
vehicle control4.200.73  
test item 25 mg/kg6.60*1.23  
test item 50 mg/kg4.501.42  
test item 100 mg/kg4.801.68  
EMS 200 mg/kg59.68£5.4  
* significantly different (p<0.01) compared to corresponding vehicle control group using Dunnett's test. Analysis of dose-response using a linear trend test was not significant (p 0.455)
£ significantly different (p<0.001) compared to corresponding vehicle control group 
kidneytail intensity (%)SD  
vehicle control2.830.30  
test item 25 mg/kg3.030.27  
test item 50 mg/kg2.880.45  
test item 100 mg/kg3.070.52  
EMS 200 mg/kg82.92*4.71  
* significantly different (p<0.001) compared to corresponding vehicle control group 
     
   
     
Historical data Comet assay Negative control  
     
 LiverDuodenumStomachKidney
Tail Intensity (%)Tail Intensity (%)Tail Intensity (%)Tail Intensity (%)
Males and FemalesMales and FemalesMales and FemalesMales and Females
Mean1.963.062.4512.10
SD0.921.521.398.46
n85456030
Lower control limit (95% control limits)0.27 -0.86 -1.07 -1.35
Upper control limit (95% control limits)3.656.975.9625.55
SD = Standard deviation   
n = Number of observations   
Kidney: Historical control data from experiments performed in Feb 2012 – July 2019
Liver, Stomach, Duodenum: Historical control data from experiments performed in Jan 2018 – July 2019
     
Historical data Comet assay Positive control (200 mg/kg bw EMS orally dosed for two consecutive days)
     
 LiverDuodenumStomachKidney
Tail Intensity (%)Tail Intensity (%)Tail Intensity (%)Tail Intensity (%)
Males and FemalesMales and FemalesMales and FemalesMales and Females
Mean89.5341.1755.1684.92
SD6.8914.0314.2313.82
n80445930
Lower control limit (95% control limits)79.720.7834.7472.81
Upper control limit (95% control limits)99.3661.5678.5897.03
SD = Standard deviation   
n = Number of observations   
Kidney: Historical control data from experiments performed in Feb 2012 – July 2019
Liver, Stomach, Duodenum: Historical control data from experiments performed in Jan 2018 – July 2019

Applicant's summary and conclusion

Conclusions:
When tested in the comet assay, dipotassium tetrachloroplatinate did not induce a biologically significant increase in DNA damage in the liver, kidney, glandular stomach or duodenum of rats administered up to 100 mg/kg bw/day by gavage on three consecutive days. As such, this compound was considered to negative under the conditions of this assay.
Executive summary:

The potential for dipotassium tetrachloroplatinate to cause DNA damage was evaluated in a study following OECD 489 and according to GLP. Male Wistar rats (5/group) were given gavage doses of 25, 50 or 100 mg/kg bw/day of the test item on three consecutive days, or a vehicle control. The concurrent positive control group received two doses of EMS (200 mg/kg bw/day). Comet analyses were conducted on preparations of liver, glandular stomach, duodenum and kidney tissues.


 


There was no increase in % tail intensity in the liver, kidney or duodenum, indicating that the test item was not genotoxic to these tissues. A statistically significant increase in the mean tail intensity was observed in stomach cells of the low dose group (25 mg/kg bw/day) However, the increase was not dose related and no significant trend was observed. Therefore, the findings were considered not biologically relevant.