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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001-02-22 - 2001-09-26
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study has no deficiencies, but is a dose range study only.
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not applicable
Remarks:
dose-range finding study
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentapotassium bis(peroxymonosulphate) bis(sulphate)
EC Number:
274-778-7
EC Name:
Pentapotassium bis(peroxymonosulphate) bis(sulphate)
Cas Number:
70693-62-8
Molecular formula:
H3K5O18S4
IUPAC Name:
pentapotassium bis(peroxymonosulphate) bis(sulphate)
Details on test material:
- Name of test material: Oxone® Monopersulfate Compound
- Description: White powder
- Analytical purity: 95.7 %
- Lot/batch No.: H-24607
- Stability under test conditions: The stability of Oxone® Monopersulfate Compound in water was confirmed at nominal concentrations of 1 mg/mL and 100mg/mL during ambient temperature storage for 2 days and refrigerated storage for up to 15 days, representing the maximum period from preparation to completion of use.

Test animals

Species:
rat
Strain:
other: CD (Crl: CD (SD) IGS BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd., Margate, Kent, England
- Age at study initiation: approx. 27 days
- Weight at study initiation: 82 – 100 g (males); 73 – 92 g (females)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Deionised water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

Formulations were prepared on a daily basis in the first week and once weekly for the second week by direct dilution of the test substance.
Control animals received the vehicle alone at the same dosage volume.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of KMPS triple salt in water was confirmed at nominal concentrations of 1 mg/mL and 100mg/mL during ambient temperature storage for 2 days and refrigerated storage for up to 15 days, representing the maximum period from preparation to completion of use.
Duration of treatment / exposure:
14 days
Frequency of treatment:
Once daily, 7 days per week, approx. at the same time each day.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 5, 40 and 100 mg/mL (formulations were prepared on a daily basis in the first week and weekly for the second week by direct dilution of the test substance)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 50, 400 and 1000 mg/kg bw
Basis:
other: as 10 mL/kg bw were applied
No. of animals per sex per dose:
3 animals/group/sex
Control animals:
yes, concurrent vehicle
Details on study design:
not indicated
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
Observations
- Clinical signs: Yes
Animals were observed at regular intervals following dosing each day. Any signs of ill health, behavioural change or toxicosis were recorded. A detailed physical examination was performed once each week.
- Mortality/Viability: Yes
All animals were checked early in each working day and again in the late afternoon to look for dead or moribund animals.

Body weight: Yes
Rats were weighed at allocation, Day –1, immediately prior to treatment (Day 1), daily during treatment Week 1 and before necropsy (Day 15).

Food consumption: Yes
The quantity of food consumed by each rat was recorded in each week of treatment. Food intake per rat (g/rat/week) was calculated using the total amount of food given to and left by each cage.

Water consumption: No

Ophthalmoscopic examination: No

Haematology: No

Clinical Chemisty: No

Urinalysis: No
Sacrifice and pathology:
Organ Weights: Yes
organs: kidneys, liver, spleen

Gross and histopathology: Yes
All dose groups were necropsied and all macroscopic findings were recorded.
Macroscopic abnormalities were preserved and fixed.
Other examinations:
None
Statistics:
No statistical analyses were conducted due to the small numbers of animals per group.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Please refer to tables 1 and 2, which are presented under “Remarks on results including tables and figures”




CLINICAL SIGNS
There were no clinical signs indicative of toxicity noted on this study. Salivation was noted for 2/3 males receiving 400 mg/kg bw/day and all animals receiving 1000 mg/kg bw/day, this was thought to be due to the taste of the formulations.

MORTALITY
There were no unscheduled deaths

BODY WEIGHT AND WEIGHT GAIN
There was no effect on bodyweight gains. Test group animals actually gained more weight and had a higher terminal body weight than control animals.

FOOD CONSUMPTION AND COMPOUND INTAKE
Overall, there was no toxicologically relevant effect on food consumption. From Table 3, page 25 of the report, it is evident that in both sexes of rats, food consumption was slightly, but not statistically significantly higher at all dose levels during the entire study period. This increase in food consumption was not dose-related with the exception of the second study week in males. However, the overall conclusion made in the study report is considered to be justified since there was no treatment-related toxicity observable up to and including the highest tested dose level of 1000 mg/kg bw/day. Thus, the slight and not statistically significant increase in food consumption in both sexes is not indicative for a toxicologically adverse effect.

