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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
20.03.2003 - 22.09.2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study performed according to the guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
The appearance of Potassium permanganate was dark violet - purple crystalline powder with bronze lustre.

Potassium permanganate has been used as a surrogate for sodium permanganate where data are not available. Read-across from potassium permanganate to sodium permanganate is appropriate from the toxicological point of view as the most toxicologically relevant part of the substances is the same (permanganate). The contribution of the sodium/potassium ions to the toxicity of the respective substances is likely to be minimal. The toxicity of both substances is therefore likely to be very similar and will be dominated by local (site of contact) irritant/corrosive effects and systemic toxicity due to the absorption of manganese ions. This toxicophore similarity is adequate justification for waiving the conduct of specific studies with sodium permanganate and the dossier reflects this waiving proposal by including summaries of read-across studies where appropriate.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
The rats were supplied from SPF breeding, BioTest, s.r.o., 281 25 Konarovice, Czech Republic, RCH CZ 21760152. Age at the start of the study was 6-7 weeks, and animals were acclimitised for a minimal of 6 days. 20 males and females were included in the dose-ranging study and 36 males and females was used in the main study. All animals were housed in SPF animal house, 2 rats of the same sex in one plastic cage in a controlled environment. Animals were fed a complete pelleted diet for mice and rats and were allowed unrestricted access to drinking water. Optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 22±3oC, a relative humidity of 30-70% and a 12-hour light/ 12-hour dark cycle.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Six groups of animals were included in the study - 4 main groups and 2 satellite groups.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Determination of the test substance was performed by spectrophotometry and the test substance stability and homogeneity was determined by measuring the absorbance of its water solution in the visible range of the spectrum. The stability of the test substance in applied form at 2 concentration levels was checked over a 120-minute interval (at 0 min, 30 min, 60 min and 120 min). The homogeneity of the applied form was also checked by determining the concentration of the test substance in 3 areas of the solution (the bottom, middle and the surface of the container) at two concentration levels (100 mg/100 mL and 1000 mg/100 mL).
Duration of treatment / exposure:
The administration of the test and control substances lasted 28 days, after that the satellite animals were observed for the next 14 days without treatment.
Frequency of treatment:
The treated and control groups were administered daily by gavage for a period of 28 days. The animals were treated for 7 days a week at the same time (8.00-10.00am).
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 40, 100, 250 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
36 males and 36 females were included in the main study.

Main group
1. group - control with water for injection, 0 mg/kg/day - 6 males and 6 females
2. group - the lowest dose, 40 mg/kg/day - 6 males and 6 females
3. group - intermediate dose, 100 mg/kg/day - 6 males and 6 females
4. group - the highest dose, 250 mg/kg/day - 6 males and 6 females

Satellite groups
5. group - satellite control with water for injection, S 0 mg/kg/day - 6 males and 6 females
6. group - satellite the highest dose, S 250 mg/kg/day - 6 males and 6 females
Control animals:
yes, concurrent vehicle
Details on study design:
Before starting the main study, a dose-range finding study with a 14 day application period was performed. The dose levels 30, 60, 120 and 240 mg/kg/day (in water for injection) was chosen with respect to the results of the acute toxicity study. Macroscopic changes of organs were found at dose levels of 60, 120 and 240 mg/kg/day. Based on these results - the dose levels of 40, 100 and 250 mg/kg/day were chosen for the main study.
Positive control:
Not included in this study: not required

Examinations

Observations and examinations performed and frequency:
Health condition recording and clinical observations were performed daily. More detailed clinical assessments were performed pre-test and weekly during the study. Functional observation batteriy (FOB) was performed during Week 4.

The body weight and food consumption were measured weekly and detailed clinical observation was carried out at the same interval. Water consumption was measured twice a week. Haematology (animals were starved for approximately 18 hours before blood collection but were allowed unrestricted access to water) and biochemical analysis of blood and urine was performed, followed by gross necropsy and histopathology at the end of the study.
Sacrifice and pathology:
weights of the liver, kidneys, adrenals, gonads, epididymides, uterus, thymus, spleen, brain, pituitary and heart were recorded. Animals were sacrificed for gross pathological examinations. Histopathology was performed on a comprehensive list of tissues from all animals.
Other examinations:
No further information provided.
Statistics:
Statistical analysis was performed using the ANOVA test at a significance level of 0.05. Results from haematology, blood chemistry and biometry of organ were statistically analysed. The control group with vehicle was compared with three treated groups and the satellite control with vehicle was compared with the satellite highest dose group.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY

No effects.

