Sodium permanganate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 August to 2 December 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study conducted by the National Toxicology Program

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Remarks:

FDA

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

10034-96-5

Cas Number:

10034-96-5

IUPAC Name:

10034-96-5

Constituent 2

Reference substance name:

Manganese (II) sulfate monohydrate

IUPAC Name:

Manganese (II) sulfate monohydrate

Details on test material:

A read-across is proposed from managanese (II) sulfate: chemical formula MnSO4H2O, molecular weight 168.95. Sodium permanganate is a strong oxidising agent and will be reduced to managanese (II) in the stomach.
Manganese (II) sulfate monohydrate was obtained in one lot (003261) from the J.T. Baker Chemical Company (Glen Ellyn, IL). Identity and purity analyses were conducted by the analytical chemistry laboratory, Midwest Research Institute (Kansas City, MO).
The chemical, a white, slightly efflorescent crystalline compound, was identified as manganese (II) sulfate monohydrate by infrared and ultraviolet/visible spectroscopy. The infrared spectrum matched a literature reference (Miller and Wilkins, 1952), and the absence of a signal in the visible spectrum indicated that no manganate (VI) or permanganate (VII) species were present. The purity was determined by elemental analyses, weight loss on drying, chelometric titration, and spark source mass spectroscopy. Elemental analyses for manganese, sulfur, and hydrogen were in reasonable agreement with theoretical values for manganese (II) sulfate monohydrate. Weight loss on drying indicated 10.6% ± 0.01% water, consistent with a theoretical value of 10.7% for manganese (II) sulfate monohydrate. Spark source mass spectrometry confirmed manganese as the major component. The most significant impurities were sodium(640 ppm), potassium (120 ppm), and silicon (160 ppm). Chelometric titration indicated a purity of 97.7% ± 0.4%. The overall data indicated that the manganese was in the divalent state and supported a purity of greater than 97%.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were male and female F344/N rats obtained from Charles River Breeding Laboratories (NY). At receipt, the rats were an average of 31 days old. They were quarantined for 19 days prior to exposure. Before the beginning of the studies, five male and five female rats were randomly selected for parasite evaluation and gross observation for evidence of disease. At the end of the studies, serologic analyses were performed on 5 control animals/sex using the protocols of the NTP Sentinel Animal Program.
Rats were housed 5 per cage, individuals were identified by ear clip/notch and toe clip. Feed (NIH-07 open formula meal rat and mouse diet, Ziegler Brothers, Inc.) and water were available ad libitum. The rats were housed in polycarbonate cages (Lab Products, Inc.) on stainless steel racks, with heat-treated hardwood chips as bedding.
The temperature of the animal room was 23.3±2°C, the relative humidity was 40-80%. Fluorescent lighting was provided for 12 hours/day, and there were aproximately 12 air changes per hour.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

A premix with manganese (II) sulfate monohydrate and feed was prepared by blending with a spatula; premix and remainder of feed was layered in a
Patterson-Kelley twin-shell blender and mixed for 15 minutes with an intensifier bar on for the first 5 minutes. Dose formulations were prepared once.
Groups of 10 male and 10 female rats were fed diets containing 0, 1600, 3130, 6250, 12500, or 25000 ppm manganese (II) sulfate monohydrate. The level of manganese in the diet received by controls was approximately 92 ppm. The appropriate feed was supplied twice weekly and was available ad libitum.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability analyses of the dose formulations were conducted by the analytical chemistry laboratory using a spectrophotometric method. Homogeneity was confirmed; stability of the dose formulations was established for 2 weeks in the dark at room temperature and for 1 week exposed to air and light. A subsequent study confirmed the stability of the dose formulations for 3 weeks under the conditions listed above. No direct speciation was performed. However, complete recovery from dose formulations was achieved and other likely species are not soluble in dilute acid which was used for extraction. These findings strongly support the conclusion that the manganese remained in the divalent state. The dose formulations were prepared weekly. Dose formulations were discarded 21 days after the date of preparation.
Periodic analyses of the dose formulations of manganese (II) sulfate monohydrate were conducted at the study laboratory and at the analytical chemistry laboratory using spectrophotometric methods. Dose formulations were analyzed three times during the study. All dose formulations were within the specified 10% of the target concentration.

Duration of treatment / exposure:

93-94 days (13 weeks)

Frequency of treatment:

Daily -ad libitum in diet

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1600, 3130, 6250, 12500 or 25000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10 rats/sex/dose

Control animals:

yes, plain diet

yes, historical

Details on study design:

Animals were assigned to treatment groups by weight intervals. Animals from each interval were randomized and proportionately assigned to cages, then the cages were assigned to dose groups using an appropriate table of random numbers.
Dose levels were chosen for this study based on the results obtained in the 14 day repeat dose toxicity test: 25000 ppm was chosen as the highest dose for the 90 day study based on a reduction in mean body weight gain in the 50000 ppm male and female rats.

Positive control:

A positive control was not included.

Examinations

Observations and examinations performed and frequency:

Clinical findings were recorded weekly. Feed consumption was recorded weekly by cage. The rats were weighed at the beginning of the studies and weekly thereafter. At the end of the study, blood was collected from the vena cava of all animals for haematology analyses (haematocrit, haemoglobin, erythrocytes, mean erythrocyte volume, and leukocyte count and differential).