ORGAN WEIGHTS
There were no inter-group differences from controls that were considered to be attributable to treatment.

GROSS PATHOLOGY
There were no macroscopic abnormalities considered to be related to treatment with Oxone Monopersulfate Compound. Cysts in the kidneys were noted in 1/3 females receiving 1000 mg/kg bw/day and 2/3 males and 2/3 females receiving 400 mg/kg bw/day compared with none in the controls. These cysts were spontaneous lesions and were not considered to be related to treatment with the test substance.

HISTOPATHOLOGY:
No histopathological examination of organs was performed on termination of the study.



Effect levels

Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: NOEL was based on the absence of any treatment related effects up to including the top dose level of 1000 mg/kg bw/d

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Body weight gain and food consumption – group mean values

-

Males

Females

Dosage
(mg/kg bw/day)

0

50

400

1000

0

50

400

1000

Weight gain (g)

-

-

Day 0-14

100.2

113.0

112.3

115.3

52.1

70.4

62.6

58.3

Food consumption
(g/animal)*

-

-

Week 1-2

344

370

363

393

258

279

277

277

* Cumulative food consumption

Table 2: Macropathology and organ weights relative to bodyweights

-

Males

Females

Dosage
(mg/kg bw/day)

0

50

400

1000

0

50

400

1000

Kidneys
No. examined
Cyst(s)


3
0


3
0


3
2


3
0


3
0


3
0


3
2


3
1

Liver
No. examined
Hernia


3
0


3
0


3
0


3
0


3
0


3
1


3
0


3
0

Skin
No. examined
Hairloss


3
0


3
0


3
0


3
0


3
0


3
0


3
0


3
1

Terminal body weight (g)
Mean
S.D.*


241.1
12.2


256.4
22.1


250.6
14.8


254.8
37.1


173.2
13.4


193.8
14.8


183.8
13.6


178.5
6.2

Kidney weight (g)
Mean
S.D.


0.9008
0.0315


0.8638
0.0205


0.8828
0.0235


0.9364
0.0878


0.9882
0.0659


0.9644
0.1195


0.9245
0.0525


0.9888
0.0896

Liver weight (g)
Mean
S.D.


5.4957
0.2235


5.4873
0.1973


5.6646
0.5914


5.7013
0.2678


5.1509
0.5081


5.3871
0.4898


5.1061
0.5007


5.5501
0.3919

Spleen (g)
Mean
S.D.


0.2179
0.0316


0.2265
0.0380


0.2778
0.0157


0.2636
0.0242


0.2567
0.0279


0.2714
0.0330


0.2535
0.0248


0.2609
0.0167

Applicant's summary and conclusion

Conclusions:
Dosages of up to 1000 mg/kg bw/day for 14 days were well tolerated by both sexes, which was selected for the high dose level for a subsequent 13-week oral study in rats.
Executive summary:

Materials and methods

The repeated dose toxicity of KMPS triple salt was investigated in a test similar or equivqlent to OECD Guideline 407 in male and female CD rats by daily administration of dose levels of 0, 50, 400 and 1000 mg/kg bw/day via gavage for a period of 14 days. Dose levels were based on a acute oral toxicity study (Doc. D_K1.OralGav.R.DPT 567/012276/AC, IUCLID section 7.2.1). In the 14-day study, animals had free access to food and drinking water during the study. Clinical signs and mortality/viability were observed at regular intervals following dosing each day. Body weights recorded daily during treatment Week 1 and before necropsy.

On termination of the study a macroscopic examination of all animals was performed.

Results and discussion

There were no treatment related effects on the recorded parameters. The observed cysts were spontaneous lesions and were not considered to be related to treatment with the test substance. There was a slight, but not statistically significant increase in food consumption in both sexes of rats. Since no treatment-related toxicity was observable up to and including the highest dose level of 1000 mg/kg bw/day tested, the slight and not statistically significant increase in food consumption in both sexes is not indicative for a toxicologically adverse effect. A reduction rather than an increase in food consumption is in general of higher importance for the assessment of treatment-related toxicity. In the 14-day dose-range-finding study, the increase noted is clearly not associated with any toxicologically adverse effect.