BODY WEIGHT AND WEIGHT GAIN

Bodyweights and weight gains were lower in both sexes at 250 mg/kg bw/d; effects were reversible.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)

Food consumption was reduced in both sexes at 250 mg/kg bw/d.

FOOD EFFICIENCY

Food conversion efficieny was reduced in both sexes at 250 mg/kg bw/d,

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)

Water consumption was reduced in both sexes at 250 mg/kg bw/d,

HAEMATOLOGY

Effects on white blood cell counts were seen at 250 mg/kg bw/d

CLINICAL CHEMISTRY

Total protein and albumin, urea, calcium and ALP were increased in males at 250 mg/kg bw/d. Total protein and albumin were also lower in females at 250 mg/kg bw/d.

URINALYSIS

Significant effects on pH, SG and protein content were seen at 250 mg/kg bw/dd

NEUROBEHAVIOUR

FOB revealed minor and reversible changes at 250 mg/kg bw/d.

ORGAN WEIGHTS

Males: decreased (abs) liver weight at 250; increased (rel) liver weights in all treated groups. Increased (abs) testes weight in all treated groups. Increased (abs) epididimes weight qt 100 and 250.

Females: slightly increased (rel and abs) kidney and spleen weight at 250. Increased (abs and rel) uterus weights in all treated groups.


GROSS PATHOLOGY

Treatment-related effects were limited to the stomach at 250 and to a lesser extent at 100. No treatment-related effects were seen on the uterus.

HISTOPATHOLOGY: NON-NEOPLASTIC

Treatment-related effects were limited to the stomach at 250 and to a lesser extent at 100. No treatment-related effects were seen on the uterus or other organs.

Effect levels

Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Gastric irritation at 100 mg/kg bw/d: not relevant for the risk assessment

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Results following analysis of the stability of the test substance show that the test substance in water was homogeneously dissolved and stable for at least 120 minutes.

Treatment-related effects were seen at 250 mg/kg bw/d. Findings were characterised by reduced weight gain, food and water consumption, changes in organ weights and clinical chemistry parameters. Treatment-related pathology was limited to the stomach, consistent with local irritation. It is unclear which parameters are secondary to the bodyweight effects or local irritaiton of the stomach. Less marked effects on the stomach were seen at 100 mg/kg bw/d.

Additional effects on organ weights were seen in all treated groups but may be related to bodyweight effects and are not considered to be related to treatment in the absence of any pathological correlates.

Applicant's summary and conclusion

Conclusions:
The results of the study show that the efefcts of potassium permanganate administration are largely limited to local gastric irritation and sceondary effects on bodyweight and food consumption. Additional effects on clinical chemistry parameters and organ weights may be secondary. Efefcts at 100 mg/jg bw/d were limited to gastric irritation. Patahology did not reveal any additonal targets.
Executive summary:

Groups of rats were gavaged with potassium permanganate at dose levels of 0, 40, 100 or 250 mg/kg bw/d for 28 days. There were no deaths and no signs of toxicity. FOB revealed mminor behavioural changes at teh top dose level. Bodyweight, weight gain, food consumption, food conversion and water conumption were reduced at 250 mg/kg bw/d. Haematology revealed effects on white blood cell counts at 250 mg/kg bw/d; clinical chemistry parameters and urinalysis were also affected in this group. Organ weight changes were noted in all treated groups but are not considered to be clearly related to treatment as they may be secondary to bodyweight effects and were without andy pathological correlates. Pathology showed that effects were limited to the stomach, with local irrittation at 250 mg/kg bw/d and to a lesser extent at 100 mg/kg bw/d. No additional target organs were identified.

A NOAEL of 40 mg/kg bw/d acn be identified for this study, however it is noted that the effects at this dose level (gastric irritation) are not of relevance to teh human risk assessment.