Sacrifice and pathology:

A necropsy was performed on all animals. The brain, heart, right kidney, liver, lungs, left testicle, and thymus were weighed. Tissues for microscopic examination were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 µm, and stained with haematoxylin and eosin.
A complete histopathologic examination was performed on all control and high-dose animals. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, blood, bone marrow (sternum), brain, cecum, colon, duodenum, oesophagus, heart, kidney, liver, lung, mammary gland, mandibular lymph node, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial or clitoral gland, prostate gland, salivary gland, spleen, stomach, testes/epididymis, thyroid, gland, trachea, thymus, urinary bladder, and uterus.

Other examinations:

No other examinations reported.

Statistics:

Pairwise comparisons and were used to identify differences between control and treated groups. The significance of pairwise comparisons was determined according to the methods of Dunnett (1955), Williams (1971, 1972), Shirley (1977), Dunn (1964), Jonckheeres test (1954) or the Mann-Whitney U test.

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):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

No rats died during the study. The mean body weight gain in males receiving 3130 ppm was marginally lower than that of the controls and was significantly lower in the three highest female dose groups than the controls (Table 1). Final mean body weights of all exposed animals were within 5% of those of the controls. Feed consumption by exposed rats was similar to that by the controls (Table 3). Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1700 mg/kg body weight in males and 115 to 2000 mg/kg in females. Females ingested an average of 20% more manganese (II) sulfate monohydrate than males in the corresponding exposure groups.
Absolute and relative liver weights of all exposed males and of the female 25000 ppm group were significantly lower than those of the controls. The absolute and relative lung weights of all exposed females were also significantly lower than those of controls. No other biologically significant organ weight differences were observed between exposed and control animals. Although the total leukocyte counts were similar in exposed and control males, neutrophil counts were significantly higher in all exposed male groups, whereas lymphocyte counts were significantly lower in the 6250, 12500, and 25000 ppm groups. In contrast, the total leukocyte counts of 6250, 12500, and 25000 ppm females were significantly lower, primarily because of lower lymphocyte counts. A marginal but significant increase in percent hematocrit and erythrocyte counts occurred in males exposed to 6250, 12500, or 25 000 ppm. The relationship between these differences and the ingestion of manganese (II) sulfate monohydrate is not clear. No clinical or histopathologic findings were attributed to administration.

Effect levels

1

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male

Basis for effect level:

other: All exposed males exhibited absolute and relative liver weights that were lower than controls

Remarks on result:

not determinable

Remarks:

no NOAEL identified

2

Dose descriptor:

NOAEL

Effect level:

3 130 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Effects on body weight gain were seen at doses of 6250 ppm and above

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1. Survival, body weights and feed consumption

Concentration (ppm)	Survival^a	Mean body weight and Weight Changes^b(g)			Final Weight Relative to Controls (%)	Feed Consumption^c
		Initial	Final	Change		Week 1	Week 13
Male
0	10/10	136±5	291±4	155±4		14.9	13.1
1600	10/10	142±4	294±5	152±4	101	14.5	13.5
3130	10/10	149±3	291±4	141±4	100	14.8	13.6
6250	10/10	148±2	294±3	146±3	101	15.0	9.6
12500	10/10	150±11	290±6	140±11	99	14.9	14.9
25000	10/10	140±4	284±6	144±4	97	14.1	14.4
Female
0	10/10	99±1	184±2	84±2		10.7	9.2
1600	10/10	103±1	181±2	79±2	99	10.8	9.3
3130	10/10	96±1	175±2*	80±3	95	10.9	9.2
6250	10/10	101±1	176±2*	75±1**	96	10.7	14.3
12500	10/10	106±1**	178±1*	73±2**	97	10.7	10.5
25000	10/10	104±1**	174±3**	70±2**	95	12.1	10.3

* Significantly different (P≤0.05) from the control group by Williams' or Dunnett's test.

** P≤0.01

a Number of animals surviving at 14 days/number initially in group

b Weights given as mean ± standard error.

c Feed consumption is expressed as grams per animal per day.

Applicant's summary and conclusion

Conclusions:

No NOAEL could be identified for male rats on the basis of liver weight differences. A NOAEL of 3130 ppm for female rats can be assigned on the basis of reduced body weight gain at doses of 6250 ppm and higher.

Executive summary:

Groups of 10 male and 10 female rats received diets containing 0, 1600, 3130, 6250, 12500, or 25000 ppm manganese (II) sulfate monohydrate for 90 days. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1700 mg/kg body weight in males and 115 to 2000 mg/kg in females. All rats survived to the end of the study. Mean body weight gains were marginally lower than that of controls in males exposed to 3130 ppm or more; mean body weight gains were significantly lower than that of the controls in females exposed to 6250, 12500, or 25000 ppm. At the end of the study, absolute and relative liver weights of all exposed male rats and of 25000 ppm female rats were significantly lower than those of controls. The total leukocyte count in males was similar between exposed and control rats; however, neutrophil counts of all exposed groups were greater than those of the controls, whereas lymphocyte counts of the 6250, 12500, and 25000 ppm groups were significantly lower than those of the controls. Total leukocyte counts in 6250, 12500, and 25000 ppm females were significantly decreased because of a decrease in lymphocytes. Male rats also demonstrated marginal but significant increases in percent haematocrit and erythrocyte count in the 6250, 12500, and 25000 ppm groups. No clinical or histopathologic findings in rats were chemical related.

No NOAEL could be identified for male rats on the basis of liver weight differences. A NOAEL of 3130 ppm for female rats can be assigned on the basis of reduced body weight gain at doses of 6250 ppm and higher.